IMS Magazine Fall 2017

IMS MAGAZINE THINK. LEARN. DISCOVER.

FALL 2017

CANCER THERAPEUTICS VIRAL HIJACKING Utilizing Vaccinia virus to target tumour cells

PRECISION DEPLOYMENT Ultrasound-gene delivery system for cancer therapy

CALM AMIDST BATTLE Rethinking palliative care and cancer

Student-led initiative IMS MAGAZINE FALL 2017 CANCER THERAPEUTICS 1

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IN THIS ISSUE Letter from the Editors............................... 4 Director’s Message.................................... 5 Commentary............................................... 8 Retrospective........................................... 10 Feature..................................................... 12 Close-up................................................... 24 Future Directions...................................... 26 Student Spotlight..................................... 28 BMC Feature............................................ 30 Viewpoint................................................. 32 SURP Research Day................................. 38 Tips for Surviving Grad School................. 40 Book Review............................................ 42 Travel Bites............................................... 43

Types of Cancer Therapies

MAGAZINE STAFF EDITORS-IN-CHIEF

Anna Badner Lindsay Caldarone

EXECUTIVE EDITORS

Beatrice Ballerin Jonathon Chio Meital Yerushalmi Natalie Osborne

JOURNALISTS & EDITORS

Aadil Ali Aaron Wong Alaa Youssef Aravin Sukumar Arpita Parmar Arman Hassanpour Chantel Kowalchuk Cricia Rinchon Jessie Lim Josh Rapps Melissa Galati Mirkamal Tolend Muhtashim Mian Pontius Tang Priscilla Chan Sarasa Tohyama Stephanie Beldick Tazeen Qureshi Valera Castanov Yekta Dowlati Yena Lee

DESIGN EDITORS

Amanda Miller Chelsea Canlas Jerry Gu Lisa Qiu Patricia Nguyen

PHOTOGRAPHERS

Grace Jacobs Krystal Jacques Iris Xu Mikaeel Valli

SOCIAL MEDIA TEAM

Tahani Baakdhah Louise Pei

SPONSORSHIP TEAM

Carina Freitas

Other therapies Microbubbles – miniscule gas bubbles just 0.003 of a millimetre wide – are used to improve diagnostic ultrasound imaging because they are thousands of times more reflective than normal body tissues4 (read more on page 20).

Systemic therapy Surgery Surgery involves surgical removal of cancer (tumours)

Systemic therapy involves drugs that travel in the bloodstream throughout the body.

Therapies include: Chemotherapy Attacks rapidly growing cells

Radiation therapy Radiation therapy uses high-energy beams or particles to kill cancer cells

Hormonal therapy Reduces cancer causing hormones in the body

Unlike traditional radiation therapy, radiosurgery uses a high, concentrated dose of X-ray treatment

Supportive therapies and palliative care This form of therapy can reduce side effects and improve the patient’s quality of life

Targeted drugs Attack specific sites on cancer or cells that help grow cancer Gene therapy Agents that disrupt the DNA of cancer cells (eg. modified viruses)

targeted at a specific site (eg. brain tumour) which minimizes radiation damage to surrounding tissue and limits side effects5 (read more on page 10).

Oncolytic Virotherapy exploits the selective and infectious nature of viruses and turns them into therapeutic agents to target and destroy cancer cells6 (see page 18 to learn about a new vaccinia virus an IMS researcher is developing).

In 2015, Canada ranked 11th out of 80 countries in an international ‘Quality of Death Index’ by the Economist’s Intelligence Unit. This index measures the availability and quality of end-of-life care from hospice and palliative care facilities7 (read more on page 16).

Imaging technologies including CT, PET and MRI

Active surveillance A type of care that monitors cancer over time to decide whether to start treatment later

were traditionally used mainly to diagnose or monitor cancer. But advances in imaging technology and robotics are making real time, image-guided surgical removal of tumours a reality in the University Healthy Network’s Guided Therapeutics program (read more on page 22).

References 1. Mullan F. Seasons of survival: reflections of a physician with cancer. N Engl J Med [serial online]. 1985 [cited 2017 Oct 14];313: 270-273.

Available from: DOI: 10.1056/NEJM198507253130421 2. Surveillance Research Program, Division of Cancer Control and Population Sciences, National Cancer Institute. American Cancer Society, Surveillance and Health Services Research. 2016 [cited 2017 Oct 14].

3. Cancer Treatment & Survivorship Facts & Figures 2016-2017. American Cancer Society. 2017 [cited 2017 Oct 14].

4. Blomley MJK, Cooke JC, Ungar EC et al. Microbubble contrast agents: a new era in ultrasound. BMJ [serial online]. 2001 [cited 2017 Oct 14];322(7296): 1222-1225.

5. Nieder C, Grosu AL, & Gaspar LE. Stereotactic radiosurgery (SRS) for brain metastases: a systematic review. Radiat Oncol [serial online]. 2014 [cited 2017 Oct 14]; 9: 155. Available from: doi: 10.1186/1748-717X-9-155 6. Gutierrez, AA. Embracing the Promise of Oncolytic Virus Immunotherapy. Drug Discovery & Development. 2017 [Cited 2017 Oct 14]. Available from: https://www.dddmag.com/article/2017/09/embracing-promise-oncolyticvirus-immunotherapy 7. Line, D. The 2015 Quality of Death Index, Ranking palliative care across the world: A report by the Economist Intelligence Unit. The Economist [newspaper online]. 2015 Oct 06 [cited 2017 Oct 14]. Available from: http://www.eiuperspectives.economist.com/healthcare/2015-quality-death -index

12 FEATURE INFOGRAPHIC

By Chelsea Canlas

MScBMC Candidate

Copyright © 2016 by Institute of Medical Science, University of Toronto. All rights reserved. Reproduction without permission is prohibited.

The IMS Magazine is a student-run initiative. Any opinions expressed by the author(s) are in no way affiliated with the Institute of Medical Science or the University of Toronto.

Cover Art

By Jerry Gu MScBMC Candidate

IMS MAGAZINE FALL 2017 CANCER THERAPEUTICS 3

LETTER FROM THE EDITORS

LETTER FROM THE

U

EDITORS

Photo by Meital Yerushalmi

pon beginning our term as the new Editors-In-Chief, we were surprised to discover that there has never been an issue of the IMS Magazine entirely devoted to Cancer. With a long-standing history in cancer research and a plethora of distinguished faculty, this was a logical focus. It also gave us the opportunity to highlight the immense achievements of Dr. Pamela Catton, who has been a leader in radiation oncology and helped implement the Bachelor of Science program in Medical Radiation Sciences, in the Institute of Medical Science (IMS) 50th Anniversary “Retrospective” article.

Other features include Dr. Arjun Sahgal’s innovative implementation of stereotactic radiosurgery to treat spine metastases, as well as Dr. Howard Leong-Poi’s success with ultrasound-mediated gene therapy. Further, Dr. Jonathan Irish provided insights into the Guided Therapeutics Program at the Princess Margaret Hospital and their state-of-the-art developments in surgical technology. Our journalists also sat down with Dr. Andrea McCart to discuss the use of vaccinia virus for cancer gene therapy, and with Dr. Gary Rodin for an overview of palliative care.

In other articles, we have an interview with Dr. Howard Mount, a Student Spotlight piece on Melissa Polonenko, and a conversation with IMS alumni Adam Santoro. Also of interest may be a recap of this year’s Summer Undergraduate Research Program (SURP), a compilation of graduate school survival tips, and a review of Amanda Lang’s novel, “The Beauty of Discomfort”. Our viewpoint articles contain a critical assessment of healthcare economics, the collaborative care model, and alternative cancer therapies.

We would also like to thank Dr. Mingyao Liu and the IMS for their continued support, our journalists and editors for all their hard work, and the extraordinary Design Team whose remarkable efforts are key to the production of this issue. We are especially grateful for all the training, advice, and guidance of the outgoing Editors-In-Chief, Sarah Peters and Petri Takkala.

To conclude, we hope you enjoy the content and, as always, strongly encourage feedback. Please let us know your thoughts by email, through our website (www.imsmagazine.com), or even in person.

Happy Reading!

Lindsay Caldarone

Anna Badner

Lindsay is currently a MSc student in the IMS studying the role of neutrophil extracellular traps in lung transplantation under the supervision of Dr. Shaf Keshavjee at the Toronto General Hospital Research Institute.

Anna is currently a PhD student in the IMS studying therapies for traumatic spinal cord injury under the supervision of Dr. Michael Fehlings at the Krembil Research Institute.

4 | IMS MAGAZINE FALL 2017 CANCER THERAPEUTICS

DIRECTOR’S MESSAGE

DIRECTOR’S MESSAGE

W Photo by Tahani Baakdhah

DR. MINGYAO LIU Director, Institute of Medical Science Professor, Department of Surgery Senior Scientist, Toronto General Research Institute, University Health Network

e welcome the start of a new academic year with the Fall 2017 issue of the IMS Magazine. This issue is centered around the diverse and rapidly evolving field of cancer therapeutics. In keeping in line with the interdisciplinary nature of the Institute of Medical Science, this issue examines a wide array of research initiatives within our institute, from palliative care to ultra-sound mediated cancer gene therapy. I am excited to be able to present the work of esteemed faculty members within the IMS, including Drs. Andrea McCart, Howard Leong-Poi, Gary Rodin, Jonathan Irish, and Arjun Sahgal. This issue also features a Retrospective article focusing on Dr. Pamela Catton, a champion and pioneer in the field of cancer education and patient-centered cancer care, and a co-founder of Medical Radiation Science Professional Master Program in IMS. We are also fortunate to include a commentary from Dr. Ori Rotstein, a former director of IMS, on Dr. Pamela Catton.

This issue delves into the complex ethical and social issues surrounding the state of healthcare, including cancer and beyond. Our journalists discuss alternative cancer therapies, debate collaborative care models in Canada, and draw on what they have learned through IMS coursework to explore the economics of healthcare.

The collaboration that exists within the IMS comes through in this issue. Not only is the spirit of teamwork clear through the sophisticated research that is highlighted throughout the issue, but it is also evident through the different facets of IMS included in the issue: the Summer Undergraduate Research Program, the Biomedical Communications Program, and other IMS student groups such as the Raw Talk Podcast, to name a few.

This issue even includes a section of advice for incoming students, written by current students.

I would like to congratulate the incoming Editors-in-Chief, Anna Badner and Lindsay Caldarone, on their new leadership roles. I would also like to congratulate the entire IMS Magazine team on producing another thoughtful and thought-provoking issue.

The IMS is a truly a community, and this issue of the IMS Magazine expresses this clearly, while focusing on the incredible research in the field of cancer therapeutics being led by our faculty and students. I am proud to be a member of such a community, and I look forward to the academic year ahead.

Sincerely, Mingyao Liu, MD, MSc Director, Institute of Medical Science

IMS MAGAZINE FALL 2017 CANCER THERAPEUTICS 5

RAW TALK PODCAST

Scientists Talk, We Listen Conversations that go beyond science and data New episodes every other Friday

rawtalkpodcast.com @rawtalkpodcast 6 | IMS MAGAZINE FALL 2017 CANCER THERAPEUTICS

Ori Rotstein Lecture

in Translational Research Friday, October 6, 2017

Keynote Speaker: Dr. Connie Eaves Distinguished Scientist, Terry Fox Laboratory, British Columbia Cancer Agency Professor, Departments of Medical Genetics, Pathology & Laboratory Medicine, University of British Columbia

“The Rising Challenge and Thrill of Complexity in Biomedical Research” Panel Discussion: “Revolutionizing Translational Research: Can we do Better?”

Moderator: Dr. Ori Rotstein, Surgeon-in-Chief, St. Michael’s Hospital

Panelists: Dr. Minna Woo Head, Division of Endocrinology and Metabolism, UHN Dr. Mohammad R. Akbari Director, Research Molecular Genetics Laboratory, Women's College Hospital Dr. Katherine Siminovitch Senior Scientist, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital Dr. Cindi Morshead Chair, Division of Anatomy, Donnelly Centre for Cellular and Biomolecular Research

9am - 12 noon

ims.utoronto.ca/event/ori-rotstein-lecture

Women’s College Hospital Cummings Auditorium, 2nd floor 76 Grenville Street, Toronto IMS MAGAZINE FALL 2017 CANCER THERAPEUTICS 7

COMMENTARY

ETHICS

in Clinical Trials

By Mirkamal Tolend and Samia Tasmim

C

linical trials aim to elucidate the viability of new treatments or interventions on humans, and are indispensable to the progress of medical science. Although double-blind, randomized, controlled trials are the pinnacle of clinical trials, these are not always practical or ethical to conduct for every clinical question.

As such, the interplay of ethics, uncertainty, and the need for high quality scientific evidence makes clinical trials unique.

in 1947. Astonishingly, this study, which was supposed to run for six months, went on for 40 years. It finally ended when the Associated Press covered the study and an advisory committee ruled that it was ethically unacceptable. Although the participants and their families were later compensated financially and given medical assistance, this trial is an example of the horrific trials that some groups were subjected to.2

The importance of ethics in clinical research is seen in documents as old as the Hippocratic Oath. Unfortunately, it took a dark period in research history, involving atrocities such as the use of war prisoners for human experimentation in the Second World War, to cement the emphasis of clinical trial ethics. To ensure such unethical research does not recur, explicit codes of ethical conduct were outlined in the Nuremberg Code, the Declaration of Helsinki, and the Belmont Report.1 Currently in Canada, all federally funded research involving humans or human biologic material must strictly adhere to the Tri-Council Policy Statement.

As the potential benefit of clinical research is usually experienced by future patients rather than by the study participants, ideal participants would be motivated purely by altruism to consent to a study. Policies on informed consent, patient safety monitoring, and careful, peer-reviewed assessment of the study’s scientific and methodological rigor are all important to prevent patient exploitation. The reason for participating in a clinical study may not be purely altruistic when there is the problem of undue inducement, meaning that the process of providing voluntary informed consent is influenced by the financial benefits of participating. For some patients, these benefits may outweigh the risks associated with the study.3 Certain patient groups, such as those who do not respond to current standard-of-care treatments or those from low socioeconomic backgrounds, who would be unable to otherwise obtain either the standard or the experimental treatment may be considered especially vulnerable with regard to participating in a clinical trial.4 To avoid exploitation of these study participants, it is important to be aware of the potential reasons patients may expose

One of the longest-running controversial clinical trials was the Tuskegee study of syphilis, which ran for 40 years from 1932 to 1972 in Tuskegee, Alabama.2 600 African American men (with or without syphilis) were simply told the purpose of the study was to evaluate “bad blood�. They acquiesced to the study in exchange for free food, burial insurance and medical tests. Notably, they did not receive treatment for syphilis, even after penicillin became the standard of treatment starting 8 | IMS MAGAZINE FALL 2017 CANCER THERAPEUTICS

themselves to treatments of unproven effectiveness. Thus, the requirement of scientific and ethics review board approvals before the start of clinical trials is important to ensure that patients are not enrolled in studies with obvious flaws in internal validity, the results of which will be of poor quality and not worth the risk of exposing patients to unnecessary risk.

Certain biases are important to avoid in clinical trials.5 One prominent example is selection bias, which occurs when the method that is used to sample the cases into the study cohorts leads to a baseline difference between the cohorts. This may differentially affect study results if such a difference confounds the study outcome.

Various design-based and analysis-based techniques exist to control for the effect of the confounder variable. These safeguards include matching, restriction, stratification, and multivariable adjustment. However, these techniques can only adjust for known and measured confounders. To protect against bias from known as well as potential unknown confounders, randomization is applied. Hence, a proper randomization is an important design feature in clinical trials to improve internal validity. At times randomization is not possible due to practical or ethical reasons. To account for this, properly controlled observational studies with large sample sizes have become increasingly rigorous in design, yielding high quality evidence for clinical questions not amenable to randomized controlled trials.

Ethical issues may affect the interpretation of data. Moving a patient from the treatment

COMMENTARY

“... an extreme manifestation of the ethical obligation of the clinician overriding the ethical obligation of the scientist.” group to the control group, or vice versa, can be ethically necessary, if a patient cannot tolerate the side effects of a new treatment for instance. Intention to treat analysis, as opposed to analysis by treatment received, is an approach to analyzing these cases that “cross over”. The outcome of a patient is analyzed according to the group the patient was initially assigned, i.e., if a treatment patient crosses over to the control cohort, their outcome still belongs to the treatment group data. This method preserves the benefit of the randomization to control for the confounders, which is important because patients who need to cross over may have baseline differences in confounding variables. The negative impact this will have on the study is an underestimation of the treatment effect size, i.e., the difference in the outcome between the treatment and control groups, which is an extreme manifestation of the ethical obligation of the clinician overriding the ethical obligation of the scientist. However, in practice, having the more conservative estimate of the clinical trial result is often favored, as this method preserves the control for confounding, and

allows participant safety to be better ensured.

Ethical issues also affect the generalizability of results. For instance, during a trial, if an interim analysis shows that treatment of interest shows a significant benefit on early available data, the continued use of placebos or the status quo treatment may be considered unethical.1 However, this assumes that the treatment benefit seen in the interim analysis on early data will persist in the long-term and/or across a greater sample. This assumption may not hold up if adverse effects are difficult to predict for the long term, or if the definition of improvement from the perspective of the patient changes over the course of extended treatment. Furthermore, generalizability of clinical trials can be challenging. Deciding the eligibility criteria in clinical trials can range from two extremes: a pragmatic approach, which is less restrictive and more similar to daily clinical practice, or the explanatory approach, which is highly restrictive to the specific disease presentation under

question and occurs in controlled settings.

Ethical considerations may favor the explanatory approach, since patients who are less likely to benefit from the treatment are excluded. A problem may arise when results from an explanatory trial are overgeneralized to less controlled scenarios and to patients who differ from the clinical trial patients in terms of risk factors, comorbidities, treatment adherence.

Ethics in clinical trials is a broad topic.

This brief overview has hopefully sparked an interest in readers to dig deeper and get familiarized with the various ethical considerations in planning, conducting, analyzing, and interpreting clinical trials.

References 1. Nardini C. The ethics of clinical trials. Ecancermedicalscience; 2014 Jan [cited Sep 5] Available from: doi:10.3332/ecancer.2014.387.

2. Centers for Disease Control and Prevention. https://www.cdc. gov[cited Sep 5] Available from: https://www.cdc.gov/tuskegee/ timeline.htm 3. Arnason G, Van Niekerk A. Undue fear of inducements in research in developing 4. countries. Camb Q Healthc Ethics. 2009 Apr [cited Sep 5] Available from: doi: 10.1017/S0963180109090215. PubMed PMID: 19250565.

5. Weigmann K. The ethics of global clinical trials: In developing countries, participation in clinical trials is sometimes the only way to access medical treatment. What should be done to avoid exploitation of disadvantaged populations? EMBO Reports. 2015 Apr [cited Sep 5] Available from: https://www.ncbi.nlm.nih.gov/ pmc/articles/PMC4428044/.

6. Jadad AR, Enkin MW. Bias in Randomized Controlled Trials, in Randomized Controlled Trials: Questions, Answers, and Musings.

Second Edition, Blackwell Publishing Ltd, Oxford, UK; 2007 [cited Sep 5] Available from: doi: 10.1002/9780470691922.ch3

IMS MAGAZINE FALL 2017 CANCER THERAPEUTICS 9

RETROSPECTIVE

Thinking Outside the Box

Dr. Pamela Catton

Photo courtesy of the family of P. Catton

By Lindsay Caldarone

C

ompassionate physician, brilliant researcher, and devoted mentor; while entirely accurate, these descriptions do not begin to do justice to Dr. Pamela Catton’s legacy. Her illustrious career, the changes she implemented within the Institute of Medical Science (IMS) and beyond, and even the anecdotes told by colleagues and friends reflect her innovation, intelligence, authenticity, and utmost dedication to her work.

Dr. Pamela Catton completed her medical degree at the University of Ottawa, and her residency at the University of Toronto in 1982. She followed in her father’s footsteps by entering the field of radiation oncology. She worked at Sunnybrook Hospital, followed

by Princess Margaret Hospital (PMH) in Toronto. In 1999, Dr. Catton became the Director of Medical Education at the Princess Margaret Cancer Centre (PMCC). In addition to practicing radiation oncology, she held various leadership positions throughout her career including Director of the Breast Cancer Survivorship Program at PMCC, Director of Oncology Education at the University Health Network, and Professor and Vice Chair of the Department of Radiation Oncology at the University of Toronto (UofT).

Dr. Catton was committed to education and learning. Dr. Mary Gospodarowicz, the Medical Director of the PMCC, and friend and colleague to Dr. Catton, explains that Dr. Catton believed that “radiation 10 | IMS MAGAZINE FALL 2017 CANCER THERAPEUTICS

oncology is a multi-professional department; not only physicians, but educators, nurses [and more]… should have the opportunity for academic advancement.”

To accomplish this, Dr. Catton and Dr. Gospodarowicz developed and implemented a Bachelor of Science program in Medical Radiation Sciences (MRS), jointly offered by the Department of Radiation Oncology at UofT and The Michener Institute for Applied Health Sciences. This program was the first of its kind and, since its inception in 1999, has trained more than 1,500 radiation therapists. Nicole Harnett, who holds an Assistant Professorship in the UofT Department of Radiation Oncology and whom Dr. Catton hired to develop the curriculum for the MRS program, remembers how Dr. Catton expanded on her vision: “[She believed] that radiation therapy as a profession could and would have an increasingly important role in radiation therapy as a treatment modality... Stemming from [the MRS program] was the vision that there is more that radiation therapists could do.” Dr. Catton and Ms. Harnett took on a province-wide research project on advanced practice in radiation therapy.

Through this project, the development of a Master’s program was “imminent… to provide education that people need to perform the role [of radiation therapist]”.

Thus, the Master of Health Science in Medical Radiation Science program at UofT was born. As Dr. Gospodarowicz explains,

this was a “work of love… that doesn’t get done overnight, and does require leadership and a champion: someone who believes that the opportunity for advancement of all professionals involved in the program is important. Pam was this champion.”

This type of dedication and practical thinking was typical of Dr. Catton. “She couldn’t see something that needed to be fixed and not try to fix it,” says Ms. Harnett. “If she believes in something, it’s not going to not happen–it may change shape or format, but it will happen.” Dr. Catton was brilliantly innovative, but never let her ego cloud her judgment of what was best for her patients, students, or staff.

Her loyalty and commitment were not just reserved for those in her professional life, but also applied fiercely to her family and, in particular, her dogs, who go hand-inhand “as a unit”. “Once you crossed her path, you were on her radar,” explains Ms. Harnett, going on to explain how deeply Dr. Catton cared for everyone in her life. “[She was] a bright light here. A nexus for all kinds of things.”

In true interdisciplinary style, her legacies transcend the realm of formal education at UofT to include an impressive research canon, active involvement within the Royal College of Physicians and Surgeons of Canada, and contribution to the establishment of the Canadian Radiation Oncology Foundation, the charitable arm

RETROSPECTIVE

of the Canadian Association of Radiation Oncology. Her legacies also include a never-ending sense of humor, and even a new verb: “to be Pam-ed”. Ms. Harnett explains, “it didn’t matter what you did or how hard you worked, once you gave [your work] to her, you got Pam-ed–she would completely take it apart, build it back up, give it back to you and make you feel like you did the great work.” Like all aspects of her character, “Pam-ing” was evident in her personal and professional life. She constantly found the root of the problem or the lesson to be learned, and shared this in a constructive way.

Perhaps the legacy that best encapsulates the essence of Dr. Catton is ELLICSR: Health, Wellness & Survivorship Centre.

ELLICSR (pronounced ‘elixir’) is the product of a $3.7M budget, with support from the Canada Foundation for Innovation, the Ministry for Research and Innovation.

Fueled by Dr. Catton’s inexhaustible creativity, passion, and commitment, ELLICSR provides a physical space for cancer survivors, researchers, and clinicians to collaborate and explore ways to improve the cancer survivorship experience.

Through ELLICSR, patients can escape the clinical environment and focus on what they need in order to improve their personal wellness. ELLICSR provides access to a wide range of services, from community groups and clinicians to yoga classes and cooking demonstrations. They also hold an annual National Cancer Survivors Day event to celebrate cancer survivors as well as the efforts put forth by all staff and healthcare providers. The ELLICSR website explains, “ELLICSR is where the non-medical side of cancer treatment happens”.

Dr. David Wiljer, who holds the position as Director of Knowledge Management and Innovation in the Radiation Medicine Program at PMH and the University Health Network, worked closely with Dr. Catton throughout the development and implementation of ELLICSR. He explains that “her spirit lives on tremendously” in the Centre: from the design of the building (Dr. Catton had an “impeccable aesthetic” and would “intentionally wear the colors she wanted the architect to include in the palette” during meetings with the design

Ori D. Rotstein, MD Professor and Associate Chair of Surgery, University of Toronto Surgeon-in-Chief, St. Michael’s Hospital Director, Keenan Research Centre for Biomedical Science, St. Michael’s Hospital Keenan Chair in Research Leadership Dr. Pam Catton struck the Institute of Medical Science (IMS) like an arrow zeroing in on the bullseye of a target: straight and unfaltering. She was committed to establishing the Master of Health Science in Medical Radiation Science at the IMS, a first of its kind in Canada. Not only was the program designed to educate individuals for the workplace, Photo courtesy of Research at St. Michael’s Hospital but it also aimed to develop future leaders in the profession. Further, when Dr. Catton arrived to present her proposal to the IMS Curriculum Committee, it was refreshingly complete. Dr. Catton had done her homework–every detail required in the proposal had been thoroughly addressed. She engaged the best people to help her; in this case, Ms. Nicole Harnett. She recruited a broad range of instructors to deliver the content and even added her personal touch and passion to the course curriculum. Based on this experience, we learned the “correct” way of bringing forward a new program from Dr. Catton. Her skill as an educator was also evident. Dr. Catton and Ms. Harnett provided new approaches for evaluating courses. Awestruck with the seamless adoption of the Master of Science program and curriculum, the Curriculum Committee asked Dr. Catton to join and apply her expertise to the adoption of future courses and programs. It is certain that Dr. Catton left an indelible mark on the educational programs at the IMS. The past, present and future students, staff and faculty will forever feel her impact.

team), to the energy of the team (“we all always ask, what would Pam do?”).

ELLICSR focuses on patient-centered health, beyond medical services. Dr. Wiljer writes, “[ELLICSR] was fundamentally designed to co-create new ideas and new knowledge with the patients and the survivors themselves.”1 This is not a typical research project, but rather a novel paradigm for cancer education. The research team at ELLICSR aims to improve the health of cancer survivors by assessing longterm effects of cancer on survivors and their families, enhancing the survivor experience, and empowering survivors by promoting self-care strategies and enhancing patient-physician interactions. The program has provided invaluable information about the cancer survivor experience. ELLICSR at PMH was the first program of its kind, and has since been replicated globally.

As Dr. Wiljer describes, “Dr. Catton… rather than merely accepting a definition that fits in a box, chose to redefine and reimagine cancer education and constantly recreated its parameters to meet

the evolving challenges of the field…”1 ELLICSR interwove her creativity, her dedication to her patients, her focus on learning and teaching (which “were virtually indistinguishable” for Dr. Catton1), her passion for doing the right thing, and her one-of-a-kind spirit. “The Pam that was the mentor, teacher, disciplinarian, and researcher was the same person,” says Ms. Harnett, “you always knew what you were getting.” Although Dr. Catton passed away in December 2014, her contributions to cancer research, patient lives, and the education of students, colleagues, and friends remain tangible within the UofT and IMS community. As Dr. Wiljer points out, “most importantly, she always insisted on having fun with whatever challenge she took on and showed others how to find the joy too.”1 References 1. Wiljer D. The Competencies of a Cancer Educator: Redefining the Future. J Canc Educ (2015) 30:190–192.

IMS MAGAZINE FALL 2017 CANCER THERAPEUTICS 11

INFOGRAPHIC

Types of Cancer Therapies Systemic therapy Surgery Surgery involves surgical removal of cancer (tumours)

Systemic therapy involves drugs that travel in the bloodstream throughout the body.

Therapies include: Chemotherapy Attacks rapidly growing cells

Radiation therapy Radiation therapy uses high-energy beams or particles to kill cancer cells

Hormonal therapy Reduces cancer causing hormones in the body Targeted drugs Attack speciďŹ c sites on cancer or cells that help grow cancer Gene therapy Agents that disrupt the DNA of cancer cells (eg. modiďŹ ed viruses)

12 | IMS MAGAZINE FALL 2017 CANCER THERAPEUTICS

INFOGRAPHIC

Other therapies Microbubbles – miniscule gas bubbles just 0.003 of a millimetre wide – are used to improve diagnostic ultrasound imaging because they are thousands of times more reflective than normal body tissues4 (read more on page 20).

Supportive therapies and palliative care This form of therapy can reduce side effects and improve the patient’s quality of life

Active surveillance A type of care that monitors cancer over time to decide whether to start treatment later

Unlike traditional radiation therapy, radiosurgery uses a high, concentrated dose of X-ray treatment targeted at a specific site (eg. brain tumour) which minimizes radiation damage to surrounding tissue and limits side effects5 (read more on page 10).

Oncolytic Virotherapy exploits the selective and infectious nature of viruses and turns them into therapeutic agents to target and destroy cancer cells6 (see page 18 to learn about a new vaccinia virus an IMS researcher is developing).

In 2015, Canada ranked 11th out of 80 countries in an international ‘Quality of Death Index’ by the Economist’s Intelligence Unit. This index measures the availability and quality of end-of-life care from hospice and palliative care facilities7 (read more on page 16).

Imaging technologies including CT, PET and MRI were traditionally used mainly to diagnose or monitor cancer. But advances in imaging technology and robotics are making real time, image-guided surgical removal of tumours a reality in the University Healthy Network’s Guided Therapeutics program (read more on page 22).

References 1. Mullan F. Seasons of survival: reflections of a physician with cancer. N Engl J Med [serial online]. 1985 [cited 2017 Oct 14];313: 270-273.

Available from: DOI: 10.1056/NEJM198507253130421 2. Surveillance Research Program, Division of Cancer Control and Population Sciences, National Cancer Institute. American Cancer Society, Surveillance and Health Services Research. 2016 [cited 2017 Oct 14].

3. Cancer Treatment & Survivorship Facts & Figures 2016-2017. American Cancer Society. 2017 [cited 2017 Oct 14].

4. Blomley MJK, Cooke JC, Ungar EC et al. Microbubble contrast agents: a new era in ultrasound. BMJ [serial online]. 2001 [cited 2017 Oct 14];322(7296): 1222-1225.

5. Nieder C, Grosu AL, & Gaspar LE. Stereotactic radiosurgery (SRS) for brain metastases: a systematic review. Radiat Oncol [serial online]. 2014 [cited 2017 Oct 14]; 9: 155. Available from: doi: 10.1186/1748-717X-9-155 6. Gutierrez, AA. Embracing the Promise of Oncolytic Virus Immunotherapy. Drug Discovery & Development. 2017 [Cited 2017 Oct 14]. Available from: https://www.dddmag.com/article/2017/09/embracing-promise-oncolyticvirus-immunotherapy 7. Line, D. The 2015 Quality of Death Index, Ranking palliative care across the world: A report by the Economist Intelligence Unit. The Economist [newspaper online]. 2015 Oct 06 [cited 2017 Oct 14]. Available from: http://www.eiuperspectives.economist.com/healthcare/2015-quality-death -index

IMS MAGAZINE FALL 2017 CANCER THERAPEUTICS 13

Radiosurgery FEATURE

for spine tumours

Dr. Arjun Sahgal MD, FRCPC Professor of Radiation Oncology

an interview with Dr. Arjun Sahgal

Photo by Meital Yerushalmi

By Sarasa Tohyama

D

r. Arjun Sahgal is a pioneer in the implementation of stereotactic radiosurgery to treat spine metastases in Canada. He has also played an instrumental role in accelerating the field of spine radiosurgery globally. A staff radiation oncologist at the Sunnybrook Health Sciences Centre and clinician-scientist in the Odette Cancer Research Program at Sunnybrook Research Institute, Dr. Sahgal is also a professor in the Department of Radiation Oncology at the University of Toronto. I had the opportunity to sit down with Dr. Sahgal to discover more about his innovative therapeutic strategy.

David Larson. Traditionally, radiosurgery has been considered a targeted radiation technique used to treat brain metastases.

As the technology evolved to deliver highly precise radiation in the body, a few early adopters, including those at UCSF, began to treat spine metastases. The main intent was to maximize local tumour control and prevent malignant spinal cord compression. I had the opportunity to learn the technique–which had yet to be implemented in Canada–and develop it further for mainstream practice, rather than a one-off treatment offered in a few specialized centres.

Can you tell us about your academic trajectory?

In San Francisco, I saw firsthand the patient-reported benefits of spine radiosurgery as they achieved complete pain relief, long-term local tumour control, and no damage to the spinal cord. I wanted to make this therapy available for Canadians.

However, I realized that many questions

I was trained in Toronto as a resident and went on to complete a fellowship in radiosurgery at the University of California San Francisco (UCSF) with Professor 14 | IMS MAGAZINE FALL 2017 CANCER THERAPEUTICS

remained unanswered regarding its safe practice, and that this therapeutic strategy for spine metastases was an untouched area globally. My goal was to build a robust program for the University of Toronto, as I worked at the time in both the Sunnybrook Odette Cancer Centre and the Princess Margaret Cancer Centre.

How does radiosurgery differ from conventional radiation therapy?

The main difference between the two is the radiation dose and exposure to the surrounding healthy tissues. The dose used in radiosurgery is three to four times greater compared to conventional palliative external beam radiotherapy. As early adopters, we challenged the dogma that dose does not matter for spine metastases. We argued in our publications and at scientific meetings that by escalating the dose, we can achieve both better tumour control and

FEATURE

complete pain relief, without damaging the adjacent spinal cord. The bottom line is that we believed dose matters, and we were in the era of applying the technology to allow for high precision spine radiation.

It was time to bring this technique to the forefront of global practice.

What has been your most significant finding?

Our biggest accomplishment thus far has been figuring out the optimal dose for spine radiosurgery, which we found to be 24 Gray (Gy: a unit of ionizing radiation) in two-fractions. We established this ideal dose through our observations of treating patients initially with 24 Gy in three-fractions which was common practice, followed by a single fraction of 24 Gy, which we found was too toxic. Ultimately, our observations, understanding of radiobiology, and response assessment led us to develop this new dose for spine radiosurgery. In developing this dose, we also had to find an appropriate spinal cord constraint.

Through an international collaboration, we have published landmark papers on spinal cord tolerance that guided safe practice globally and have been incorporated into clinical trials.1-5 Of particular significance along our trajectory of developing the dose was the observation of radiation induced vertebral compression fracture (VCF). Our data suggested a 10% risk of VCF with our approach, and through collaborations with the MD Anderson and Cleveland Clinic, we determined a complication-dose response relationship.

We have since investigated risk factors for VCF with Dr. Cari Whyne’s biomechanics lab. We’ve also developed new approaches to enhance response while performing cement augmentation–a technique used to stabilize VCFs–with Dr. Albert Yee and his photodynamic therapy program for spinal metastases.

It is important to examine the safety profile to its fullest so that everybody understands what to expect of this radiation dose–both in terms of local control and expected side effects, such as fracture, pain, and radiation myelopathy, which is a rare condition where radiation causes damage to the white matter in the spinal cord. Once you establish safe guidelines for practice, you will know how to consent your patients properly. We certainly have achieved this through dedicated research over the last decade.

Where is your research currently going?

Currently, we are testing this 24 Gy two-fractions dose against conventional radiation in a national phase III randomized controlled trial (SC-24) sponsored by the Canadian Clinical Trials Group (CCTG). Our hope is that institutions across Canada can emulate our spine radiosurgery program and use it as a better treatment option compared to standard radiation treatment. This trial is currently more than halfway done. We also contribute our data to the AOSpine EPOSO global spine registry, which is near its first phase of completion and represents a major international initiative to collect high quality outcome data for spinal metastases.

Mikki Campbell, as project lead, has been instrumental in the success of this program and is currently helping develop it at other academic programs.

What is one area in your field that future research should focus on?

a comparison between postoperative conventional radiation and postoperative radiosurgery. We are surely in need of leaders in the development of postoperative spine radiosurgery.

Lastly, as a clinician-scientist, why do you think it is important to combine both clinical work and research in your field?

The biggest driver is to advance patient care. As a clinician-scientist, you can take your research directly into the clinic and develop something that is geared to improve patient treatment on a local and global scale. If you can do this systematically, you can really make a global impact.

References: 1. Thibault I, Whyne CM, Zhou S, et al. Volume of Lytic Vertebral Body Metastatic Disease Quantified Using Computed Tomography-Based Image Segmentation Predicts Fracture Risk After Spine Stereotactic Body Radiation Therapy. Int J Radiat Oncol Biol Phys.

2017 Jan 1;97(1):75-81. doi: 10.1016/j.ijrobp.2016.09.029. Epub 2016 Sep 28.

2. Thibault I, Chang EL, Sheehan J, et al. Response assessment after stereotactic body radiotherapy for spinal metastasis: a report from the SPIne response assessment in Neuro-Oncology (SPINO) group.

Lancet Oncol. 2015 Dec;16(16):e595-603. doi: 10.1016/S14702045(15)00166-7. Review.

3. Al-Omair A, Masucci L, Masson-Cote L, et al. Surgical resection of epidural disease improves local control following postoperative spine stereotactic body radiotherapy. Neuro Oncol. 2013 Oct;15(10):1413-9. doi: 10.1093/neuonc/not101.

4. Sahgal A, Atenafu EG, Chao S, et al. Vertebral compression fracture after spine stereotactic body radiotherapy: a multi-institutional analysis with a focus on radiation dose and the spinal instability neoplastic score. Clin Oncol. 2013 Sep 20;31(27):3426-31. doi: 10.1200/JCO.2013.50.1411. Epub 2013 Aug 19.

5. Sahgal A, Whyne CM, Ma L, Larson DA, Fehlings MG. Vertebral compression fracture after stereotactic body radiotherapy for spinal metastases. Lancet Oncol. 2013 Jul;14(8):e310-20. doi: 10.1016/ S1470-2045(13)70101-3. Review

One of our biggest interests now is to move onto the postoperative patient.

Traditionally, we have treated patients postoperatively with a lower dose of radiation to control the tumour, even though they have undergone a massive operation prior. However, there is an incongruence with this philosophy. We are hoping that the postoperative phase will be the focus of the next randomized trial. Specifically, IMS MAGAZINE FALL 2017 CANCER THERAPEUTICS 15

FEATURE

Palliative Care & Cancer Photo by Iris Xu

Dr. Gary Rodin, PhD Professor of Psychiatry, University of Toronto Head of the Department of Supportive Care, Princess Margaret Cancer Centre, Joint University of Toronto/University Health Network Harold and Shirley Lederman Chair in Psychosocial Oncology and Palliative Care Director, Global Institute of Psychosocial Palliative and End-of-Life Care

Bringing CALM to cancer patients around the world

By Alaa Youssef

P

atients with advanced cancer often find themselves struggling to achieve “double awareness”, that is, to manage physical symptoms, depression, fear, anxiety, and demoralization while also trying to spend their remaining lives meaningfully. For decades, palliative care was marginalized, poorly funded, and not recognized as part of the mainstream care, leading to a reduced quality of life in patients with advanced cancer. However, important new developments in palliative and supportive care have the potential to improve these patients’ quality of life.

Pioneering work at the Princess Margaret Hospital (PMH) under the leadership of Dr. Gary Rodin has led to impressive progress in the field of psychosocial and palliative medicine. Palliative care is now recognized as a vital component of care for patients with terminal conditions, such as late-stage cancer. Dr. Gary Rodin is the Head of the Department of Supportive Care, Director of the Global Institute of Psychosocial Palliative and End-of-Life Care (GIPPEC), and a Professor of Psychiatry at the University of Toronto. A recent interview with Dr. Rodin highlights his team’s significant contributions to the field.

Until recently, there were large gaps in 16 | IMS MAGAZINE FALL 2017 CANCER THERAPEUTICS

research, knowledge, and clinical care in palliative medicine. Patients with advanced diseases often suffered unnecessarily, and might spend their final days in a hospital or emergency department instead of the comfort of their home. Dr. Rodin’s team began to study this problem through observational studies, which showed that patients with metastatic cancer face a set of predictable challenges that can be addressed. Further, Dr. Camilla Zimmerman, clinician-scientist and collaborator, has shown that patients who referred to palliative care earlier in the course of their illness had a better quality of life compared to those seen near the end of life.1 Evidence from these extensive studies has allowed us to develop targeted interventions such as CALM to address gaps in care for advanced cancer patients.

Managing Cancer and Living Meaningfully (CALM), is a brief evidence-based counselling intervention designed to help relieve psychosocial distress and promote psychological growth and development for these patients.2 The intervention is delivered by a highly trained multidisciplinary healthcare team over three to six semi-structured sessions. These sessions are tailored to address patients’ specific needs across four

key domains: 1) symptom control and relationships with healthcare providers; 2) self-concept & personal relationships: helping patients maintain their sense of identity and self-esteem while restoring equilibrium in their relationships; 3) spiritual well-being or sense of meaning and purpose; and 4) future oriented concerns and planning for the end of life. According to Dr. Rodin, there are predictable challenges in each of these four key domains, but there was not a systematic approach to help patients face these challenges.

“We can compare this to mountain climbing. If you were to climb a high mountain, you would prepare, and we haven’t had a systematic approach to help people with metastatic cancer prepare in this way,” says Dr. Rodin. “We haven’t prepared and supported these patients enough to manage this journey.”

A cancer patient in the CALM intervention describes how CALM has impacted them, “I have to prepare myself for death, and [the therapist] is managing to [help me] because feeling that I’m able to grow as a person, makes me feel like I will be able to handle death in a peaceful way.3” CALM’s systematic approach has been well-received both nationally and

FEATURE

“We haven’t paid enough attention to teaching pain and symptom control, communication, and how to provide emotional support” internationally, and the intervention has significantly impacted the well-being of patients with metastatic cancer. Dr. Rodin’s research has shown that patients with advanced cancer who received the CALM intervention were less depressed, better able to plan for the end-of–life, and better at communicating with their health care providers compared to those who did not receive the intervention. Qualitative research on CALM has highlighted the meaningfulness and importance of this intervention to patients, who often referred to it as a “reflective and safe” space for them to talk about their fears and wishes.

Notably, CALM has had a global impact, as trials in Italy, Germany, and other parts of the world have replicated its effects.

Recently, Dr. Rodin’s team developed another intervention known as EASE (Emotional and Symptom Focused Engagement). This intervention focuses on patients with acute-onset diseases, such as acute myeloid leukemia (AML). This disease may be cured, but requires intensive treatment and has a high risk of mortality. These patients face a different set of challenges compared to patients with solid tumours. Patients with AML may not have had physical symptoms before being suddenly admitted to the hospital, but the intensive treatments they receive can cause distressing physical symptoms. These sudden changes can be highly distressing and many patients experience Post Traumatic Stress Disorder “PTSD”-like symptoms.

EASE is a combined psychosocial intervention that focuses on psychological support to manage anxiety and a palliative intervention that focuses on symptom control, starting early in the patient’s hospitalization. After demonstrating the feasibility and potential benefit of EASE in a pilot study, Dr. Rodin’s team will soon be launching a multi-centre trial in Toronto and Vancouver, which may expand to additional sites.

Internationally, there has been great

“We teach doctors how to do many things, but we haven’t paid enough attention to teaching pain and symptom control, communication, and how to provide emotional support,” says Dr. Rodin. “At one time, these skills were the core of medicine, but with the development of technology in modern medicine, they became neglected.

We need to train health care providers in these skills, as we do with other important skills in medicine.” interest in training healthcare professionals to administer CALM and other psychosocial interventions. Dr. Rodin’s team have trained healthcare providers in Asia, the Middle East, Europe and South America, including China, Japan, and more than 20 other countries around the world.

Dr. Rodin is also the director of a network called the Global Institute of Psychosocial and Palliative Care (GIPPEC). The GIPPEC and CALM training initiative initially developed independently, but both have grown through their synergy and common goal to improve quality of life for patients and families living with advanced disease. Efforts at GIPPEC are focused on building global networks in palliative and supportive care, with partnerships in China, Europe, and Africa. They have held workshops in many countries, training healthcare providers to deliver these interventions systematically and to engage more comfortably in sensitive conversations with their patients.

The GIPPEC is currently conducting studies in Kenya and Uganda, examining the quality of dying and death. This research is intended to deepen our understanding of how to improve the quality of death in these countries. Through these international collaborations, GIPPEC aims to generate meaningful evidence that advances clinical practice and enhances global access to psychological and palliative care for individuals with advanced and terminal diseases.

According to Dr. Rodin, training health care providers in how to provide supportive care is an important goal in medical education.

The integration of education in supportive care with that of other aspects of medicine, will help us to graduate health care providers with the skills to care for patients with complex needs, and to provide medical care that is humane and holistic.

Dr. Rodin wishes to acknowledge the Canadian Institutes of Health Research, the Canadian Cancer Society and the Princess Margaret Cancer Centre for their support of his research program.

References: 1. Zimmermann C, Swami N, Krzyzanowska M, Hannon B, Leighl N, Oza A, Moore M, Rydall A, Rodin G, Tannock I, Donner A, Lo C. Early palliative care for patients with advanced cancer: a cluster-randomised controlled trial. Lancet. 2014;383(9930):1721-30.

2. Lo C, Hales S, Jung J, Chiu A, Panday T, Rydall A, Nissim R, Malfitano C, Petricone-Westwood D, Zimmermann C, Rodin G. Managing Cancer And Living Meaningfully (CALM): phase 2 trial of a brief individual psychotherapy for patients with advanced cancer. Palliat Med. 2014;(3):234-42.

3. Nissim R, Freeman E, Lo C, Zimmermann C, Gagliese L, Rydall A, Hales S, Rodin G. Managing Cancer and Living Meaningfully (CALM): a qualitative study of a brief individual psychotherapy for individuals with advanced cancer. Palliat Med. 2012;(5):713-21.

IMS MAGAZINE FALL 2017 CANCER THERAPEUTICS 17

FEATURE

Exploring the potential of

Vaccinia Virus

to target and kill tumour cells

By Yekta Dowlati

D

r. Andrea McCart is an associate professor in the Department of Surgery at the University of Toronto (UofT) and a scientist at the Toronto General Hospital Research Institute (TGHRI). She completed her medical degree and surgical residency at the University of Western Ontario. While completing her Master’s degree in pathology—looking specifically at mutations in the p53 gene, which acts to suppress tumor formation—Dr. McCart became interested in gene therapy and surgical oncology. To pursue her dreams, she did a fellowship with Dr. David Bartlett at the National Cancer Institute in the United States to investigate gene therapy with a type of virus called “vaccinia virus”. Over the course of her fellowship, they discovered that the vaccinia virus played a greater role as an anticancer therapeutic than the gene therapy itself. After completing her residency and surgical oncology fellowship, she came to the UofT because she considered it the most ideal institute to combine both her research interests and surgical career.

Oncolytic viruses have been investigated in a broad range of preclinical models, and some have also reached the clinical trial stage, showing promising results.

For example, the herpes virus has been approved as a therapy for melanoma. The viruses are unique as they are tumor selective, and this selectivity depends on the type of the virus.

Vaccinia virus has been the continued 18 | IMS MAGAZINE FALL 2017 CANCER THERAPEUTICS

focus of Dr. McCart’s research with oncolytic viruses. She considers her most significant research accomplishment to date to be the development of a novel vaccinia virus with Dr. Bartlett, which is now in clinical trials. They refer to the virus as “doubled-deleted virus” because it is missing two different genes. This is considered a landmark trial of one of the early viruses, showed thus far to be safe in patients. She currently uses it as her gold standard virus to compare with new viruses candidates.

The new viruses are required to be better than the double-deleted virus before they are investigated further.

The vaccinia virus can infect any kind of cancer cell; however, with the mutations made—such as in the double deleted virus model—the virus is dependent only on dividing cells. In addition, vaccinia is a large virus that can only escape the bloodstream in tissue with leaky vasculature, such as tumor vasculature. These combined characteristics allow vaccinia to effectively target tumor cells. From an experimental viewpoint, Dr. McCart’s lab focuses on animal models of abdominal cancers—such as mesothelioma, colon, and ovarian cancer—and tries to cure the animals with these viruses. Upon successful results, the viruses may then progress to clinical trials.

Dr. McCart’s research group is currently conducting two main projects. The first project aims to develop novel vaccinia viruses that are simultaneously better at targeting tumor cells and are safer in animal

FEATURE

“Patients are the biggest motivation for my work.”

Photo by Krystal Jacques

Dr. Andrea McCart, PhD Associate professor, Department of Surgery at the University of Toronto (U of T) Scientist, Toronto General Hospital Research Institute (TGHRI). models. These aims are accomplished by engineering novel gene mutations into the parental virus. The new viruses are then tested in vitro and in animal models to determine if they are better at killing cancer cells and if they are as safe, or safer, than the gold standard double-deleted virus. The second project involves enhancing vaccinia and other viruses’ abilities to kill tumors by manipulating the tumor microenvironment.

In animal models, they are modulating various aspects of the tumor microenvironment to study the effects on the viruses’ ability to spread, kill cancer cells, and lead to an anti-tumor immune response. In the future, these manipulations can be used to enhance the viruses’ effects in cancer patients.

In Dr. McCart’s opinion, it is still too early to know whether this type of intervention can improve survival rate and treatment outcomes in patients with abdominal cancers, as studies are still at the preclinical level. Nevertheless, early clinical trials have shown both safety and therapeutic responses for oncolytic viruses in general. Patients are somewhat apprehensive about receiving a virus as their treatment.

To date, patients may acquire flu-like symptoms but typically experience no

major side effects. It is probably too early to confirm the efficacy of vaccinia virus, as no phase three trials have been conducted yet. For instance, herpes virus has been demonstrated as efficacious for melanoma based on large clinical trials and is in the line of other immunotherapies for melanoma. No clinical studies are far enough along to show how effective the vaccinia virus may be for abdominal cancers in patients.

Aside from working on vaccinia virus, Dr. McCart performs hyperthermic intraperitoneal chemotherapy (HIPEC), a technique that she imported to Mount Sinai after her surgical oncology fellowship at the National Cancer Institute in Bethesda. For patients with peritoneal cancers specifically derived from colon cancer, appendix cancer, or peritoneal mesothelioma, a long surgery is initially performed to remove all the tumors. Then, heated chemotherapy solution is delivered into their abdominal cavity to penetrate and eradicate all of the remaining invisible cancer cells. After this procedure, the patient may not need any other therapy and the cancer will be gone. This is currently a standard treatment, but only

select patients qualify for it because the disease must be confined to their abdomen and be surgically removable. As a result, only approximately 20% of patients qualify. Overall, this procedure has been performed around the world and has improved survival. In an ideal world, down the road, Dr. McCart would like to combine HIPEC with the virus therapy— however, this may be years away.

Dr. McCart hopes that in the near future they can run a clinical trial using these viruses in abdominal cancer patients, optimistically even in combination with surgeries. In her opinion, this intervention can either be given ahead of time to eradicate some of the tumors or after the surgery for the microscopic disease. Even though survival has improved even up to 50% in some, the other 50% of patients require attention. “Patients are the biggest motivation for my work. Some I can help through surgery, but for the ones that don’t qualify or recur, obviously I’d like to find better treatments,” says Dr. McCart.

IMS MAGAZINE FALL 2017 CANCER THERAPEUTICS 19

FEATURE

Ultrasound-Gene Delivery Applications in Cancer Research:

AN INTERNATIONAL JOURNEY

Dr. Howard Leong-Poi, MD, FRCPC, FACC, FASE (Left) Staff Cardiologist, St. Michael’s Hospital Associate Scientist, Keenan Research Centre for Biomedical Sciences Associate Professor, Department of Medicine, University of Toronto Dr. Pratiek Matkar, PhD (Right) Previously a PhD student at Institute of Medical Science, University of Toronto Photo by Grace Jacobs

By Priscilla Chan

W

hat do microbubbles—miniscule gas filled bubbles just three micrometres (μm) across—have to do with the future of non-invasive cancer treatment? Originally used as a contrast media to improve ultrasound images, microbubbles are now being harnessed for their novel therapeutic properties. Specifically, microbubbles may be used in targeted gene delivery to treat a variety of conditions, from cardiovascular diseases to cancer. I sat down with Dr. Howard Leong-Poi, a clinician-scientist at St. Michael’s Hospital, to talk about his work in non-invasive cancer therapy, specifically the application of ultrasound and microbubbles.

“Essentially, it’s the use of gas-filled microbubbles for a variety of purposes,” explains Dr. Leong-Poi. Microbubbles can be administered intravenously into the systemic circulation. Ultrasound waves cause these microbubbles to expand and 20 | IMS MAGAZINE FALL 2017 CANCER THERAPEUTICS

contract, resonating strongly at high frequencies. Importantly, compared to soft tissue, microbubbles have a greater capacity to reflect ultrasound waves. In other words, microbubbles can be used to enhance the resolution of greyscale ultrasound images.1 This approach can be used for more than just diagnostics; it can also be applied for therapeutics. With sufficient excitation, microbubbles are ready to burst, opening up the vascular endothelium. As Dr. Leong-Poi describes it, “it’s a mechanical form of gene transfection.” Ultrasound-targeted microbubble destruction exploits this property to increase the efficiency of drug, protein, and gene delivery. Dr. Leong-Poi’s lab has used ultrasound and microbubbles for targeted gene delivery to treat peripheral artery disease, heart failure, and acute myocardial infarction. More recently, his team started looking into ultrasound-mediated gene therapies for cancer.

Currently, cancers are treated using a combination of surgery, chemotherapy, and radiation. Tumours can be partially or completely removed through surgery, but the procedure is invasive and mainly applicable to localized tumours that have not spread. Chemotherapy and radiation are also reasonably effective, but patients are left to deal with the many systemic side effects associated with the treatments.

“They work on cancer for a reason,” says Dr. Leong-Poi, “they’re toxic.” In contrast, ultrasound-mediated gene therapy may provide a non-invasive alternative.

Dr. Leong-Poi and his colleagues have shown that microbubble delivery of a short hairpin (sh)RNA specific to VEGFR2, a gene contributing to neovascularization—the formation of new blood vessels—reduces angiogenesis (blood vessel formation) in an in vivo tumour model.3 His team also optimized the ultrasound pulse rate to achieve maximal

FEATURE knockdown of the gene. Their idea was to reduce angiogenesis in order to limit tumour growth. While this technique may not be able to make tumours disappear completely, Dr. Leong-Poi is hopeful that it might make tumour resection easier or be used in addition to other therapies.

Before ultrasound-mediated gene therapy can be implemented as a cancer treatment, organ accessibility needs to be considered.

“Any organ or body system or disease state that is accessible to ultrasound could potentially be used for focused gene-delivery,” says Dr. Leong-Poi. However, there are a few natural barriers to ultrasound: air and bone. Tumours found in more superficial organs, such as the liver, may be treated with ultrasound-mediated gene therapy, while tumours located in the brain, spinal cord, or lungs pose a challenge. Some researchers have overcome these barriers by directly injecting microbubbles and administering ultrasound to specific organs, but Dr. Leong-Poi reminds us that “this takes away from the non-invasive nature” of the technique.

Perhaps an even greater challenge in translating ultrasound-mediated gene therapy to the clinic is the fact that it is a highly targeted technique. Although it may be able to limit growth of the primary tumour, ultrasound-mediated gene therapy does not address secondary tumours that have metastasized. Therefore, Dr. Leong-Poi believes that it may be hard to convince some oncologists of the technique’s clinical value. However, in his opinion, patients with hepatocellular carcinoma (liver cancer), head and neck cancers, and other “more locally invasive” cancers are more likely to benefit from this therapy.

After discussing his lab’s work, I was still left with one question: How does a cardiologist get involved in cancer research? “It was mainly through an IMS graduate student actually,” says Dr. Leong-Poi. Pratiek Matkar joined Dr. Leong-Poi’s lab as an international PhD student in 2012 from Pune, India. “He knew about some of the work we did on the cardiovascular side, but his particular interest was in cancer,” recalls Dr. Leong-Poi. “He asked: ‘Can [ultrasound] be applied to cancer?’ and [he] knew other investigators that have done that, but I hadn’t really thought about going down that route, in all honesty. Pratiek was a real catalyst for us and he’s been very successful.”

This image has been modified from: Leong-Poi H. Contrast ultrasound and targeted microbubbles: diagnostic and therapeutic applications in progressive diabetic nephropathy.

Semin Nephrol. 2012; 32(5):494-504.

Pratiek’s work has largely focused on the mechanistic aspects of cancer. In his most recent publication, Pratiek used ultrasound-targeted microbubble destruction to study the role of neuropilin-1, an angiogenic protein, in endothelial-to-mesenchymal transition and fibrosis in pancreatic ductal adenocarcinoma (pancreatic cancer).4 Through Pratiek’s studies, Dr. Leong-Poi thinks that ultrasound therapeutics may be better suited to study cancer mechanisms than to treat cancer.

Nevertheless, he points out that understanding the underlying mechanisms can inform how we approach the development of other cancer therapies.

What’s next for Dr. Leong-Poi’s lab?

“We’re applying for grants to look at viral gene delivery.” He explains that although plasmids and non-viral vectors may be safer, viral vectors may be necessary to achieve more widespread and longer-lasting delivery. In terms of cancer research, Dr. Leong-Poi remarks, “It was a unique opportunity, and the road ahead depends entirely on future funding!” Whether or not another student will follow in Pratiek’s footsteps is unclear, but what is clear is that the work Dr. Leong-Poi’s lab has done thus

far has made a meaningful contribution to our collective scientific knowledge. For this reason, Dr. Leong-Poi remains excited for the future of cancer research: “Even if you’re not the one to take it across the finish line, maybe someone else will be able to do that.”

As for Pratiek? We hear that he has successfully defended his PhD thesis.

Congratulations Dr. Matkar and we wish you the best in your future endeavors!

References 1. Blomley MJK, Cooke JC, Unger EC, Monaghan MJ, Cosgrove DO. Science, medicine, and the future: Microbubble contrast agents: a new era in ultrasound. BMJ [Internet]. 2001;322(7296):1222–5.

Available from: http://www.bmj.com/cgi/doi/10.1136/ bmj.322.7296.1222 2. Mayer CR, Geis NA, Katus HA, Bekeredjian R. Ultrasound targeted microbubble destruction for drug and gene delivery. Expert Opin Drug Deliv. 2008;5(10):1121–38.

3. Fujii H, Matkar P, Liao C, Rudenko D, Lee PJ, Kuliszewski MA, et al. Optimization of Ultrasound-mediated Anti-angiogenic Cancer Gene Therapy. Mol Ther - Nucleic Acids [Internet].

2013;2(May):e94. Available from: http://linkinghub.elsevier.com/ retrieve/pii/S2162253116301524 4. Matkar PN, Singh KK, Rudenko D, Kim YJ, Kuliszewski A, Prud GJ, et al. Novel regulatory role of neuropilin-1 in endothelial-to-mesenchymal transition and fibrosis in pancreatic ductal adenocarcinoma.

Oncotarget. 2016;7(43):69489–506.

IMS MAGAZINE FALL 2017 CANCER THERAPEUTICS 21

FEATURE

The GTx Program:

“A multi-functioning team-based approach for cancer therapeutics”

By Jonathon Chio

F

or many patients, surgery plays a critical role in the diagnosis and treatment of newly-identified tumours. The introduction of novel imaging, robotics, and the emerging era of nanomedicine integrating into the operating room has brought about a great need for multidisciplinary teams that can effectively incorporate these technologies in the surgical environment. At the University Health Network, the TECHNA Research Institute (TECHNA) is focused on advancing surgical technologies to improve health. The Guided Therapeutics (GTx) Program, one of TECHNA’s Five Core Centres of Excellence, is composed of scientists, physicists, image technologists, surgeons, radiologists, and engineers who develop advanced image-guided technologies for the surgical management of cancer. Dr. Jonathan Irish is the Medical Director for the GTx Program and Director of Clinical Faculty for TECHNA. Here we reveal how the collaborative efforts of his multidisciplinary translational research team make a tremendously positive impact on the surgical management of cancer.

The Princess Margaret Cancer Research Tower houses the GTx Lab, in which a translational research process begins through pre-clinical testing of surgical technologies in the lab’s imaging and surgical facilities. Once the newly-developed technology is proven effective through laboratory testing, the trial progresses into its clinical phase, in which the procedure of interest is performed in a dedicated research operating room (GTx-OR), located at Toronto General Hospital.

This unique operating room (OR) was designed to facilitate the implementation of innovative image-guidance techniques in the surgical removal of tumours. In comparison to conventional techniques, these techniques achieve greater precision and accuracy, which are of paramount 22 | IMS MAGAZINE FALL 2017 CANCER THERAPEUTICS

Photo by Mikaeel Valli

Dr. Jonathan Irish, MD, FRCSC, FACS, MSc Core Lead, Techna Institute for the Advancement of Technology for Health (Techna), Cancer Clinical Research Unit, Princess Margaret Cancer Centre Professor, University of Toronto Chief of Surgical Oncology, University Health Network and Mount Sinai Hospital Faculty, Institute of Medical Science, Faculty of Medicine, University of Toronto Provincial Head, Surgical Oncology Program, Cancer Care Ontario importance in highly-complex anatomical sites including surgery of the skull base, chest, pelvic bone and the head and neck. It is through the implementation of these novel image-guided technologies in surgery, interventional radiology, and radiation medicine that the GTx Program seeks to revolutionize cancer treatment.

To that end, the GTx Program developed

the ‘X-Eyes’, a global positioning system (GPS)-like surgical navigation platform that allows surgeons to accurately resect tumors while leaving surrounding healthy tissue intact.

This dashboard interface has been refined by GTx team members, including Research Associate Michael Daly, over the

FEATURE past 8 years. Through its aim to accurately present positional information in an intuitive, user-friendly manner, X-Eyes provides pre- and intra-operative imaging, surgical tool tracking, and guidance in surgical planning. To describe their image-guided navigation dashboard, the team often analogize the patient’s anatomy to an area represented by map. As the anatomy changes throughout the surgical procedure, intraoperative imaging solutions update the map in real-time, reflecting changes in tissue deformation.

Furthermore, the complex anatomy of the head and neck necessitates constant tracking of the location of the surgical tool relative to recognizable points of anatomy.

The ‘X-Eyes’ surgical dashboard addresses both of these challenges through its capacity to provide intra-operative imaging and surgical tool tracking.

At the start of the surgical procedure, a pre-operative computed tomography (CT) or magnetic resonance imaging (MRI) is displayed on the ‘X-Eyes’ dashboard that clearly differentiates the tumour from surrounding healthy tissue. Additional imaging may be obtained by the GTx-OR CT scanner immediately prior to the procedure. The Siemens Artis Zeego (a multi-axis imaging system) uses Cone Beam CT technology and robotics to scan the patient in the OR, creating an updated 3D image of the patient and surgical tools relative to their anatomy. GPS-like sensors are attached to the tools, providing live tracking information displayed on the dashboard. As the procedure progresses, new information is collected by the surgical navigation system to update the anatomy, delivering the real-time information to the operating team. This GPS-for-surgery system is fully customizable and modular, allowing new ideas to be launched within the platform as different challenges are brought forward to be solved. The GTx team’s ongoing work to improve surgical planning, pre-operative and intra-operative imaging, and surgical tool tracking is broadly applicable in medicine, including in thoracic and orthopaedic surgeries. With the adaptation of advanced technology to deliver the aforementioned multi-faceted information to the integrated dashboard, it is appropriate to have a multi-disciplinary team of experts in related areas such as medical physics, engineering, and software development to

perform translational research.

Radiation treatment and surgery provide targeted therapy for the treatment of tumors. The GTx Program developed a collaboration between scientists and clinicians from each of these two practices to implement image-guided technologies that support combined therapy with both of these treatment modalities. GTx radiation physicist Dr. Robert Weersink works on linking radiation therapy with surgical imaging and pre-surgical planning techniques. This is accomplished, in part, by comparing a tumour’s size and location as identified surgically versus through imaging, including CT, MRI, and positron emission tomography (PET).

Such a comparison is currently under evaluation for mucosal cancers in the head and neck, as these diseases can be difficult to locate accurately due to the low resolution of traditional scanning equipment.

Notwithstanding the role of an oncologist in identifying tumour location through imaging, an alternative method is being examined—one that uses the administration of molecular agents to detect tumor location.

Along with Dr. Irish, Drs. Harley Chan, Jason Townsen, and Nidal Muhanna are working on the introduction of novel contrast agents into operating room imaging.

Their collaborative work with research groups investigates both liposome- and porphysome-based nanoparticles for imaging and therapy in pre-clinical cancer models, with a plan to go to clinical trial.

In collaboration with Dr. Gang Zheng’s and Drs. Jinzi Zheng and Christine Allen’s groups, whose research focuses on the porphysome and liposome nanoparticles, respectively, the GTx team will take advantage of the inherent theranostic characteristic of these nanoparticles (capable of providing both diagnostic and therapeutic properties). Delivery of biocompatible, non-toxic, and multi-functional nanoparticles with a long half-life into tumours will render them visible due to the nanoparticles’ photoacoustic and photonic imaging capabilities, and enable their ablation using photothermal or photodynamic therapy techniques. The use of nanoparticles in the operating room setting will represent a promising breakthrough in theranostics, as they are used in both diagnosing and treating cancer through photoacoustic imaging and photodynamic and photothermal

therapies, respectively. Equipped with cutting-edge technology, the GTx Program provides the ideal resources and support to translate the research from pre-clinical studies to clinical use.

In addition to its research on nanoparticles, the GTx program also offers 3D printing solutions for various surgical needs, such as structural reconstruction after tumour removal, prototyping medical devices, and developing surgical phantoms. For example, when performing jaw surgery to remove a tumour from the mandible, the lower jaw bone can be reconstructed by fixing a plate to stabilize autologous bone taken from another part of patient’s body. To facilitate this, 3D printing is combined with CT imaging to generate a model of the patient’s mandible used to fabricate a reconstruction plate prior to surgery. With his engineering background, Dr. Harley Chan is able to design and print personalized disease-free models or perform digital surgery simulating tumour removal from the mandible for 3D printing. This model undoubtedly reduces operation time and anesthetic use, thereby improving patient outcomes and reducing overall healthcare costs.

The introduction of a high-performance and multi-functional team to bring technology-driven innovations to surgery and radiation oncology is beneficial to patient care. The motto of the GTx Program—”To Create, To Innovate, To Translate, To Evaluate and To Educate”—is clearly imprinted in the multidisciplinary GTx team. The research output from the GTx program, including the image-guided navigation platform X-Eyes, is currently used in clinical trials within the GTx OR at Toronto General Hospital. It is also clear that collaboration is the key to success, as the GTx team increasingly incorporates nanomedicine and nanotechnology into the diagnostic and therapeutic paradigm for cancer care. Dr. Irish’s team is an excellent example of the future of biomedical research and surgery, one that avoids “silos” and embraces collaboration and partnership. The GTx Program is a team of individuals from all aspects of science united by the goal of positively influencing patient outcomes through use of innovations in cancer surgery—“a sum that is greater than its parts”.

IMS MAGAZINE FALL 2017 CANCER THERAPEUTICS 23

CLOSE-UP

CLOSE-UP ON DR. HOWARD MOUNT On creating a graduate program by and for the individual student

By Melissa Galati

I

f you are a graduate student in the Institute of Medical Science (IMS), you have probably interacted with Dr. Howard Mount on more than one occasion. He may have conducted your graduate school interview, welcomed you during your first MSC1010Y class, or possibly advised you during times of crisis in his role as a graduate coordinator (GC). When I sat down with Dr. Mount—who, in addition to being a GC, is also the IMS Director of Education and scientist at the Tanz Centre for Research in Neurodegenerative Diseases—I expressed my surprise that we had never interviewed him for the IMS Magazine. He responded with a small smile, “I’m more of a behindthe-scenes kind of guy.” Indeed, by the end of our conversation, I had to wonder if there was any aspect of the IMS Dr. Mount wasn’t involved in.

It may or may not surprise you to know that Dr. Mount, who completed his undergraduate degree at the University of Toronto (U of T), was initially interested in ecology. He worked for the National Research Council Environmental Secretariat throughout his BSc and MSc and became interested in behavioural toxicology. One of the earliest signs of toxicity in an organism, Dr. Mount explains, is behavioural change. He wondered whether you could infer the presence of toxic metals or organics in the water by looking at the behaviour of aquatic organisms. He envisioned that he would become an environmental consultant and work to assess man’s impact on the environment.

Instead, Dr. Mount’s enthusiasm for toxicology led him to pharmacology, specifically, how the use of certain drugs would cause long-lasting change in the brain. He took advantage of a long-standing exchange program between U of T 24 | IMS MAGAZINE FALL 2017 CANCER THERAPEUTICS

and the Rudolf Magnus Institute in the Netherlands to study the effect of amphetamines in behavioural sensitization. When he returned to Canada, Dr. Mount spent the better part of a year trying to determine where he wanted to pursue his PhD. He ultimately chose to study with Dr. Remi Quirion at McGill University. Dr. Quirion, now the chief scientist of the Province of Quebec, is known as one of Canada’s most prolific neuroscientists. Dr. Mount’s doctoral dissertation focused on the release of cellular dopamine from mesencephalic neurons in response to excitatory amino acids.

At the end of his degree, Dr. Mount again took some time to think carefully about potential postdoctoral fellowships. He advises students considering academia to do the same due to the dramatic differences in training environments. He joined Dr. Ira Black at the Robert Wood Johnson Medical School. “He wasn’t going to take me,” Dr. Mount recalls, “but this is where those grant proposals you write as an exercise in graduate school become really important. I happened to have a copy of a paper I had written for a course, which was also the “Future Directions” section of my PhD.” When Dr. Black asked what he wanted to study, Dr. Mount pulled out the paper and proposed the experiments he had written about. His future mentor responded with enthusiasm. Based on this experience, Dr. Mount is heavily in support of writing up a project proposal as an exercise in graduate school courses. He laughs and notes that he didn’t actually get a good grade on the paper, but, “You never know when you’re going to need these things. If it’s something that’s original, you can come back to it.”

During his fellowship, Dr. Mount uncovered a novel cell-survival pathway in

Purkinje cells in the cerebellum, which are depleted in the neurodegenerative disorder ataxia-telangiectasia (AT). He continued to study AT as an independent investigator at U of T and now works on other neurodegenerative diseases, including Alzheimer’s Disease (AD). He uses animal models to look at early changes in brain chemistry associated with behavioural changes. To study the brains and signalling molecules of these animals, which are often tricky to measure, Dr. Mount uses instantaneous heat inactivation via a 10kW magnetron (a really powerful microwave) that his lab couples with neurochemical assay techniques. His students have used this approach to demonstrate early loss of noradrenaline in AD that could be restored with an alpha2-receptor antagonist, a therapy that was eventually brought into the clinic for the treatment of AD. His lab has also used this approach to determine the ex vivo metabolic state (energetic charge) of specific brain regions, before the onset of frank brain pathology.

In addition to his research on neurodegenerative diseases, Dr. Mount is highly committed to improving the graduate school experience for students. After serving on the IMS admissions committee for a number of years, Dr. Mount was appointed to graduate coordinator in 2007. He explains that graduate coordinators are the guidance counsellors of the department, “we gravitate towards this because we like talking to students. It’s very much about sharing insights and helping people work out what they want to do.”

When I asked him what he enjoys most about this role, he answers that it’s been delightful for many reasons. He has become more aware of the diverse research at U of T, but mostly he has enjoyed listening to students and helping those in crisis.

CLOSE-UP “It’s incredibly rewarding because we’ve had so many success stories—so many students who were suffering needlessly and possibly seeking help in the wrong places.

The trick is, how do we get students to come in, to see a graduate coordinator, and get support from the system early?”

Most commonly, students become burnt out, particularly when they do not know what their future holds. Mental health concerns, communication problems with supervisors, and impostor syndrome are not uncommon. On this subject Dr. Mount comments, “Impostor syndrome is an interesting one because it keeps us motivated to be scholarly and rigorous in our work. It’s something that one deals with all of one’s life. I think understanding that is actually calming.” When asked if he’s experienced imposter syndrome, he responds, “Oh yea, sure. In all sorts of domains.

And that’s the stimulus to study. To learn something, and not sit back and “wing it” or finesse an issue.” The trick, he says, is learning how to harness your anxieties or insecurities—to “get your butterflies to fly in formation”, to paraphrase the Robert Gilbert quote.

In addition to being a graduate coordinator, Dr. Mount is also Director of Education at the IMS. He’s continually working to modify and create a curriculum that is better for all students. When he started, he set out to redesign the IMS MSC1010Y seminar course. Students, he realized, wanted quick insights into a variety of different fields. On the other side, faculty members wanted to teach a small series of lectures (as opposed to an entire course). “We realized that people think in smaller packages, and that a lot of short courses would be possible.” The concept of modules emerged. Around 30 have been introduced over the last few years and new ones are always emerging.

Modules have also provided opportunities for postdoctoral fellow participation—one of the challenges facing the community right now. There are very few sessional lectureships and most teaching assistant positions go to students, Dr. Mount explains. “How do we create opportunities for postdocs that don’t exploit their labour, but help them in their professional development?” Another way to engage postdocs is through participation in program development committees. Dr. Mount, who oversees the curriculum committee and its

Photo by Krystal Jacques

Dr. Howard Mount, MSc, PhD Principal Investigator, Tanz Centre for Research in Neurodegenerative Diseases Associate Professor Department of Psychiatry, Department of Medicine, Division of Neurology, Department of Physiology Director of Education and Graduate Coordinator, Institute of Medical Science three subcommittees, expresses earnestly, “We want community involvement.” Many of the meetings are open to everyone and he encourages interested individuals to join the discussion. The committees discuss all aspects of the curriculum.

In addition to modifying the existing program, Dr. Mount also works on developing new initiatives. He was a key player in developing the IMS Translational Research Program, Canada’s first in-kind professional Master’s program. He is now working with the IMS’s Drs. Neil Sweezey and Norm Rosenblum on a diploma program for medical students in health science—still in approval stages—as well as thinking about how the IMS will engage in professional skills development. In particular, he stresses the importance of mentors in this process. “There’s an increasing realization that you have to [meet with] someone other than your supervisor about certain matters—particularly where you want to go in life and what ancillary skills you want to develop to round out your CV.” He envisions a system where all students engage in creating an individual plan that is not part of their thesis work, but rather entirely for their professional development. This type of program is

still in its early stages but is something that many departments are interested in developing. “We’re always trying to figure out ways to engage a broader community in a thoughtful way that doesn’t detract from our mandate and ensures that we’re delivering a quality curriculum.”

When asked for a final piece of advice for students, Dr. Mount states, “This is supposed to be fun. It’s a privilege to have protected time for scientific research.

When it’s not fun, something’s wrong.” Dr. Mount recalls his own graduate school experiences, which were enjoyable in large part due to a supportive network and close relationship with his supervisor—something that is sometimes lacking at U of T. But he is hopeful that there is a growing awareness of this need and that improvements in peer and faculty mentoring arrangements for students are on the horizon.

IMS MAGAZINE FALL 2017 CANCER THERAPEUTICS 25

FUTURE DIRECTIONS

From IMS to the

AI revolution By: Aravin Sukumar

W

e are entering into a new era of technology that has only been depicted in sci-fi movies such as Ex Machina and A.I. (Artificial Intelligence). What is common in these movies are robotic characters that can simulate human behavior and intelligence.

As we speak, the world is taking advantage of new advances in programming and computer hardware to create intelligent systems. Adam Santoro is one of these individuals. Adam, a Ph.D. graduate from the Institute of Medical Science (IMS), is a Research Scientist at DeepMind–an artificial intelligence (AI) company focused on creating intelligent systems that can learn to solve some of our world’s most complex problems. Capitalizing on the rise in AI technologies, which have recently been covered in Forbes, The New York Times, and The Economist, Adam followed his passion in the field of AI, where he has succeeded by applying the intangible skills acquired throughout his graduate studies. Evidently, AI has many potential applications for scientific disciplines within the IMS community, especially considering that the University of Toronto (UofT) is a globally-recognized leader in the fields of AI and machine learning.

Follow your passion Adam completed his Bachelor’s degree at UofT with a double major in Biochemistry & Physiology before pursuing his Ph.D. in Neuroscience in the lab of Dr. Paul Frankland. Outside the lab, he loves being 26 | IMS MAGAZINE FALL 2017 CANCER THERAPEUTICS

Adam Santoro, PhD, Institute of Medical Sciences active and regularly goes to the gym, which helps him to clear his mind. “Many people have shower epiphanies; I tend to have gym epiphanies,” Adam mentions.

In addition, he enjoys music composition and playing different instruments. In the lab, his research focused on ‘systems memory consolidation’; in other words, how our memories transform over time.

His main findings, published in the Journal of Neuroscience, suggest that over time, our memories about specific events transform from being highly detailed to limited to only pertinent information. Adam explains, “If you went to a grocery store, you tend to remember details such as the store layout or employee names; yet, with time, these memories become broader, such as ‘the store sells fruit’.” Adam believes

this process of memory transformation “enhances new learning in constantly changing environments; enabling us to forget specific details that are potentially irrelevant, and remembering more general knowledge that is more broadly applicable to the tasks we may face in the future.”

It was at the mid-point of his Ph.D. that he became intrigued by the possibility of incorporating computational approaches to his study of the brain. This interest was sparked by Dr. David Marr, a highly influential neuroscientist, who introduced a framework for understanding intelligent systems by examining them from a computational level. This led to deeper theoretical questions: for instance, what qualities define an intelligent system.

Adam was motivated to learn more about

FUTURE DIRECTIONS intelligent systems, and how research on the human brain can shape how we design an intelligent system. “Be a lifelong learner and keep learning and reading about anything that interests you,” Adam advises. After completing his Ph.D. in 2015, Adam began to work for DeepMind, which aims to design intelligent systems that can help us understand human behavior and intelligence.

Learning about deep learning at DeepMind

Based in London, UK, DeepMind was founded in 2010 and later acquired by Google in 2014. Employing over 500 scientists, engineers, and administrators, their overall mission is to create intelligent systems that can solve problems. Adam finds many similarities between working at DeepMind and his experience in graduate

‘machine learning,’ which describes the ability of programs to learn from their environment and improve their abilities at performing a task in the future. Each machine learning-based system consists of a neural network capable of converting an input (e.g. pixel values of an image) into an output (e.g. label as cat). This neural network is reminiscent of the human brain, which consists of layers of neurons that sequentially process data and produce a specific output. It is this layer-based machine learning, referred to as deep learning, that enables these artificial neural networks to be powerful problem-solvers by collecting and using data to train themselves into an intelligent system. Adam is currently working on relation reasoning, a key aspect of an intelligent system, which is the ability to

“As more people join this AI movement, we are one step closer to creating a world reminiscent of the sci-fi movies we have all watched in awe.” school, including the proposing, planning, and execution of experiments, analysis of data, and writing papers. DeepMind has received global attention for creating AlphaGo, the first computer program to defeat a professional player in the classical board game Go; in fact, AlphaGo defeated the game’s world champion, Lee Sedol.

This game presented great challenges for AI programs to successfully outplay a human, underlying the magnitude of DeepMind’s achievement in developing the AlphaGo. The key feature of DeepMind’s technology is that their system is not programmed for specific tasks, but can learn from experience: for instance, allowing it to learn and play different games. This process is referred to as reinforcement learning. This process of learning falls under the concept of

make sense of the interactions between objects or entities. Published earlier this year, Adam’s research describes a relation networks algorithm, a specific deep learning algorithm that enables programs to assess the relations between objects. For example, the algorithm may compare the size of an object to that of a collection of other objects.

Notwithstanding the immense potential for AI in diverse applications such as self-driving cars, medical diagnostics, healthcare, and more, there are some who see potential pitfalls. Stephen Hawking proposes that programs superior to the human mind pose risks, from the loss of jobs due to automation to global security.

Adam and many others in the field assure us that the best minds in the world are pondering these potential pitfalls. For

example, in conjunction with Apple, Google, Amazon, Facebook, IBM, and Microsoft, DeepMind founded Partnership in AI, an organization devoted to ensuring that AI is used to benefit society. Acting in the public’s interest, this organization educates the public on the progress of AI and leads a dialogue on best practices in its implementation.

Across the abyss of scientific disciplines: AI

Transitioning from your current research discipline into another field can be daunting. Adam felt that his transition from academic neuroscience to the computer science industry presented a steep learning curve and required a lot of self-learning, especially in programming. “A good Ph.D. experience involves getting thrown into the deep end and not drowning,” Adam reflects on his experiences in graduate school. He believes that if you are really interested in something, you should pursue it. “Do not consider your Ph.D. as a path to becoming an expert on a random molecule that only three people in the world know about; your Ph.D. is a sandbox for scientific thinking, where you learn how to think about problems and how to answer them.”

Adam and many others are convinced that the field of AI and machine learning is gradually becoming embedded into many disciplines of medical research, such as the diagnosis of rare diseases using a facial recognition AI software. Adam believes it is possible for anyone to build and train a neural network with a little bit of programming, linear algebra, and calculus.

There is also open-source software, such as Google’s TensorFlow, that allows beginners to explore machine learning. His advice to the IMS community: “Don’t shy away from quantitative methods; machine learning and AI are already influencing analyses in many scientific fields, and their influence is only going to grow stronger.” As more people join this AI movement, we are one step closer to creating a world reminiscent of the sci-fi movies we have all watched in awe.

IMS MAGAZINE FALL 2017 CANCER THERAPEUTICS 27

STUDENT SPOTLIGHT

SPOTLIGHT ON

MELISSA POLONENKO Listening & Learning about Audiology Research

By Arpita Parmar

Melissa Polonenko, an audiologist and PhD candidate at the Institute of Medical Science (IMS), comments on her journey as a clinician-scientist with an insatiable curiosity for research.

M

elissa Polonenko, an audiologist and PhD candidate at the Institute of Medical Science (IMS), comments on her journey as a clinician-scientist with an insatiable curiosity for research.

Melissa began her training as an undergraduate student at the University of Western Ontario, where she completed a degree in Medical Sciences with specializations in physiology and biochemistry.

Inspired by an undergraduate psychology course on human sensation and perception, she decided to volunteer at the National Centre for Audiology (NCA), where research in both basic science and clinical hearing is conducted. At the NCA, she worked in multiple audiology clinics.

But, her interest in pediatric populations made the Child Amplification Lab most memorable. In explaining her interest, she says, “Hearing is very important in children, especially in the early years as it strongly linked to speech and language development.”

After her initial experience in audiology, Melissa decided to pursue a Master’s degree in audiology and gain more clinical experience as an audiologist at the Glenrose Rehabilitation Hospital in Edmonton, Alberta. She was excited about the big move out west, where she could pursue her outdoor hobbies of hiking, 28 | IMS MAGAZINE FALL 2017 CANCER THERAPEUTICS

outback camping, and whitewater rafting in addition to being surrounded by the Canadian Rockies. At the Glenrose Rehabilitation Hospital, Melissa’s patients ranged from babies to adults. Working in a multi-disciplinary team, her roles included diagnosing hearing loss, managing hearing aids, providing patient care through telehealth, conducting hearing, vestibular, and evoked potential tests as well as adult cochlear implant candidacy assessments.

After three years of being fully immersed in a clinical setting, Melissa decided to shift her focus to research and embark on a journey as an audiologist-scientist.

Melissa decided to move back to Ontario to complete her doctoral training at the IMS, “Toronto is a clinical research powerhouse. There is plentiful stimulating research happening in one concentrated area.” She currently works under the supervision of Dr. Karen Gordon, an IMS faculty member that is also an audiologist by training. In explaining her choice, Melissa states, “The IMS [is] an ideal fit for someone training as a clinician-scientist.”

To support her learning and help contextualize her research more broadly, Melissa is also enrolled in the Collaborative Program in Neurosciences (CPIN).

At the Hospital for Sick Children (SickKids), Melissa is a part of an inter-disciplinary team of otolaryngologists and audiologists within the cochlear implant program. She collaborates on several unique clinical projects that aim to integrate both clinical and basic research in audiology to augment patient outcomes.

This is, in part, an ongoing goal of her research that focuses on how asymmetric hearing, or differences in hearing ability across one’s ears, affects brain development. “Back in the day, if you were bilaterally deaf (deaf in both ears), you

would only get one implant. The problem with this is that your brain reorganizes to preferentially respond to sounds from the one ear in which you have hearing.”

However, the ability to hear with both ears is imperative, particularly in children.

They are most vulnerable to the adverse effects of asymmetric hearing due to the influence of hearing on brain and psychosocial development.

Melissa explains that relative to those with bilateral hearing, children who are only able to hear through one ear have impaired school performance. This is in part due to their effort in trying to hear what is being said rather than learning and understanding the message being communicated. Dr. Gordon’s research recommends giving bilateral implants to pediatric patients at the same time or at least 1.5 years apart.

Staying within this time is necessary for the implants to facilitate bilateral auditory development. “If a second implant is given to a teenager who has experienced years [of unilateral deafness], the brain will respond abnormally to the sounds being heard from the new cochlear implant— as if it doesn’t know what the sound is, (since) it has been deprived for so long,” Melissa explained. Their ongoing research has contributed to Sick Kids refining their criteria when determining which children can receive a cochlear implant.

As part of her thesis, Melissa studies the changes occurring in children with unilateral deafness after receiving a cochlear implant in the impaired ear. She is interested in how the cochlear implant, which sends electric pulses that stimulate the cochlear nerve, integrates acoustic hearing from the ear without a cochlear implant. More importantly, she desires to identify how this combined electro-acoustic hearing affects various outcomes, such

STUDENT SPOTLIGHT

Photo by Mikaeel Valli

Melissa Polenenko, PhD Candidate

as brainstem and cortical development, speech, behavior, and even music perception. Melissa’s project started off with 10 children, but now has over 100 participants. As Melissa’s research indicates that bilateral hearing in early childhood affects the mapping of auditory input in the brain and influences the development of speech, language as well as balance, she now studies how brains accept and integrate hearing from pairs of cochlear implants after initially experiencing unilateral deafness.

When reviewing her research experience at Sickkids, Melissa highlights the gift of having an ethnically diverse and clinically heterogeneous study population. In addition, as she follows the development of

these children over several years, Melissa has a gratifying and rewarding opportunity to see how things change (and improve) over time. She comments, “The families are very grateful for our program at SickKids and tell us how much their child loves their new implant.”

Melissa also explains how her clinical experience as an audiologist, prior to pursuing her PhD, was very helpful. It let her apply technical expertise and knowledge of clinical assessment tools to inform the direction of her research. Additionally, she describes the immense value of having worked with families and children in her past, as “knowing how to interact with

children can make or break data collection in pediatric research.” Furthermore, when asked about her advice to future and current graduate students, Melissa stresses the importance of being open-minded and exploring different possibilities: “Always ask questions, you never know what you will discover. And don’t be afraid to put the work in.”

IMS MAGAZINE FALL 2017 CANCER THERAPEUTICS 29

BMC FEATURE

Master of Science in

BIOMEDICAL COMMUNICATIONS

Lisa Qiu, 1T8 I began to cultivate my skills at The Academy of Realist Art in Toronto from the age of 11 and graduated recently. Meanwhile, I continued to pursue the sciences, completing my undergraduate studies with a specialist in Laboratory Medicine & Pathobiology at the University of Toronto.

Throughout this time, I was keen on using science to make a difference but often found myself to be most communicative and useful through application of my artistic skills. As these two distinct interests continue to diverge throughout my schooling, I was fortunate to learn about the Biomedical Communications program. I am honoured and ecstatic to now be a member of a community of such talented and driven individuals from whom I have much to learn. Already, I feel I have made the right choice for me and foresee a lifetime of fulfillment!

30 | IMS MAGAZINE FALL 2017 CANCER THERAPEUTICS

Chelsea Canlas, 1T8 Shortly after my graduation, I worked as a graphic communications designer and worked on many projects, including creating print and environmental graphics for cultural institutions. Although I had found the work interesting, I felt the most fulfilled creating conceptual diagrams and illustrations for science museums. I enjoyed the challenge of taking complex ideas and finding an engaging and universal solution that can be communicated to all audiences. With this realization, I took a leap of faith and went back to school to further my science education.

Now as a student of the BMC program, I am so honoured to be a part of a community of scientists, artists and innovative thinkers. My goal is to create opportunities for others to be curious and constantly learn, and ultimately advance the public’s education of health and medical science.

IMS MAGAZINE FALL 2017 CANCER THERAPEUTICS 31

VIEWPOINT

The deadly

truth behind

alternative

cancer

therapies By: Chantel Kowalchuk

C

ancer is terrifying. We are all aware of the physical, emotional, and mental exhaustion that comes with cancer, either through firstor second-hand interaction with this awful illness. Unfortunately, some of that physical and emotional burden is not due to cancer itself, but is instead related to the treatments.

Chemotherapy, radiation, and surgery are some of the most common treatments for cancer, and though they have definite therapeutic efficacy, they frequently result in terrible side effects such as nausea, hair loss, and fatigue. To make matters worse, those treatments are not effective for all patients, resulting in exposure to the trauma of the treatments and their 32 | IMS MAGAZINE FALL 2017 CANCER THERAPEUTICS

side effects without achieving the desired outcome. Wouldn’t it be nice if there were therapies that could cure cancer, without any side effects or trauma? Well, there are!

At least, so say the websites of the health professionals found through a simple Google search of “alternative cancer therapies”.

Reading about alternative cancer treatments online, it is easy to be amazed by the variety of treatments available that apparently cure cancer. Vitamin C, specific diets, probiotics, sunshine, and turmeric are all treatments described on one website that discusses natural cancer treatments and claims to have 15 million monthly visitors.1 A Google search for “alternative cancer therapies” results in

some poorly made webpages full of sensational writing, strongly indicating they are scams. Yet alongside these are legitimate looking websites including statements from doctors and health professionals, which explain that these alternative treatments will cure cancer.

These claims are backed up with a bevy of patient testimonies and scientific sounding explanations, with the perfect combination of scientific terminology and buzzwords. Some of these claims even cite scientific papers (though these papers are predominantly published by the same groups selling the treatments, and have small sample sizes). It is understandable how, particularly in a vulnerable state, one could believe these claims.

VIEWPOINT

“Health practitioners need to be proactive and educate patients on the potentially deadly consequences of choosing alternative therapies.”

However, believing those claims can turn a potentially treatable disease into something unmanageable, waste valuable time, and eventually cost a life, according to a recent study from the Yale School of Medicine.2 The data on efficacy of alternative medicine is minimal, so a group of researchers in the lab of Dr. James Yu took it upon themselves to determine if there were actually any therapeutic benefits from alternative medicine. They followed 281 cancer patients who chose to undergo only alternative treatments, and matched them to 560 patients who opted for traditional treatment. Perhaps unsurprisingly, patients who chose alternative medicine had a significantly higher risk of death compared to conventional cancer treatment. The most dramatic risk was in women with breast cancer, where choosing alternative treatment put them at a fivefold increased risk of death.2 Opting for alternative treatment is not a rare decision among patient populations.

In addition to the aforementioned study from Yale, which followed 281 patients who had opted for alternative treatments2, a study from one Norwegian hospital found that 20% of its cancer patients chose alternative treatments,3 while researchers from Alberta found that 1 in 100 breast cancer patients choose alternative treatments.4 A variety of reasons could lead a person to choose alternative therapies, such as fear, trust in anecdotal evidence (we all have a friend’s brother’s teacher who was cured by meditating with crystals), high costs of conventional treatments, hatred of “big pharma”, or belief in a cancer conspiracy. Furthermore,

treatments such as vitamin C and turmeric, which are familiar and a part of our daily lives, are easier to understand and less intimidating than radiation and radiotherapy. However, misinformation or lack of information for the patient remains an underlying issue that can lead patients to choose life-risking alternative cancer therapies.

Everyone is entitled to their own choices about their health; however, these choices must be educated choices, based upon the correct and comprehensive information on treatment options, side effects, alternatives, and risks. Everyone should have the right to make informed decisions, and the current state of cancer treatment and patient education does not provide that opportunity. There is not enough research in the field of alternative cancer therapies to conclude they should be completely disregarded; currently, while it is not legal to sell a product claiming to specifically cure cancer, it is legal to can make implicative statements, such as a product which “activates the body’s ability to heal itself ”, and support this with anecdotal evidence. The FDA has issued over 90 warning letters to companies marketing cancer cures over the past 10 years, 14 issued within their most recent 2017 report.5 Yet there are plenty of companies that continue to promote their products as cancer cures, thanks to the Internet and social media.

These alternative treatments are not going anywhere.

both the risks and rewards viewpoint.

Health practitioners need to be proactive and educate patients on the potentially deadly consequences of choosing alternative therapies. It is essential that patients can understand the difference between science-based medicine and anecdotes, the placebo effect, and the risks of relying on the Internet as a primary source of health-related information. Once all that information is given to the patient, then the choice is truly theirs. Hopefully, they will choose evidence-based medicine, supported by controlled clinical trials and statistical significance; if they continue to opt for alternative therapies, that is their prerogative. Regardless, a patient should not make a choice which could determine life or death without knowing all the facts.

A licensed physician needs to be the one to provide that information, not Google.

References

1. Dr. Axe. 10 Natural Cancer Treatments Revealed [Internet]. [cited 2017 Sep 7]. Available from: https://draxe.com/10-natural-cancertreatments-hidden-cures/ 2. Johnson SB, Park HS, Gross CP, Yu JB. Use of Alternative Medicine for Cancer and Its Impact on Survival. JNCI J Natl Cancer Inst [Inernet]. 2018 Jan 1 [cited 2017 Sep 7];110(1):54–71. Available from: http://academic.oup.com/jnci/article/doi/10.1093/jnci/ djx145/4064136/Use-of-Alternative-Medicine-for-Cancer-and-Its 3. Risberg T, Kaasa S, Wist E, Melsom H. Why are cancer patients using non-proven complementary therapies? A cross-sectional multicentre study in Norway. Eur J Cancer [Internet]. 1997 Apr [cited 2017 Sep 7];33(4):575–80. Available from: http://www.ncbi. nlm.nih.gov/pubmed/9274437 4. Blackwell T. Cancer patients are losing valuable time — and risking their lives — with alternative therapies, doctors say. National Post [Internet]. 2015 Nov 15; Available from: http://nationalpost.com/ health/cancer-patients-are-losing-valuable-time-and-risking-theirlives-with-alternative-therapies-doctors-say 5. Commissioner O of the. Press Announcements - FDA takes action against 14 companies for selling illegal cancer treatments. [cited 2017 Sep 7]; Available from: https://www.fda.gov/NewsEvents/ Newsroom/PressAnnouncements/ucm554698.htm

Thus, the responsibility falls to the doctors and health practitioners to ensure their patients adequately understand why they suggest a specific treatment, from IMS MAGAZINE FALL 2017 CANCER THERAPEUTICS 33

VIEWPOINT

The Collaborative Care Model:

Strength in unity By: Stephanie Beldick

M

edical specialties are currently structured to provide patients with specialized care within a focused healthcare arena, leading to the compartmentalization of responsibility between different physicians. Targeting this fragmentation, collaboration amongst specialists is becoming increasingly recognized as the solution. However, to date, there has been limited adoption across the country, especially in smaller centres. As a result, this article seeks to explore the benefits and caveats of collaborative care as well as the challenges in its implementation into medical practice and the Canadian healthcare system.

Through the timely cooperation and teamwork of multiple healthcare specialists, collaborative care aims to provide population-based and patientcentered treatment. In Ontario, this usually takes its form through letters of communication between a patient’s primary care physician and the specialists to whom they are referred. Yet, with a rise in multiple chronic comorbidities and an aging population, there is a need for large-scale implementation of integrated care. Importantly, large institutes, such as the University Health Network, which have the capacity to implement this 34 | IMS MAGAZINE FALL 2017 CANCER THERAPEUTICS

approach, have made strides towards collaboration, specifically by establishing polyclinics. Similarly, telemedicine is also gaining popularity for cross-centre care.

Nevertheless, despite the success, these strategies remain largely absent in most community settings across the country.

Numerous clinical trials have shown the effectiveness of the collaborative care model.1 Chronic conditions, such as cancer, diabetes, and vascular diseases provide poignant examples of the instrumental role of this approach.

As these conditions are frequently associated with depression and anxiety that worsen patient outcomes, there are striking improvements when primary care providers work closely with teams of nurses, social workers, and psychiatrists.2-3 Not only does the collaborative care model positively impact health outcomes, but it also reduces long-term healthcare costs. Patients with diabetes and/or coronary heart disease with comorbid depression benefit from more depressionfree days and an increased number of quality-adjusted life years (QALYs) when an ongoing rapport with a nurse care manager is maintained.4 Moreover, given that sustained depression in this cohort of patients has been shown to lead to

vascular complications and dementia, the collaborative care model is also costeffective beyond the time of intervention.4 Acknowledging the benefits of collaborative, patient-centred care to patients and communities, medical teaching centres are at the forefront of implementing this model. These innovative centres practice a holistic and unified approach to teaching communication and teamwork. An excellent example is the St. Michael’s Family Health Team, which consists of multiple healthcare specialists, including physicians, chiropractors, psychologists, and acupuncturists.5-6 Together, this strategy provides a platform through which patients benefit from comprehensive care, in addition to training healthcare providers to be members of an interdisciplinary team.

The benefits of the collaborative care model are not, however, ubiquitous. One randomized trial sought to implement the model to improve outcomes in patients with childhood asthma, but failed to show a significant difference between the collaborative care model and the standard care group. The authors suggested that the nonsignificant result could stem from insufficient participation in workshops by patients and families, along with various

VIEWPOINT

other site-specific and administrative discrepancies.7 Similarly, a study by Katon et al. (2012) showed that comorbid depression was reduced in patients with diabetes and/or coronary heart disease, while other clinical measures such as hemoglobin A1C, systolic blood pressure, and low-density lipoprotein cholesterol levels did not differ between the groups after 12 months. 4 While these studies’ findings indicate that the collaborative care model is not universally beneficial across all health outcome measures, it has been shown as an overall effective approach at reducing healthcare costs and improving patient quality of life.2,8-9 Indeed, there are barriers to promoting a broader implementation of the collaborative care model. Added shortterm costs can create an economic burden on the public healthcare system, as demonstrated in a study from Johnson et al. (2016) that assessed the cost-effectiveness of collaborative care in patients with depression and type 2 diabetes. However, the increase in shortterm costs was compensated for by the increase in QALYs that resulted from team-based monitoring and increased follow-up care.10 The way that the model is implemented across centres may

present another hurdle, thereby limiting the efficacy. Governmental resources to support the programs will need to be allocated appropriately and consistently in order to establish structured and successful collaborative care models.

Canada is certainly on its way toward a universal collaborative care model, however, there is still some work to be done. As a community, we need to continue supporting this approach by encouraging its continued incorporation into healthcare education and funding programs that will help to make it easier for current clinicians to participate in team-based practice. Potential benefits of the collaborative care model are the longterm cost-effectiveness and improved health outcomes, which are enhanced through communication among various specialists, access to holistic care, and encouraging patients to take an active role in their own care. It is evident that the collaborative care model is strengthening medical practice and patient care, and while the Canadian medicine has taken steps toward a more unified system, improvements to implementation will be necessary

References

1. Summers RF. Integrated behavioral health care and psychiatric training. Academic Psychiatry. 2015 Aug 1;39(4):425-9.

2. Ivbijaro GO, Enum Y, Khan AA, et al. Collaborative care: models for treatment of patients with complex medical-psychiatric conditions. Current psychiatry reports. 2014 Nov 1;16(11):506.

3. Huffman JC, Mastromauro CA, Beach SR, et al. Collaborative care for depression and anxiety disorders in patients with recent cardiac events: the Management of Sadness and Anxiety in Cardiology (MOSAIC) randomized clinical trial. JAMA internal medicine. 2014 Jun 1;174(6):927-35.

4. Katon W, Russo J, Lin EH, Schmittdiel J, Ciechanowski P, Ludman E, Peterson D, Young B, Von Korff M. Cost-effectiveness of a multicondition collaborative care intervention: a randomized controlled trial. Archives of general psychiatry. 2012 May 1;69(5):506-14.

5. Innovative program at St. Mike’s integrates chiropractic care.

Hospital News, cited 2017 Oct 6. Available from: http:// hospitalnews.com/innovative-program-at-st-mikes-integrateschiropractic-care/ 6. Koehler G. St. Michael’s chosen by WHO as example of integrated and people-centred health care. St. Michael’s Newsroom, 2016 June 3, cited 2017 Oct 6. Available from http:// www.stmichaelshospital.com/media/detail.php?source=hospital_ news/2016/0603a 7. Homer CJ, Forbes P, Horvitz L, et al. Impact of a quality improvement program on care and outcomes for children with asthma. Archives of pediatrics & adolescent medicine. 2005 May 1;159(5):464-9.

8. Duarte A, Walker J, Walker S, et al. Cost-effectiveness of integrated collaborative care for comorbid major depression in patients with cancer. Journal of psychosomatic research. 2015 Dec 31;79(6):465-70.

9. Sockalingam, S., Mulsant, B. H., & Mylopoulos, M. (2016).

Beyond integrated care competencies: The imperative for adaptive expertise. General hospital psychiatry, 43, 30-31.

10. Johnson JA, Lier DA, Soprovich A, Al Sayah F, Qiu W, Majumdar SR. Cost-Effectiveness Evaluation of Collaborative Care for Diabetes and Depression in Primary Care. American journal of preventive medicine. 2016 Jul 31;51(1):e13-20.

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VIEWPOINT

Debating the Proposed Tax Changes Made by the Federal Government By : Cricia Rinchon

T

he Institute of Medical Science (IMS) is known for its doctoral research stream, but an up-andcoming program is the Translational Research Program (TRP). The TRP targets students aiming to integrate their domain expertise with projects that emphasize experiential learning and translational thinking. It offers modules such as Intellectual Property Foundations, Translation Thinking, and Health Economics. As an IMS student, I had the privilege of taking the Health Economics Module, coordinated by Dr. Tatiana Lomasko, CEO and founder of Science to Business New Zealand and Science to Wellness New Zealand. The module had an intimate class size of 20 participants.

Throughout the module, we were introduced to the fundamentals of economics and economic analysis, and the interplay between economics and evaluation in health care policy.

We applied these principles in an entrepreneurial scenario. Equipped with this knowledge, our challenge for the final class was to work as a group to present on a topic of our choice and facilitate a subsequent class discussion.

One group decided to discuss the proposed tax changes made by the Federal Government towards private corporations.

In brief, on July 18, 2017, the Canadian Federal Department of Finance released its proposals for tax reforms that apply 36 | IMS MAGAZINE FALL 2017 CANCER THERAPEUTICS

to private corporations. The aim of these reforms are to tighten loopholes for the wealthy. The proposed rules identified in Budget 2017 by Finance Minister Bill Morneau will: 1. limit sprinkling income using private corporations, 2. prevent holding a passive investment portfolio inside a private corporation, 3. restrict the conversion of a private corporation’s regular income into capital gains.

Incorporation is the legal process used to form a corporate entity or company, and two-thirds of practicing members of the Royal College of Physicians and Surgeons of Canada (Royal College) in Ontario are incorporated.

Of note, income sprinkling is a prominent loop hole. Income sprinkling is described as a tax-planning arrangement resulting in income that, in the absence of the particular arrangement, would have been taxed as income of a high-income individual, but is instead taxed as income of another lower-income individual, typically a family member of the highincome individual. The effect of the arrangement can be to have income subject to a lower effective income tax rate. Income sprinkling is advantageous to high-income individuals, in particular the principals of private businesses, as they can ‘opt out’ of all or part the progressivity

of the personal income tax system to their own benefit. For example, two neighbours living and working in Ontario can each earn $220 000 in 2017. Neighbour #1 is an employee of a mid-sized company, and Neighbour #2 is the owner of an incorporated consulting business and works from home. Neighbour #1 pays $79 000 in income tax for the year. On the other hand, the owner of the incorporated consulting business paid $44 000 in income taxes due to income sprinkling.

The government believes that this $35 000 difference is “fundamentally unfair” and erodes the tax base and the “integrity” of the tax system.

If the legislation passes with the addition of Mr. Morneau’s recommendations, owners of professional corporations, specifically doctors and dentists, will feel the most acute tax-planning pain due to their reliance on income sprinkling. The Ontario Medical Association (OMA) once negotiated the right of its members to incorporate, and recent negotiations resulted in the government committing to share structure of physician professional corporations to include non-voting shares for family members. Thus, these changes may have a huge negative impact on Ontario healthcare, as this law could discourage physicians from practicing in Canada, expanding clinical services, and hiring new staff. All these lead to increased waitlist times.

VIEWPOINT

“Healthcare is integral to the machinery of any society and one of the top priorities.”

Moreover, the government wants to tax investment income generated savings held within private corporations in an equivalent manner to savings held directly by an individual. It believes that it is unfair that corporate owners have more money left to invest after paying taxes on income than individuals. Corporate active business income is taxed in Ontario at 15% up to the $500 000 small business limit, and at 26.5% above that limit (vs.

53.3%). The removal of the corporation’s ability to be paid refundable taxes upon the distribution of the passive investment income in dividends results in an effective rate of tax upon the passive investment income of 73%. This government’s proposal to change the taxation of passive investment income within private corporations will affect the vast majority of doctors, and they use their professional corporation to save income for retirement.

These changes will significantly reduce the amount of investment income available to incorporated members to fund their retirement.

While these amendments are targeted at small business owners, it is important to note that small business owners invest capital, take risks to earn income, and have no job security. Rather, small business owners have 3-4 individuals depending on them to provide work. Employed individuals who are paid salary do not share in this risk-taking, and they receive

the aforementioned benefits. In this way, the OMA does not believe it is appropriate or justified to tax small business owners in the same fashion as employed individuals.

Importantly, doctors are a unique cohort of small business owners who often accumulate more than $250 000 in student debt, have fixed billable rates controlled by the government, and whose services directly affect the health and lives of individuals.

According to a survey from Concerned Ontario Doctors, 85% of respondents reported that these proposed tax changes will force them to change how they practice medicine: 11% plan to leave Ontario, 21% plan to leave Canada, 26% plan to retire earlier, and a shocking 11% plan to leave medicine entirely and re-train for a new career. Moreover, of the 31% of Ontario doctors who plan to stay in Canada, many plan to reduce working hours (75%), reduce patient services (55%), reduce OHIP services (68%), and lay-off staff (39%). For the doctors remaining, this will likely exacerbate burnout rates, increase waitlist times, and discourage expansion of clinic services and hiring new staff.

best solution to tackling governmental problems. Instead, we need to view healthcare in Canada not as a zero-sum game, but as an opportunity to innovate win-win solutions for both physicians and non-physicians. Government spending can be reduced in less important areas in order to reduce governmental budget deficits.

Healthcare is integral to the machinery of any society and one of the top priorities.

Tampering with its core workers will always cause disagreement and conflict.

Simultaneously, government officials should investigate in greater depth to ensure that all incorporations under physicians are performed with ethical intentions. Any attempts at tax dodging, sheltering, or unreasonable acts of economic gain using the advantage of incorporation should be halted.

Streamlining healthcare services–through research, automation of menial tasks, and financial compromise between business owner and government–lies in the future.

Physicians and the government need stronger members to act as liaisons between the two groups and develop a more ethical method of austerity.

Perhaps directly affecting the tax rate of small businesses everywhere is not the IMS MAGAZINE FALL 2017 CANCER THERAPEUTICS 37

IMS NEWS

Summer Student

Excellence at SURP Research Day 2017 T

By: Tahani Baakdhah

he 41st annual Institute of Medical Science (IMS) Summer Undergraduate Research Program (SURP) Research Day was held on August 15th, 2017. This prominent program, with growing international presence, brings together undergraduate and medical students to learn, explore, and exchange scientific knowledge. In a supportive and stimulating environment, students were given the opportunity to interact with highly qualified investigators on diverse subjects, including molecular biology, cognitive science, clinical investigation, and bioethics. Following the success of this year’s Research Day, I had the

Photo by Priscilla Chan

Photo by Priscilla Chan

38 | IMS MAGAZINE FALL 2017 CANCER THERAPEUTICS

opportunity to interview Dr. Vasundara Venkateswaran for insights about the program, mentorship, and event highlights. Dr. Venkateswaran is an Associate Professor at the Department of Surgery (Urology) and, among her many other roles, she is the Director of the IMS SURP. When asked about SURP, Dr. Venkateswaran enthusiastically states that “directing the program for 7 years has been a great experience and I was extremely excited to see another batch of enthusiastic students participate in our summer research program this year.”

The program, which begins in June, had 91 students this year and each spent their summer working on research projects in laboratories across the various affiliated and teaching hospitals in Toronto. This also gave them the chance to participate in individual laboratory meetings, analyze data, present at journal clubs, and even attend clinical research rounds.

To complement the students’ research, the IMS held weekly lectures, which included research presentations by IMS faculty, graduate studies information sessions, and workshops on practical skills. After three months of hard work, the students had the opportunity to present their research findings through podium or poster presentations at the SURP Research Day on August 15th.

According to Dr. Venkateswaran, this year’s success was most evident through the students’ enthusiasm, excitement, and their confidence while showcasing

IMS NEWS

their results as well as in answering the challenging questions posed by the judges.

Dr. Cindi M. Morshead, Professor and Chair of the Anatomy Division at the University of Toronto, was this year’s keynote speaker. As Dr. Morshead obtained her PhD at the University of Toronto, under the supervision and expertise of Dr. Van Der Kooy, it was especially inspiring to hear about the exiting work and success of alumni. The talk was titled, “Activating resident neural stem cells to promote repair: A stroke of genius”.

The afternoon session involved engaging poster presentations, awards, and concluding remarks by Dr. Mingyao Liu, Director of IMS. The oral presentation award was received by Reha Kumar and the honorable mention to Sebastian Acosta. As posters were organized into groups, the best candidate in each group was awarded a poster prize, including Sylvia Almeida, Priscilla Chan, Saly Halawa, Jessica Johns, Lior Levy, Zijian Lou, Joelle Soriano, Jaya Tanwani, Simone Valade, and Sunny Zheng. The honorable mentions for the posters include Zachary Blatman, Emaan Chaudry, Ryan Gotesman, Shaun Hanycz, Richard Li, Michael Mehta, Isabel Shamsudeen, Gaurav Talwar, Tony Yao, and Shatabdy Zahid. All students received a certification of participation on the successful completion of the Summer Program.

“... brings together undergraduate and medical students to learn, explore, and exchange scientific knowledge.”

At the end of the Research Day, Dr. Venkateswaran congratulated the summer students on their research achievements, wishing them the very best in all their future endeavors. She also thanked all the supervisors for their invaluable efforts in providing students with the environment, motivation, and guidance in their research. In addition, she sent her sincere appreciation to all the funding partners, the faculties, and students who served as speakers and judges at the Research Day. Overall, it was another successful SURP summer.

Photo by Priscilla Chan

Photo by Priscilla Chan

IMS MAGAZINE FALL 2017 CANCER THERAPEUTICS 39

Tips for Surviving Graduate School Cooling weather, colorful leaves and the sudden addition of pumpkin flavoring into food—some of hallmarks of Fall—indicate the start of a new academic year. With this in mind, the IMS Magazine reached out to the student community seeking tips and advice for new graduate students. Here are some of our favorites:

@thepurplelilac 1. Be social, start twitter or instagram accounts to share your science journey with others.

2. Take your time designing your

Brahmdeep Saini

It’s all about finding your passion. Every morning when you wake up, you should be excited to discover something new or different. Be persistent and never stop rediscovering and redefining yourself and your goals.

experiment. Make sure you have all the reagents, protocols and clear objectives/questions.

3. Try to be organized. Write everything

you do in your lab notebook because you will certainly forget after few days.

4. It’s ok to take time off the lab to recharge and relax.

5. Join student associations, groups on-campus and online.

@melissa_Galati Side hustles like the @IMSMagazine & @rawtalkpodcast. #scicomm is a great way to come back to your work with fresh eyes & prevents burnout!

@an_ekat #scicomm is a great way to find a supportive community who’ll see you through those #gradschool woes!

40 | IMS MAGAZINE FALL 2017 CANCER THERAPEUTICS

@Archakravarthy

1. Find other PhD student friends, find an advisor you get along with, and ultimately realize there will invariably be ups and downs.

2. Knowing there will be rough periods in

advance can reduce stress from feeling like an impostor when things are looking down.

3. Also imperative that the thesis project is

something you enjoy; long term interest makes for better motivation during rough patches.

@staninscience

1. Stay even keeled - learned this fro m my

supervisor. Don’t let success/failures take your emotions for rides.

2. You will fail more than you succeed in with your

work, the idea is to learn from them - it’s also the training, not just the paper.

3. Set small goals that build up towards a bigger picture. Be a visionary.

4. Be proud of your work, but also be super @AnnaBadner

I pick a conference every year & use it as my motivation!

@usmansaeed71

Stay organized.

Set priorities, as needed. We all are dedicated, but remember that a healthy work and life balance is just as important.

rigorous. It’s not just about your success in medical research, your work matters.

5. Don’t be selfish and be responsible. Your work may give leads for future work in your field.

Crappy work gives crappy leads.

6. Read a ton. The point of graduate school is that

you become an expert at your field. Don’t be wishy-washy. Do it well and do it thoroughly.

You’re not just being evaluated by your advisors, but also evaluated by the public.

7. i.e Your work can be done mostly because of

public funding. Be responsible with that. Also your resp. to educate the public.

8. Respect others and don’t compare your CVs. Science can be a competition for jobs, but it works best in collaboration.

9. Work with others to advance the field. @criciarin

Remain curious: about your thesis topic, field as a whole, and endeavours outside of academia.

10. Ask questions & a lot of them. The chances are, no one knows the answer yet, so explore it.

11. Be honest with your advisor/supervisor. Clear communication about your goals, project, etc is so important as a graduate student.

12. Have fun! If you don’t enjoy it, your work will be crappy. Be passionate with your work.

Rigorous and passionate!

IMS MAGAZINE FALL 2017 CANCER THERAPEUTICS 41

BOOK REVIEW

The

BEAUTY of

Discomfort

By Beatrice Ballarin

I

picked up The Beauty of Discomfort: How What We Avoid Is What We Need by Amanda Lang at Indigo one evening after a long day at the laboratory with discouraging results. The aptly titled book intrigued me, for its proposition of beauty in discomfort offered a comforting perspective on my current circumstances.

Could discomfort be a part of one’s path to success?

Chronicling the experiences of business founders, university students, elite athletes, meditation gurus, and military leaders, The Beauty of Discomfort showcases failures of people from all walks of life and, astonishingly, frames them as opportunities for personal growth and development. In doing so, it not only calls for the readers to stop avoiding failure, but inspires them to embrace and even benefit from it.

“You need to confront discomfort and view it as a helpful reminder to prepare properly, rather than a signal to quit.”

This message resonated in my mind as I reflected on the examples presented in the book, and I began to wonder: why are some people able to adapt and thrive in the face of a challenge, while others succumb to the pressure?

To take it one step further, the book encourages readers to not just embrace 42 | IMS MAGAZINE FALL 2017 CANCER THERAPEUTICS

failure, but to seek it by challenging and pushing one’s own limits. Cases in point are presented as, while some of the protagonists had no other choice than with failure, some protagonists signed up for it—being determined to achieve their goals in the face of failure. Exemplifying the incongruity between passively succumbing to discomfort and actively seeking it, the book presents stories contrasting individuals facing disease and bankruptcy to those who sought challenge in their seemingly undemanding lives. In doing so, it highlights the potential for growth unraveled when you push yourself out of your comfort zone. With these examples, the book inspires readers to push their own limits and seek challenges when feeling too comfortable with where they are. In re-conceptualizing the negative attributes of failure as avenues for positive change and resilience, The Beauty of Discomfort describes how our approach to failure can determine our potential for success.

On a more personal note, I found this book to be full of great insights that I try to apply in my daily life as a graduate student. First, I try to perceive discomfort as an opportunity for personal growth.

I practice applying this new approach to my daily routine, particularly to tasks I find unpleasant, in order to build up strength and determination without

feeling discouraged or wanting to give up. Second, I try to not take criticism personally by separating my professional and personal life. As a graduate student, much of my educational and training progress depends on receiving criticism, but dwelling on it might cause unhappiness and even distract me from my ultimate goal. Following one of my favorite examples in the book, I decided to focus on constructive criticism and use it for my personal growth and success. Third, Rome wasn’t built in a day; this book reminds me that I am here for the long run, and change doesn’t happen overnight. Pushing ourselves outside our comfort zones may indeed create discomfort, but this is short-lived and critical for achieving our long-term goals.

Perhaps the most important take-home message of The Beauty of Discomfort is one of encouragement to be brave, challenge yourself, and embrace discomfort, for avoiding it would only slow you down.

The remarkable stories of resilience and personal growth in the face of adversity highlight the value of this book in inspiring readers to learn how to grow from their struggles. When life gives you lemons, will you make lemonade?

TRAVEL BITES

Life Elevated – A Road-Trip Through Utah By: Anna Badner

Canyonlands National Park

F

rom the dramatic mountain peaks of the Wasatch Range to arid desert sand dunes, Utah encompasses natural diversity. Moreover, as a home to five national parks–specifically Zion, Bryce Canyon, Arches, Canyonlands, and Capitol Reef–Utah is a hiker’s paradise. For these reasons, I was overjoyed to discover that this year’s National Neurotrauma Symposium was to be held at the Snowbird Ski and Summer Resort in Snowbird, Utah.

Equipped with new research data and a confirmation of conference registration, I began to plan the perfect trip through the American Southwest.

Arches National Park Photo by Anna Badner

The first stop was Zion National Park.

The drive into Zion Canyon, with the flowing Virgin River and towering red rock formations at your side, presented a surreal experience. Energized by the breathtaking landscape, we laced up our hiking boots and ventured onto the Watchman Trail. This short and scenic hike was meant to prepare us for the strenuous Angels Landing trek planned for the next day. Therefore, later that evening, while watching the sunset from the Watchman peak, we felt ready for what is often referred to as “one of the most

dangerous hikes in the world”, Angels Landing. Waking up early the following morning, in an attempt to beat the heat, we headed out to climb the steep inclines and narrow switchbacks of the most popular trail in the park. Angels Landing did not disappoint. The route was challenging and the views were incredible. Nevertheless, after 5 hours in the hot sun, we were ready to move on.

Bryce Canyon National Park is just a short (1.5 hour) drive from Zion, yet the difference in the landscape is dramatic. Filled with long thin conical rock foundations, called hoodoos, Bryce Canyon feels otherworldly. After enjoying the views along various lookout points, we took the Navajo Loop into the base of the valley. The trail led us up close to the steep rocky walls and colourful hoodoos, which left a truly lasting impression. After being satisfied with our picturesque photos, we finished the day off by grabbing burgers at a nearby diner in Bryce Canyon City.

The natural red rock bridge formations, known as arches, are a crucial part of Utah’s signature landscape. Found on the state license plate, they are a representative symbol of the region. Most of these structures, including the infamous Delicate Arch, are found at Arches National Park.

The park is located just outside of Moab, a popular mountain biking hub, known worldwide for its Slickrock Trail. The contrast of petrified sand dunes against the blue sky and background of the La Sal Mountains is awe-inspiring. We soaked up the scenery along a hike on the Devil’s Garden Trail, while incessantly snapping photos of the many diverse arches throughout. Feeling exhausted after hours of rock climbing in the desert, we set our sights on the Colorado River.

We followed the Colorado River to our next destination, Canyonlands National Park. Whereas the other stops were bustling with tourists, this park was relatively peaceful and remote. Most of the canyon overlooks were accessible by car, allowing for a less strenuous day of sightseeing. The far-reaching winding roads alongside great vistas permitted selfreflection and an alternative perspective.

Before we left, we had to stop by the iconic Mesa Arch, found at the end of an easy well-maintained trail, as the remaining vastness of the park made it difficult to explore further on foot.

Zion National Park Photo by Anna Badner

Bryce Canyon National Park Photo by Anna Badner

My first tour of Utah proved unforgettable.

The stunning rock formations, hikes, and sights made it the trip of a lifetime.

The new state slogan, “life elevated”, truly embodies the experience. Knowing that I only touched upon a fraction of the area’s natural beauty, I am certain that I will return to Utah.

IMS MAGAZINE FALL 2017 CANCER THERAPEUTICS 43

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