Pathways to Discovery - Fall 2020 - UChicago Medicine Comprehensive Cancer Center

Pathways TO DISCOVERY

AT T H E FO R E F R O NT O F C A N CE R CARE AND DIS COVE RY

Translational Research Knowledge Gained in the Lab Translates to Improvements in Cancer Care FALL 2020

Pathways TO DISCOVERY

AT THE FOREFRONT OF CANCER CARE AND DISCOVERY

Fall 2020 E X E C U T I V E E D I TO R

Jane Kollmer SENIOR SCIENCE WRITER

Tiha M. Long, PhD E D I TO R I A L A DV I S O R S

Michelle Le Beau, PhD Kathleen Goss, PhD CO N T R I B U TO R S

Jennifer Allocco Emily Ayshford Kate Dohner Gretchen Rubin DESIGN

Pivot Design, Inc. PRINTING

G Thomas Partners LLC

Pathways to Discovery is a publication of the University of Chicago Medicine Comprehensive Cancer Center.

T H E U N I V E R S I T Y O F C H I C AG O M E D I C I N E CO M P R E H E N S I V E C A N C E R C E N T E R 5 8 41 S . M A RY L A N D AV E .

MC1140, H212 C H I C AG O , I L 6 0 6 3 7 P H O N E 1 -7 7 3 -70 2- 6 1 8 0 FA X 1 -7 7 3 -70 2- 9 3 1 1 F E E D B AC K@ B S D . U C H I C AG O . E D U

Š 2020 The University of Chicago Medicine Comprehensive Cancer Center.

All rights reserved.

From the Director This issue focuses on translational research and its important role in advancing cancer research. Essentially, translational researchers bring discoveries from the laboratory to the clinic.

In the laboratory setting, basic scientists seek to answer fundamental questions about the molecular and cellular events that collectively result in cancer. Translational research looks for ways to capitalize on scientific advancements made in the laboratory to develop new medical interventions for the prevention, early detection, diagnosis and treatment of cancer patients or at-risk populations. These promising new approaches are then tested through studies, in humans, conducted in the clinical setting under strict protocols for safety and ethics. If successful, the tested approach could become the new standard of care.

Translational research must happen in a highly collaborative environment, where researchers with different backgrounds share information, data and ideas. This happens often at our institution because our research labs are embedded within the medical center, allowing for easy collaboration between experts.

The stories in this issue illustrate translational research examples that begin with a key insight into the biology of human cancer and result in the identification of a new medical advancement.

Because of translational research, we are able to make efficient progress in key areas of cancer research. It is our bridge between what is possible and what can become reality.

Michelle M. Le Beau, PhD Director, The University of Chicago Medicine Comprehensive Cancer Center; Arthur and Marian Edelstein Professor of Medicine

THE JOURNEY TOWARD PRECISION NUCLEAR MEDICINE TO COMBAT CANCER

BY TIHA M. LONG, PHD

Nuclear medicine has been a mainstay of cancer diagnosis and treatment for over half a century, but only recently is this field moving into the realm of precision medicine. Research teams at the UChicago Medicine Comprehensive Cancer Center draw from a rich history in this diagnostic and therapeutic area and continue to lead these advancements.

THE BEGINNINGS OF NUCLEAR MEDICINE AT UCHICAGO The seeds leading to the launch of nuclear medicine were planted at UChicago in the historic moment in 1942 when the world’s first nuclear reactor was used to create the first self-sustaining, controlled nuclear chain reaction.

As an academic institution and a hospital, there was an immense interest in harnessing nuclear technology for previously unimagined advances in the diagnosis and treatment of cancer. In 1954, the Argonne Cancer Research Hospital opened its doors on the UChicago campus. This was the largest facility ever built for the purpose of cancer research and treatment using nuclear medicine.

The Argonne Cancer Research Hospital attracted researchers and clinicians who together spawned the field of modern nuclear medicine.

The early team included Katherine Austin Lathrop, once a professor in the department of radiology, an early pioneer in radiopharmaceuticals since 1945. Paul Harper, MD, was a professor who joined the departments of surgery and radiology in 1953.

Robert Beck, a long-time faculty in the department of radiology, joined the team in 1957. And Alex Gottschalk, MD, joined the radiology faculty in 1964.

Lathrop, with colleagues Harper, Beck and Gottschalk, launched the field of modern nuclear medicine with the development of an imaging technique using a radiotracer labeled with technetium-99m (99mTc), the most commonly used medical radioisotope today.

After numerous advancements in nuclear medicine in just two decades, the installation of new equipment, and the development of powerful technologies, would allow for rapid and expansive growth of the field.

UCHICAGOMEDICINE.ORG/CANCER

1

Chin-Tu Chen, PhD, stands by the cyclotron in the modern facility installed in 2017. Photo by John Zich.

THE POWER OF THE CYCLOTRON: PRODUCING R ADIOPHARMACEUTICALS The first cyclotron at UChicago was commissioned from 1968 to 1997 and opened the door to creating numerous types of radioactive compounds for cancer research, diagnosis and therapy. The cyclotron is a particle accelerator used to create positron-emitting “isotopes,� a type of atom that is less stable, for use as radiotracers for imaging and for making radiopharmaceuticals.

After two decades without a cyclotron, Chin-Tu Chen, PhD, associate professor of radiology, led efforts for the installation of a modern facility in 2017. This new installation houses the massive IBA Cyclone 18 cyclotron and is surrounded by sterile rooms for the production of radiotracers, drug dispensing and quality control. The Cyclotron Facility, directed by Richard Freifelder, PhD, currently produces investigational drugs, such as radiotracers, which are used for positron emission tomography (PET), an imaging test used to detect cancer.

Chin-Tu Chen, Robert Beck and Malcolm Cooper were key figures in the installation of a PET facility in 1981: an early non-clinical brain PET scanner, and the first system in Chicago. In 2004, UChicago was one of the first local hospitals to install a clinical PET scanner.

PET imaging allows us to see activities inside of the body by using radioactive materials, such as radiotracers, that can detect events at the molecular level, including metabolic and enzymatic processes to detect and stage cancer. It also 2

PATHWAYS TO DISCOVERY FALL 2020

allows for monitoring the response to treatments.

Because PET imaging is highly sensitive, it can detect biochemical events that may appear ahead of a detectable tumor, in a microscopic area.

A NEW CL ASS OF PET R ADIOTR ACER WITH DIAGNOSTIC TR ANSL ATIONAL POTENTIAL Recent advancements in nuclear medicine from Comprehensive Cancer Center researchers include the creation and testing of a first-in-class, activitybased PET radiotracer. This accomplishment required the combined expertise of a medical physicist, a biological chemist and a team of researchers with the UChicago Cyclotron Facility.

Raymond Moellering, PhD, associate professor of chemistry, and Chen created a novel radiotracer that can specifically label aggressive cancer cells in breast cancer tumors in whole-body imaging.1 The common approach to tumor detection involves the glucose analog 18F-FDG, which is a non-specific glucose molecule that can enter into any fast-growing tissue. It simply detects cancer cells because they metabolize more glucose to produce energy, which is why they grow faster than non-cancerous cells.

This new approach combines the technology of PET imaging with the creation of a novel chemical probe with covalent activity. This recently developed radiotracer detects activity of the enzyme neutral cholesterol ester hydrolase 1 (NCEH1), allowing for the direct visualization of active NCEH1 that is present in aggressive triple-negative breast cancer.

“THIS IMAGING TECHNOLOGY COULD HELP CLINICAL TEAMS DETERMINE WHETHER A CANCER IS AGGRESSIVE AND INFORM TREATMENT DECISIONS.” Raymond Moellering, PhD

In addition to the capability to image aggressive tumors, researchers were able to make new discoveries using the NCEH1-activity radiotracer.

They discovered that the levels of NCEH1 were higher in the leading edge of the tumors where growth and metastasis occur. Similar results were seen in a prostate cancer model.

“This imaging technology could help clinical teams determine whether a cancer is aggressive and inform treatment decisions,” Moellering said.

“NCEH1 is elevated in many different types of aggressive cancer, so if it works to track aggressive breast cancer, it may have utility in tracking many other types of aggressive cancer.”

PET-DIRECTED THER APY HELPS MANAGE TREATMENT DECISIONS For types and stages of cancer that are difficult to detect, PET imaging may provide an option to see what other imaging techniques miss.

Sonali Smith, MD, Elwood V. Jensen Professor in Medicine, is an expert in the treatment of lymphoma. She has led recent clinical studies at UChicago, in collaboration with other academic groups, to elucidate the role of PET-directed therapy in the management of lymphoma.

In a recently published study, patients with earlystage diffuse large B-cell lymphoma (DLBCL) were scheduled for PET scans following their initial cycles of standard chemotherapy to determine how to proceed with treatments. Patients whose PET scans were negative—clear of cancer— proceeded with only one cycle of chemotherapy, whereas a positive result by PET scanning— indicating that cancer was still present—received radiation plus directed radioimmunotherapy. 2

Both patient groups from the study had positive outcomes. These results showed that PET-directed therapy was helpful for guiding treatment decisions. 2 “Overtreatment has been an issue in limited-stage diffuse large B-cell lymphoma,” Smith explained.

“The use of PET-directed therapy may allow for a reduction of the numbers of cycles of toxic drugs and reduce negative side effects, which will be welcomed by patients.”

PET imaging may benefit patients with advanced prostate cancer as well. Stanley Liauw, MD, professor of radiation and cellular oncology, and colleagues evaluated how PET contributed toward treatment decisions for patients with recurrent advanced prostate cancer referred for radiation therapy. 3 Prostate cancer recurrence after prostatectomy, removal of the prostate, is difficult to localize by conventional methods. Liauw and colleagues investigated the use of PET imaging to guide treatment decisions after prostate cancer recurrence. 3 Their study found that PET imaging was able to locate tumors in almost half of the men who underwent the test. The results of the PET scan helped clinicians to make better-informed treatment decisions for these men, and led to management changes in a significant proportion of patients.

THE FUTURE OF R ADIOPHARMACEUTICALS AND PET Extraordinary achievements in the use of nuclear medicine to diagnose and treat cancer are a part of UChicago’s history. With the recently installed modern cyclotron and PET imaging facilities, a new era of discovery and research has been sparked for Comprehensive Cancer Center clinicians and investigators. Novel radiopharmaceuticals and uses of PET imaging have the potential to evolve the field toward personalized approaches that increase precision and improve results and quality-of-life for patients.

1 Chang et al., Angew Chem Int Ed, online ahead of print, 2020 2 Persky et al., J Clin Oncol, online ahead of print, 2020 3 Solanki et al., Pract Radiat Oncol, online ahead of print, 2020

UCHICAGOMEDICINE.ORG/CANCER

3

BY TIHA M. LONG, PHD

Key insights into the progression of ovarian cancer cells have led to promising new treatment strategies.

Ovarian cancer can be a devastating disease because it is often not detected until it has spread to other tissues. Understanding the biology of ovarian tumors that have spread, or metastasized, is critical to finding new therapeutic targets and discovering novel treatments to keep patients alive and improve their quality of life. Physicians and researchers from the UChicago Medicine Comprehensive Cancer Center are dedicated to unraveling the complex biology of ovarian cancer in order to improve the treatment of metastatic disease.

Ernst Lengyel, MD, PhD, Arthur L. and Lee G. Herbst Professor of Obstetrics and Gynecology, is a preeminent oncologist specializing in the treatment of ovarian and other gynecological cancers, and a leading translational researcher working toward discovery of novel targets and treatments for ovarian cancer. Lengyel, along

4

PATHWAYS TO DISCOVERY FALL 2020

Ernst Lengyel, MD, PhD, is a leading translational researcher working toward discovery of novel targets and treatments for ovarian cancer.

with Iris Romero, MD, professor of obstetrics and gynecology, lead teams of researchers in highimpact translational studies to improve therapy options for advanced ovarian cancer. Lengyel and Romero are evaluating an area ripe for therapeutic inquiry: cancer metabolism.

Altered metabolism helps ovarian cancer cells metastasize When normal cells transform into cancer, their metabolism is reprogrammed to allow these cells to take advantage of their environment and use all available sources of energy to support rapid growth. In recent years, the altered metabolism of cancer cells has emerged as a salient area of investigation toward developing novel mechanisms for attacking and starving these cells. The spread and progression of ovarian cancer is critically linked to metabolic reprogramming.

The main site of metastatic tumor growth for ovarian cancer is the omentum, the fatty tissue of the abdomen that forms a protective layer in front of the large and small intestines. Metastatic cancer cells break away from the primary tumor of the ovary and colonize the energy-rich tissue of the omentum, where new tumors can rapidly grow.

The secret to blocking ovarian cancer progression may lie in controlling the altered metabolism of these cells to inhibit nutrient uptake and starve the cancer cells.

Exploring approaches designed to starve ovarian cancer Comprehensive Cancer Center physician-scientists Lengyel and Romero have catapulted the field of cancer metabolism forward. Together, they discovered that ovarian cancer cells interact with other types of cells in the metastatic environment to alter the metabolism of cancer cells. That experimental discovery led to the realization that drugs already approved to modulate metabolism in people, in diseases like diabetes, might be able to regulate cancer cell metabolism to block cancer progression.

In 2019, they showed that metastasis can be interrupted by a diabetes drug called metformin,1 opening the door to investigations of disrupting metabolic interactions between metastatic cells and their nutrient-rich environments.

Along a similar line of research, Lengyel showed that ovarian cancer cells interact with fat cells, or

Iris Romero, MD, focuses her research on developing new agents for gynecologic cancer prevention and treatment.

adipocytes, in a symbiotic relationship that benefits the cancer cells. 2 In this relationship, fat cells are programmed to release fatty acids and the cancer cells benefit by absorbing these energy-rich molecules, which they utilize for tumor growth.

Lengyel determined that when ovarian cancer cells come into close contact with adipose tissue, they up-regulate a surface channel protein, called CD36, that allows for efficient absorption of fatty acids from the adipose tissue into the cancer cells.

That study provided a clear picture of how ovarian cancer cells feed off of the high-fat tissue of the omentum and revealed a potential mechanism to interfere with nutrient uptake and growth of the metastasized cancer cells by blocking a route of fat absorption.

A new study by Lengyel and Romero, with staff scientist Abir Mukherjee, PhD, confirmed the upregulation and activity of CD36 and revealed the primary regulator of fatty acid distribution in metastasized ovarian cancer cells: fatty acid-binding protein-4 (FABP4), a regulator of metabolism linked to metabolic syndrome, glucose regulation and insulin resistance. 3 They discovered that the up-regulation of FABP4 allows cancer cells to effectively utilize the fatty acids that are in the environment to rapidly multiply and grow. They next asked if blocking FABP4 could be an effective therapeutic strategy to starve metastatic ovarian cancer.

UCHICAGOMEDICINE.ORG/CANCER

5

New research shows that FABP4, a regulator of cell metabolism, could potentially be blocked to starve metastatic ovarian cancer.

6

To evaluate the potential of FABP4 targeting to treat ovarian cancer, they performed extensive preclinical experiments. In laboratory models, they were able to slow down ovarian cancer growth using a small molecule inhibitor that attaches to FABP4 and prevents binding to fatty acids. The drug showed promising results in animal models, as the loss of FABP4 function led to decreased metastasis and lower cancer burden. The FABP4 inhibitor was also tested in animals in combination with the chemotherapy that is currently the standard of care for ovarian cancer. In this case, the addition of FABP4 inhibition reduced both the number and size of metastatic tumors more than using chemotherapy alone. Although the compound used in this study is not approved for use in people, additional FABP4 inhibitors that could potentially work in humans are currently under development.

metastatic sites. Lengyel and Romero found that within the metastatic ovarian tumor cells, there are higher levels of reactive oxygen species, or ROS, that can further damage the DNA, causing genetic instability which allows the cancer cells to diverge and possibly colonize additional sites in the body.

The fatty acid metabolites produced by the cancer cells also contribute to inflammation, another factor that aggravates ovarian cancer progression.

The increase in fatty acid metabolism by ovarian cancer cells not only helps cells grow rapidly, but it may also improve the ability of cancer cells to migrate beyond the abdominal cavity to new

1 Hart et al., Cell Reports 29:4086-98, 2019 2 Ladanyi et al., Oncogene 37(17):2285-301, 2018 3 Mukherjee et al., Cancer Res 80(8):1748-61, 2020

PATHWAYS TO DISCOVERY FALL 2020

The thorough investigations of Lengyel and Romero have provided direction for improved treatment of ovarian cancer. Therapies that block metabolic reprogramming of ovarian cancer cells may limit the ability of these cells to metastasize to the omentum and to other sites in the body. This clinically relevant work has great potential benefit for ovarian cancer patients in the future.

STRONGER TOGETHER: A SUCCESSFUL COMBINATION TO TREAT ADVANCED PROSTATE CANCER

BY JANE KOLLMER

A drug that held great promise in advanced prostate cancer failed in clinical trials. Several years later, a discovery made in a University of Chicago research laboratory renewed hope in its potential.

Prostate cancer is the second most frequent cancer diagnosis made in men and the fifth leading cause of mortality, accounting for approximately 360,000 deaths worldwide in 2018. Men with metastatic castration-resistant prostate cancer (mCRPC), or cancer that has spread and is not responding to standard hormonal treatments, face a poor prognosis.

Currently, researchers are looking for new ways to address this longstanding treatment challenge by testing novel therapeutic options, including cancer

MOST FREQUENT CANCER DIAGNOSIS MADE IN MEN.

therapies that identify and attack specific types of cancer cells. One such drug is cabozantinib, a type of tyrosine kinase inhibitor (TKI). The drug has been traditionally thought to work by blocking certain proteins that drive the rapid increase and survival of cancer cells, thus inhibiting the growth of the tumor.

It may also prevent angiogenesis, the growth of new blood vessels that tumors need to grow.

This new drug was tested on advanced prostate cancer through a large, phase III clinical trial named COMET-1. The trial was halted in 2014 when early results showed the drug did not extend survival in a heavily pre-treated mCRPC patient population.

In the wake of these disappointing results, the drug’s manufacturer, Exelixis, laid off about 70% of its workforce.

RENEWED HOPE The results of that study were puzzling to Akash Patnaik, MD, PhD, an accomplished physicianscientist and national expert in prostate cancer research at the UChicago Medicine Comprehensive Cancer Center. The Comprehensive Cancer Center is a major center for conducting prostate cancer research through the National Cancer Institute and private sponsors.

UCHICAGOMEDICINE.ORG/CANCER

7

Akash Patnaik, MD, PhD, published a study showing that the drug cabozantinib has powerful effects against metastatic prostate cancer.

Patnaik focuses on translating novel therapies from the laboratory to early-stage clinical trials. He was curious about why cabozantinib showed promising activity in a phase II trial of patients with mCRPC but did not extend survival in a larger phase III trial. He reasoned that a better understanding of the drug’s mechanism of action and its impact on the unique immune environment within the tumor would help identify patients who may respond to it.

At that point, Patnaik’s laboratory began studying cabozantinib’s effects in a mouse model of advanced prostate cancer. His team first saw that the antitumor effects of the drug did not depend upon the MET signaling pathway, one of the proteins targeted to hold back cell growth and angiogenesis. Instead, Patnaik’s team observed that cabozantinib stimulated tumor cells to release immune cell trafficking molecules called chemokines. These proteins send out a signal to attract

THE PUBLISHED WORK GENERATED IN PATNAIK’S LAB OPENED THE DOOR TO INVESTIGATING 16 COMBINATION TRIALS. 8

PATHWAYS TO DISCOVERY FALL 2020

neutrophils, a type of white blood cell that helps heal damaged tissues and resolve infections. This resulted in neutrophils swarming into the tumor and clearing out cancer cells.

The study was the first to demonstrate that a TKI can switch on neutrophil-mediated antitumor immunity, resulting in widespread cancer clearance. The research was published in Cancer Discovery in 2017.

“We were excited to have more evidence supporting how cabozantinib has powerful effects against metastatic prostate cancer,” said Patnaik. “But this was only the beginning because we still needed to figure out how this applies to humans and what other drugs were needed to induce a powerful immune response.”

A WINNING COMBINATION A major breakthrough in cancer is immunotherapy, or treatments that use a patient’s own immune system against cancer. One type of immunotherapy uses monoclonal antibodies that target an interaction between the cell-surface receptors— programmed cell death protein 1 (PD-1) and (PD-L1),

which are “checkpoints” that tumors exploit to turn off the immune response. By blocking this interaction, PD-1 checkpoint inhibitors can open the gates for T cells, restoring the desired immune response against cancer cells.

These new therapies have shown incredible promise, yet they only work for approximately 20% of all cancer patients and are not effective in certain specific tumor types. In particular, the responses to immune checkpoint blockade in advanced prostate cancer have been few and far between. Therefore, researchers are exploring ways to improve immuno­therapy responses. They have found that pairing immunotherapies with other treatments may be an effective approach for eliciting a better clinical response than either treatment by itself.

PAIRING IMMUNOTHERAPIES WITH OTHER TREATMENTS MAY BE AN EFFECTIVE APPROACH FOR ELICITING A BETTER CLINICAL RESPONSE THAN EITHER TREATMENT BY ITSELF. The published work generated in Patnaik’s lab opened the door to investigating 16 combination trials with cabozantinib (innate immune activation) and checkpoint inhibitors in multiple advanced solid tumors. At the 2020 American Society of Clinical Oncology Genitourinary Cancers Symposium in February 2020 in San Francisco, researchers shared exciting results from a trial that tested cabozantinib in combination with atezolizumab in patients with mCRPC, as part of a larger study called COSMIC-021. Atezolizumab is a monoclonal antibody that attaches to PD-L1 and “blocks” its checkpoint function, thus releasing the hold on the immune system, to attack cancer cells.

The study cohort included 44 patients, who were followed for a median of 12.6 months. The results showed that 32% of the patients experienced an overall response on the treatment, including two who had complete responses and 12 who had partial responses. For 80% of the patients, their disease was controlled during the study period.

Among 12 patients who had an objective response and at least one prostate-specific antigen (PSA) evaluation following the initiation of treatment, 67% had a PSA decline of at least 50%.

OF THE PATIENTS HAD THEIR DISEASE CONTROLLED DURING THE STUDY PERIOD. Patnaik said, “Given the 0% and 5% prior response rates for atezolizumab and cabozantinib singleagent trials, respectively, these data are very exciting, and a big step forward for the development of immunotherapy combinations in advanced prostate cancer.”

He continued, “It’s gratifying to see that our laboratory discovery demonstrating cabozantinib’s innate immune anti-cancer mechanism is holding true in patients.”

NEXT STEPS These promising, newly emerging clinical data set the stage for phase III trials involving this drug combination. With funding from various federal and private sources, Patnaik is also developing clinical trials involving combinations of cabozantinib with other immune checkpoint inhibitors. He will serve as co-principal investigator and national correlative science chair for an investigator-initiated clinical trial of cabozantinib with nivolumab, a PD-1 checkpoint inhibitor, run through the Prostate Cancer Clinical Trials Consortium.

The unprecedented speed at which progress is being made continues. As early as 2021, Exelixis plans to collect enough positive supporting clinical data to apply for accelerated FDA approval in metastatic CRPC. It all started with the discovery of cabozantinib’s immune mechanism in the laboratory that paved the way for the drug’s resurrection and redemption.

“The fact that a mechanistic discovery made in the laboratory in 2017 led to a clinical trial reporting positive results in 2020 is an incredibly rapid drug development timeline, a prime example of how bench-to-bedside research is able to generate promising new treatments,” Patnaik said. “We hope this strategy will alleviate suffering and improve survival for our patients with aggressive mCRPC.”

UCHICAGOMEDICINE.ORG/CANCER

9

Research

Meet the Expert Lucy Godley, MD, PhD HOSPIRA FOUNDATION PROFESSOR OF MEDICINE AND HUMAN GENETICS

Lucy A. Godley, MD, PhD, is an expert in the care and treatment of patients with diseases of the bone marrow, including leukemias, lymphomas and multiple myeloma. She also cares for patients undergoing stem cell transplantation and patients with benign hematologic conditions.

Godley has a special interest in the molecular basis of bone marrow malignancies and is an active researcher in the field. In her laboratory, she studies the basis for cancer cells’ abnormal patterns of DNA methylation as well as inherited forms of bone marrow cancers.

Godley performs translational research by applying her knowledge of fundamental networks within cancer cells to make novel insights into the pathophysiology of her patients’ diseases while offering them new treatment options.

10

PATHWAYS TO DISCOVERY FALL 2020

Research

What is the impact of your research?

By understanding what drives cancer cell growth, we hope to devise interventions to treat cancer, and slow or even prevent its development in those at increased risk.

What do you hope to accomplish during your career?

I hope to open people’s minds to the idea that the blood- and bone marrow-derived cancers are often inherited. Additionally, we should think of cancer predisposition syndromes through the lens of the biological pathways disrupted by inherited DNA variants, rather than the specific tissues where the cancers form.

How did you get interested in studying cancer?

I began working in a laboratory when I was 16 years old, and we studied inherited disorders of red blood cells as well as the biochemistry of the red blood cell membrane. I don’t think I have strayed very far from that early inspiration.

What is the most rewarding part of your job?

It’s rewarding to see how my laboratory work influences patient care and how the work can inspire younger people to devote their careers to science.

Who inspires you?

My patients really inspire me to understand why they have developed cancer.

What do you love about working at the University of Chicago?

Research Highlights Small Molecule Treatment Reduces Colon Cancer Metastasis UChicago Medicine Comprehensive Cancer Center investigators have found a new way to slow the metastasis, or spread, of colon cancer: by treating it with a small molecule that essentially locks up cancer cells’ ability to change shape and move throughout the body. Ralph Weichselbaum, MD, Daniel K. Ludwig Distinguished Service Professor and Chair of Radiation and Cellular Oncology and co-director of the Ludwig Center for Metastasis Research, and colleagues, including Comprehensive Cancer Center members Alexander Pearson, MD, PhD, and Mitchell Posner, MD, studied a small molecule called 4-hydroxyacetophenone (4-HAP), which activates a protein in the cancer cell called nonmuscle myosin-2C (NM2C). When activated, it becomes locked in place, ensuring that the cancer cell cannot travel. The investigators studied this process at both the molecular level and using human colon cancer tumors in a mouse model, and found that it significantly limited the cancer’s ability to metastasize to other parts of the body, while leaving healthy cells alone. The rate of metastasis was cut in half compared to untreated colon cancer. The team envisions using this molecule in tandem with chemotherapy and radiation to create a more effective cancer-killing treatment.

Bryan et al., Proc Natl Acad Sci USA 117:22423-29, 2020

I really enjoy the freedom we have to explore our ideas and collaborate easily.

What is one thing on your bucket list?

I would love to one day visit an island in the South Pacific, such as Tahiti, Fiji or Easter Island.

Microscopic image of colonic adenocarcinoma with tissue stain

UCHICAGOMEDICINE.ORG/CANCER

11

Research

Research Highlights (continued) Access to Insurance Does Not Alleviate the Breast Cancer Mortality Disparity Between Black and White Women The expansion of Medicaid was anticipated to help low-income populations by increasing the accessibility of healthcare. To assess if the expansion of Medicaid has had an effect on health disparities, Olufunmilayo Olopade, MD, Walter L. Palmer Distinguished Service Professor of Medicine and Human Genetics and director of the Center for Clinical Cancer Genetics and Global Health, analyzed the effects of Medicaid expansion on the Black/White breast cancer mortality ratio.

Historically, breast cancer mortality rates have been drastically different between Black and White women, where Black women, despite lower incidence of disease, show higher mortality. Olopade used breast cancer mortality data from the Centers for Disease Control and Prevention to generate a state-specific “disparity ratio” by dividing the Black mortality rate by the White mortality rate.

The disparity ratios were then compared between states with and without expanded Medicaid. In contrast to expectation, Olopade found that the Black/White mortality ratio increased in states that expanded Medicaid, significantly for younger age groups, although true for all Medicaid-eligible age groups. These results suggest that access to insurance is insufficient to alleviate disparities in cancer mortality; rather, other factors, such as the quality of local health systems, may limit a patient’s potential to benefit from policy changes such as Medicaid expansion.

Semprini and Olopade, JCO Glob Oncol 6:1178-1183, 2020

Breast cancer specialist Olwen Hahn, MD, shows a patient a breast scan.

12

PATHWAYS TO DISCOVERY FALL 2020

Myeloma cells producing monoclonal proteins of varying types (Scientific Animations)

Adding Stem Cell Transplants to a KRd Regimen Prolongs Disease Control for Newly Diagnosed Multiple Myeloma Patients Multiple myeloma is a blood cancer that is not considered “curable,” and although patients may experience prolonged periods of dormancy, the cancer often recurs. Newly diagnosed multiple myelomas are often treated with the proteasome inhibitor carfilzomib paired with lenalidomide-dexamethasone, known as the KRd regimen, to increase response rate. In an effort to further improve the effectiveness of this treatment, researchers at UChicago Medicine Comprehensive Cancer Center, led by Jagoda Jasielec, MD, assistant professor of medicine, and Andrzej Jakubowiak, MD, PhD, professor of medicine and director of the myeloma program, evaluated the addition of an autologous stem cell transplant (ASCT) to the KRd regimen. Patients were evaluated for progression-free survival and overall survival. The team found that adding stem cell transplants to patients receiving KRd resulted in prolonged disease control while still being tolerable for patients. The best patient outcomes were largely dependent upon the extended KRd treatment. The authors said the study results support the premise that incorporating ASCT to extended KRd can improve clinical outcomes and warrant further evaluation in the randomized clinical trial setting.

Jasielec et al., Blood 2020007522, 2020

News

New Faculty Other Headlines from The Forefront

Piyush Agarwal, MD, professor of surgery and urology and director of the bladder cancer program, specializes in the multidisciplinary management of bladder cancer using complex surgical techniques.

Benjamin Derman, MD, assistant professor of medicine, specializes in multiple myeloma and other plasma cell disorders.

He uses innovative techniques, including CAR T-cell therapy and stem cell transplantation, to deliver long-term success for his patients.

UChicago Medicine, in partnership with Solis Mammography, opens two new breast health centers The nation’s largest independent provider of breast health and diagnostic services, Solis Mammography, is operating sites within UChicago Medicine’s Orland Park and River East outpatient locations. The sites are staffed by UChicago Medicine radiologists who specialize in comprehensive breast care and technologists with expertise in breast imaging. The new mammography centers use up-to-the-minute breast health practices

Ari Rosenberg, MD, assistant professor of medicine, develops novel treatment strategies, including immunotherapy, for patients with head and neck cancer while also establishing methods to reduce side effects.

Visit uchicago medicine.org/ cancer for our latest news, stories and more…

and technologies to provide exceptional care in a spa-like environment designed for patient care, convenience and comfort.

During the COVID-19 pandemic, heightened safety procedures are in effect for patients and staff. These include requiring face masks, regularly cleaning all surfaces and requiring social distancing during appointments except at the point of care.

Hiroyuki Abe, MD, PhD, professor of radiology and chief of breast imaging at UChicago Medicine, said, “Now, more than ever, it’s important people feel safe when they go to a medical appointment so they can continue to get important screenings and other preventative care.”

UCHICAGOMEDICINE.ORG/CANCER

13

News

New Chicago Immunoengineering Innovation Center Opens The Chicago Immunoengineering Innovation Center has launched at the University of Chicago, with a focus on developing new technologies to treat diseases, including cancer, autoimmune disorders and, most recently, COVID-19.

Based at the Pritzker School of Molecular Engineering, the new center will catalyze fundamental and translational research in

Immunoengineering is a fast-growing field that uses engineering analysis and design approaches to understand the basic mechanisms of our immune system and develop technologies to treat complex conditions.

immunology, serving as a hub for engineers, immunologists, biologists and clinicians to collaborate and share resources to advance research in immunoengineering.

Immunoengineering is a fast-growing field that uses engineering analysis and design approaches to understand the basic mechanisms of our immune system and develop technologies to treat complex conditions. The center is co-directed by Jeffrey Hubbell, the Eugene Bell Professor in Tissue Engineering; and Melody Swartz, the William B. Ogden Professor of Molecular Engineering.

Working in partnership with the Polsky Center for Entrepreneurship and Innovation, UChicagoaffiliated Argonne National Laboratory and the immunoengineering startup community of Chicago, the center will create an ecosystem that brings technologies from the lab to treatment.

Exterior view of the William Eckhardt Research Center, where the new Chicago Immunoengineering Innovation Center is housed. (Photo by Tom Rossiter)

14

PATHWAYS TO DISCOVERY FALL 2020

News

Express Expert Cancer Opinion (EECO) Program The University of Chicago Medicine recently launched the Express Expert Cancer Opinion (EECO) Program.

This program provides any newly diagnosed patient with a prompt 15-minute video visit with one of our cancer experts—at no cost to them.

EECO is a convenient way to establish a doctor-patient relationship and learn about UChicago Medicine’s cancer program from the comfort and privacy of their home.

EECO is available for people newly diagnosed with a solid tumor, including but not limited to brain, breast, endocrine, gastrointestinal, gynecologic, head and neck, lung, melanoma and prostate cancers. Medical records are not required for the EECO appointment.

Carter with his parents, Randy and Jennifer Fortin

‘RINGING THE BELL’ MARKS MILESTONE IN CHILD’S CANCER TREATMENT After 8-year-old Carter Fortin rang a big brass bell on the sixth floor of Comer Children’s Hospital, cheers and applause filled the hallway of the pediatric cancer unit. His parents gave him a big hug. Carter had just finished his last chemotherapy treatment for a brain tumor.

“The cancer journey can be filled with many unknowns—hospital visits, inpatient stays, side effects and emotional hardships,” said Jeff Murphy, DNP, RN, vice president of children’s services at Comer Children’s. “The ringing of the bell completes that journey for the patient and, we hope, brings joy to the patient and the family.”

Fatir Khan, RN, BSN, patient care manager on the unit, spearheaded the effort to install the bell on the inpatient unit. “It’s an honor to take care of the young patients who come to our hospital for cancer care,” he said. “Going forward, this new tradition will celebrate all of these superheroes and the dedicated staff who cares for them.”

“Going forward, this new tradition will celebrate all of these superheroes and the dedicated staff who cares for them.”

—Fatir Khan, RN, BSN

UCHICAGOMEDICINE.ORG/CANCER

15

News

David Jonas

FAMILY’S $10 MILLION GIFT ACCELERATES PROGRESS IN PERSONALIZED THERAPIES Researchers at the University of Chicago Medicine Comprehensive Cancer Center will grow in their capability to come together to develop personalized therapies for hard-to-treat cancers, thanks to a $10 million gift from the Jonas family. The gift establishes the David and Etta Jonas Center for Cellular Therapy at UChicago Medicine, named for David Jonas and his late wife, Etta.

The center unites a team of experts dedicated to improving cellular therapy, especially T-cell treatments like CAR (chimeric antigen receptor) T-cell therapy, an emerging form of cancer treatment. CAR T-cell therapy works by supercharging patients’ white blood cells to seek out and destroy cancer cells. Although this therapy has, in some cases, led to complete remission, it is not always successful and is currently limited to treating certain blood cancers.

16

PATHWAYS TO DISCOVERY FALL 2020

Through the new center, Comprehensive Cancer Center researchers will work to overcome these challenges and realize the full potential of cellular therapy. This includes efforts to improve the therapy’s overall effectiveness and extend its benefits to a much broader group of patients, including those with cancers that are currently difficult to treat.

“This gift will allow us to translate these groundbreaking discoveries made in the laboratory into novel cancer therapies, which have the potential to treat not just blood cancers, but also solid tumors,” said Kenneth Polonsky, MD, dean and executive vice president for medical affairs at the University of Chicago. “If we can accomplish even part of that, it will be a major transformation in cancer therapy that will change the lives of many patients here in the United States and around the world.”

News

Faculty Awards and Honors

Karen Kim, MD, professor of medicine and Associate Director for Community Outreach and Engagement for the Comprehensive Cancer Center, has been appointed as Vice Provost for Research at the University of Chicago.

Stanley Liauw, MD, professor of radiation and cellular oncology, was named a fellow of the American Society for Radiation Oncology.

Comprehensive Cancer Center Director Michelle M. Le Beau, PhD, Arthur and Marian Edelstein Professor of Medicine, received the 2020 AACR-Margaret Foti Award for Leadership and Extraor­dinary Achievements in Cancer Research from the American Association for Cancer Research.

Rita Nanda, MD, associate professor of medicine and director of the breast oncology program, was invited by the Society of Immunotherapy in Cancer (SITC) to serve on the SITC Cancer Immunotherapy Guidelines Breast Cancer Expert Panel.

CANCER DOESN’T FIGHT FAIR.

Wendy Stock, MD, Anjuli Seth Nayak Professor in Leukemia, was selected for the 2020 ASH Mentor Award for her contributions to the professional development of numerous hematology trainees at various stages in their careers.

Maria-Luisa Alegre, MD, PhD, professor of medicine, and Thomas Gajewski, MD, PhD, AbbVie Foundation Professor of Cancer Immunotherapy, were elected to the Association of American Physicians. Gajewski was also selected by the European Society for Medical Oncology (ESMO) as the recipient of the 2019 ESMO Immuno-Oncology Award.

NEITHER DO WE.

Dr. Jessica Donington Thoracic Surgery

UCHICAGOMEDICINE.ORG/CANCER

17

5841 S. Maryland Ave. MC 1140-H212 Chicago, IL 60637-1470

@UCCancerCenter Follow us for news, events and the latest discoveries.

U C H I C AG O M E D I C I N E .O R G/C A N C E R

FOR CONSULTATIONS, REFERRALS OR PATIENT APPOINTMENTS, call 1-773-702-8222 or email ucmconnect@uchospitals.edu FOR INFORMATION ABOUT CLINICAL TRIALS, call 1-855-702-8222 or email cancerclinicaltrials@bsd.uchicago.edu TO MAKE A GIFT, call 1-773-702-6565 or email givetomedicine@bsd.uchicago.edu

"' C)

,-1

j� �m we:,

o r-C

[�·-ac3 z:... i!!: C/l

"C

A Cancer Center Designated by the National Cancer Institute

�a;;?

Comprehensive Cancer Center