Forbes Impact Report 2023

DRIVING INNOVATION AND BOLD NEW APPROACHES TO CARE Dear Friends,

We are in the midst of an exciting era of cancer research. Discoveries made in the lab and in the clinic are having a great impact on patients as treatments are improving, knowledge is growing, and survival rates are increasing.

While we are seeing immense progress and promise in the care provided for many types of cancer, we realize there is still much work to do. Several forms of this devastating disease, such as brain, pancreatic, liver, lung, and other cancers remain difficult to treat and offer patients a bleak prognosis.

At the Forbes Institute for Cancer Discovery in the University of Michigan Health Rogel Cancer Center , we are at the forefront of advancing innovative research and therapies to provide patients with better options and more hope.

The support of the Forbes family has enabled us to strengthen our ability to conduct lifesaving research and encouraged us to pursue groundbreaking ideas for treating even the most difficult cancers. We have also developed a unique team approach to science that brings together experts from diverse disciplines across U-M.

As we share the progress made by Forbes Scholars in the past year, we are also looking forward to selecting the recipients of our 2023 grants.

Max S. Wicha, M.D.

These grants, which are fully funded by philanthropy, are given to projects that seek to translate new discoveries into clinical applications with the greatest potential to benefit patients.

We especially encourage high-risk, highpotential proposals that might be too preliminary to garner support from more traditional funding organizations.

We are grateful for your interest in and support of our work. Your involvement makes it possible for Forbes Institute physicians and researchers to envision a brighter future in cancer care.

With gratitude and warm regards,

Madeline and Sidney Forbes Professor of Oncology Director, Forbes Institute for Cancer Discovery Founding Director Emeritus, Rogel Cancer Center

ENABLING MORE PERSONALIZED AND EFFECTIVE TREATMENTS

The Single Cell Spatial Analysis Program (SCSAP), established in 2019 through the U-M Biosciences Initiative and directed by Forbes Institute grant recipient Evan Keller, D.V.M., Ph.D , is exploring new ways to study cell biology to understand how cells interact, communicate, and organize. This exciting methodology looks at various stages of cancer to achieve more effective and personalized treatments.

Leading-edge research like this requires the use of new technologies, and the Forbes Institute has helped bring these resources to U-M.

Support from the institute enabled the SCSAP to purchase the GeoMx Digital Spatial Profiler, which helps Rogel Cancer Center investigators quickly obtain genomics data and perform cancer research.

Dr. Keller, who is the Richard and Susan Rogel Professor of Oncology, and urology fellow Allison May, M.D. , are exploring the progression of renal cancer. Initially, most renal cancers are diagnosed as the clear cell type but they can progress and evolve into a sarcomatoid renal cancer, which is much more aggressive.

Using GeoMx, Drs. Keller and May have examined non-cancer cells from renal cell tumors to understand how they contribute to the progression of renal cancer and its response to therapies. This work has formed the foundation for a Forbes grant supporting a team of multiple investigators from U-M.

“The Forbes Institute will allow our team to explore in depth the tumor microenvironment using multiple renal cancer samples to develop a solid understanding of how the tumor microenvironment and cancer cells interact,” says Dr. Keller. “This will allow for development of more targeted therapeutics and possibly identify factors that can inform clinical decisions.”

Nisha D’Silva, BDS, MSD, Ph.D. , has used the GeoMx in her lab to validate translational findings on nerve-tumor interactions in oral cancer. The GeoMx has also benefited the research of Marina Pasca di Magliano, Ph.D. , who is studying pancreatic cancer, which is often diagnosed late when surgery is no longer an option. Pancreatic cancer arises from microscopic lesions that cannot be seen by imaging. Very little is known about how these lesions form and what causes their progression to cancer.

Through a collaboration with the organ donor organization

Gift of Life Michigan, Dr. Pasca di Magliano’s lab received donor pancreases from otherwise healthy people. More than half these organs had the microscopic lesions. Her lab can now study these lesions and use the GeoMx to understand their gene expressions with the goal of devising ways to prevent their progression to cancer. Dr. D’Silva is the Donald A. Kerr Endowed Collegiate Professor of Oral Pathology, and Dr. di Magliano is the Maude T. Lane Professor of Surgical Immunology.

UNDERSTANDING THE PROGRESSION OF BREAST CANCER AND STOPPING ITS SPREAD

Sunitha Nagrath, Ph.D. , has collaborated with a team of physicians, scientists, and engineers to identify cancer cells in the blood of patients with ductal carcinoma in situ, or DCIS, an early-stage cancer that is present in the lining of milk ducts in the breasts but has not spread to surrounding tissue.

This work revealed cancer cells in the blood of about two-thirds of DCIS patients. Despite their prevalence, there is very little known about these cells in earlystage cancers. In 2022, Dr. Nagrath and her team set out to probe the cells further to understand what they are made of, how they behave, and if that information can be used to help patients.

By studying the RNA from the cells, Dr. Nagrath found that some cancer cells were changing to be more migratory, suggesting that they were moving away from the breast ducts where they originated to other parts of the body where

they may be able to form new tumors. Dr. Nagrath also observed changes to the DNA in the cells that other researchers have found to be associated with cancer progression.

“We hypothesize that by detecting and examining all the properties of the cancer cells, we can tell at the start of a patient’s treatment if their cancer is spreading and will come back later,” Dr. Nagarath says. “This will allow doctors to better treat and monitor patients over time to increase their chance of remaining cancer free.”

Dr. Nagrath’s lab continues to work with engineers, biologists, and clinicians to design and develop technologies to improve cancer detection and diagnosis. One such tool is a smart chip that would help capture exosomes — small vesicles given off by cancer cells — from a patient’s blood. These technologies and approaches can help solve complex problems across multiple types of cancer.

The U-M Rogel Cancer Center is most fortunate to have the Forbes family as a visionary partner. Their remarkable commitment and generosity have inspired Forbes Scholar faculty members from a range of U-M schools and departments to pursue collaborative research that has led to unique insights into the cancer problem, including discoveries with potential to improve outcomes for patients and survivors. Through clinical trials, scholar teams continue to advance new approaches for cancer detection and treatment. We are grateful and proud to have the support of the Forbes family to catalyze and sustain our pioneering cancer discovery and translational research efforts — very few institutions have access to such an impressive resource and the unique opportunities for innovation and impact that the Forbes Institute for Cancer Discovery provides.”

ERIC R. FEARON, M.D., PH.D.

Emanuel N. Maisel Professor of Oncology Director, University of Michigan Rogel Cancer Center

TARGETING MICRORNAS TO AFFECT THE PATHWAYS THAT DRIVE CANCER

Cancer cells rely on key physiological and pathological processes to stay alive — mechanisms that enable them to grow and divide, survive longer, and develop in ways that make them look like the tissue they came from. Therefore, an effector molecule that can act on multiple genes and pathways involved in regulating these processes represents an ideal target for cancer therapy.

MicroRNAs (miRNA) have excellent therapeutic potential given their roles as effector molecules working on many genes involved in these pathways. A recent Forbes Institute award recipient, Analisa DiFeo, Ph.D. , is focused on developing a drug that inhibits miR181a, a miRNA that is commonly found in tumors and correlates with poor survival across many different cancers. In high-grade serous ovarian cancer, miR-181a contributes to cellular transformation and the cancer’s spread to other areas. When miRNA was targeted with an inhibitor, the tumor’s ability to metastasize decreased.

Dr. DiFeo was able to recently demonstrate that miR-181a directly regulates pathways that control cancer stem cells, the disease’s ability to spread to other parts of the body, and its innate immunity. Thus, when this miRNA is blocked, the body’s immune microenvironment is re-activated, resulting in a decrease in tumor growth.

Funding from the Forbes Institute will enable Dr. DiFeo and her team to develop small molecule drugs that will bind and inhibit miR-181a. Dr. DiFeo was also recently awarded an R01 renewal grant from the National Cancer Institute to further her efforts to determine how miR181a regulation can stimulate a powerful anti-tumor immune response that can

be combined with existing therapies to prevent high-grade serous ovarian cancer progression and recurrence.

“As an ovarian cancer researcher, I am deeply committed to performing impactful studies, driving collaborative teamwork, and mentoring the next generation of scientists so that we can improve the lives of women affected with this deadly disease,” Dr. DiFeo says.

DiFeo Lab Researchers & Learners

REPROGRAMMING CELLS: A PROMISING FUTURE IN PERSONALIZED MEDICINE

Science’s understanding of the human genome, factors that regulate gene expression, and cancer cell development have become advanced enough to enable regenerative, personalized cancer treatments.

With support from the Forbes Institute, the lab of Indika Rajapakse, Ph.D. , has developed a patented algorithm and unique software that use genomic data to reprogram cells to generate new therapeutic cells for any patient. This work merged mathematics, engineering, biology, computer science, and even entrepreneurship as Dr. Rajapakse partnered with Lindsey Muir, Ph.D. , to co-found iReprogram, a startup company focused on advancing pioneering cell regeneration methods. iReprogram’s technology is optimizing cell reprogramming — the process that takes stem cells from a patient and reprograms them into cells that can target and kill cancer cells.

iReprogram’s platform enables better identification of the genes and optimal conditions necessary to reprogram any stem cell into a target cell. This approach eliminates costly screening trial-and-error approaches

in developing therapies and can make promising new treatments available to the public.

In addition to support from the Forbes Institute, iReprogram has also received funding from commercial collaborators, the Defense Advanced Research Project Administration (DARPA), the Air Force Office of Scientific Research, and the National Science Foundation (NSF).

NSF funding is currently enabling iReprogram to advance technology to generate stem cells from skin cells. Through a simple skin biopsy, patients can be treated with their own stem cells, bypassing the need for a donor and preventing graft versus host disease, a debilitating condition occurring in 50% of conventional stem cell transplants. This effort could also bring about other stem cell therapies.

“My excitement is that people see the power in cellular reprogramming — I believe we can reprogram cells for targeted cancer cell death,” Dr. Rajapakse says. “And just imagine what else that can lead to.”

“We are focused on changing medicine, on taking new and exciting ideas and turning them into real answers and treatments for patients and families in need of hope. The teams at the University of Michigan are world-class, and the Forbes family is thrilled to partner with them, share their vision, and support their work. There isn’t anything more impactful or meaningful that we could be a part of. We invite everyone to join us in this mission. We are making progress — and together, we will save lives.”

NATHAN FORBES

EXAMINING ULTRASOUND TECHNOLOGY’S IMPACT ON THE IMMUNE SYSTEM

As many as 80% of patients with liver tumors are not eligible for surgical treatment due to the presence of multiple tumors, poor liver function, or general health issues that would limit the success of surgery.

Histotripsy is a noninvasive therapy developed at U-M that uses focused ultrasound to destroy tumors. This novel approach is moving through clinical trials and might soon provide a new treatment option to liver cancer patients and other people diagnosed with cancers that are difficult to operate on. Additionally, histotripsy could give their immune system a boost in fighting these tumors.

Clifford Cho, M.D. , the C. Gardner Child Professor of Surgery, received a Forbes Institute grant to study whether histotripsy generates an immune response against cancer. His research team previously found that histotripsy stimulated a reaction from the immune system in lab models of melanoma and liver cancer. Dr. Cho’s team recently published their latest findings on a study of melanoma and hepatocellular carcinoma lab models. The results showed similar results — histotripsy inhibited the growth rate in treated tumors and in distant untreated tumors, suggesting an immune response.

In addition, histotripsy appeared to induce cancer cells to undergo specific pathways of cellular death that favored the stimulation of anti-cancer immune responses.

This news is promising as histotripsy continues to move closer to becoming an approved cancer treatment. In fall 2022, HistoSonics published results from a Phase I clinical trial in Spain that treated eight patients with endstage liver tumors, some of which had metastasized to other areas of the body. The trial found that histotripsy was not only safe and effective, but it could be used to successfully target and treat multiple tumors in the same procedure. In February 2023, the U.S. Food and Drug Administration approved another HistoSonics clinical trial to use histotripsy to target and destroy kidney tumors.

Dr. Cho is co-principal investigator of the #HOPE4LIVER trial, which is sponsored by HistoSonics, a U-M startup company working to commercialize the histotripsy technique. This trial, for which U-M was the largest contributor, has completed initial accrual and the results from this study are scheduled to be published shortly.

FINDING A WAY AROUND TREATMENT RESISTANCE IN BRAIN TUMORS

Research and advancements in medicine have made many cancers more responsive to care and increased survival rates. But many forms of the disease, including brain tumors like glioblastomas, remain difficult to treat and are almost universally fatal.

The immunotherapies and targeted treatments that have worked for cancers like melanoma, lung cancer, and lymphoma have been tried on glioblastomas, but haven’t returned positive results. One reason for this ineffectiveness could be that so many cancer drugs are designed to work outside of the brain and aren’t able to cross the blood-brain barrier to get to the tumor.

Forbes scholar Daniel Wahl, M.D., Ph.D., is researching new approaches to overcome treatment resistance in aggressive brain tumors. He is examining the role that purines — organic compounds that are building blocks for DNA and RNA — play in making a tumor resistant to therapies. Purines provide the necessary energy to promote cell survival, growth, and invasiveness. High concentrations of purines have been found in tumor cells. Removing its energy source could impact a tumor’s processes and make it

more susceptible to treatment. Dr. Wahl has conducted a Phase 0 clinical trial to see if a purine blocker can help make radiation or medication therapies more effective. Patients were given a purine inhibitor drug before they went into surgery. Dr. Wahl’s team would be in the operating room to take tumor tissue samples and analyze them to see how much of the drug reached the tissue. They found that a good amount of the drug got to the tumor and that its purine levels had dropped.

The clinical trial patients have already seen promising outcomes. Average survival rates for those with recurring cases of glioblastoma have increased to 16 months, compared to the typical 8-10 months following diagnosis. Some participants are still living after two years.

“It’s not final yet, but we are encouraged,” Dr. Wahl says. “The single most important thing for getting this trial going was the Forbes Institute grant. It helped us generate preliminary data that led to a major grant from the National Cancer Institute to fund this trial. I couldn’t be more grateful for how this has worked out.”

BUILDING MOMENTUM IN CANCER RESEARCH

The Forbes Institute welcomed a gene rous $1 million gift from Karen and Mitchell Padnos to launch the Karen and Mitchell Padnos Emerging Investigators program. The Padnos’ partnership represents inspiring new growth in cancer research at U-M and will support the groundbreaking and transformative work of U-M scientists.

MORE HEADLINES FROM FORBES SCHOLARS

• High levels of ammonia in colon tumors inhibits T cell growth and response to immunotherapy

• Dietary change starves cancer cells, overcoming treatment resistance

• Unraveling the biology behind aggressive pediatric brain tumor reveals potential new treatment avenue

• Machine learning creates opportunity for new personalized therapies

• Dynamic cells linked to brain tumor growth and recurrence

• Outsmarting brain cancer

• For glioblastoma, a new clinical trial fosters innovation and hope

Read these stories and more! Visit “News and Impact” at rogelcancercenter.org/ForbesInstitute

Evan Keller, D.V.M., Ph.D,

Daniel Wahl, M.D., Ph.D.

Indika Rajapakse, Ph.D.

Sunitha Nagrath, Ph.D.

Clifford Cho, M.D.

Analisa DiFeo, Ph.D.

For more information about the Forbes Institute or to make a contribution, visit rogelcancercenter.org/ForbesInstitute or contact:

Amanda Smith Senior Associate Director of Development, Cancer Programs Michigan Medicine Office of Development

734-647-2742

amandasn@umich.edu

ABOUT THE FORBES INSTITUTE

The Forbes Institute for Cancer Discovery was found ed by Sidney and Madeline Forbes, longtime Detroit-area philanthropists and dedicated friends and supporters of the University of Michigan. Nathan Forbes represents the family’s dedication to high-impact research on the Rogel Cancer Center’s National Advisory Board. The Forbes Institute’s grants are solely funded by gifts from donors, and the Forbes family invites everyone inspired to advance cancer knowledge toward cures to be a partner in their mission.