Forbes Institute Impact Report

“It is so inspiring to see the breakthroughs that are consistently being driven by University of Michigan physicians and researchers. The Forbes family is honored to partner with the incredible teams at U-M to bring more hopeful options to patients and families facing difficult cancer diagnoses. The progress we have made is moving us closer to finding cures and truly improving the lives of survivors, and we thank everyone who has supported us in this mission.” — Nathan Forbes

Moving Discovery from the Lab to the Clinic

Max S. Wicha, M.D.

Madeline and Sidney Forbes Professor of Oncology Director, Forbes Institute for Cancer Discovery

Next-Generation Solutions in Biology and Human Health

The U-M Single Cell Spatial Analysis Program is helping to grow the university into a recognized leader in applying high-resolution spatial multiomic analysis within individual cells and in cells within tissues. Multiomic analysis uses data sets from multiple “omes” — such as the genome, proteome, transcriptome, epigenome, metabolome, and microbiome — to analyze complex big data and identify relevant biomarkers of disease.

Led by Evan Keller, Ph.D., the Richard and Susan Rogel Professor of Oncology, the Single Cell Spatial Analysis Program received Forbes support to acquire the Nanostring GeoMx, a technology platform that enables multiomic analysis of tissue. This tool has been used by a number of Forbes Scholars and other researchers at U-M to study biomarkers that can predict therapeutic response, profile tumor microenvironments, uncover drug mechanisms, understand disease mechanisms, and analyze pre-clinical models. A couple of projects that have benefited from this technology include:

Molecular Dissection of Multifocal Prostate Cancer

Simpa S. Salami, M.D., MPH, associate professor of urology at U-M, is examining the origin of lymph node metastasis in primary multifocal prostate cancer, which occurs when there is more than one distinct tumor focus or nodule present in the same prostate.

Sixty to 80% of primary prostate cancers are multifocal. When the prostate is removed for cancer treatment, the gland often has distinct tumor areas in various stages of evolution. At present, it is not certain which nodule is most significant in driving the overall biology of the disease. It is also unknown how germline alterations in genes such as BRCA1/2 impact the tumor immune microenvironment.

Understanding which nodule plays the most prominent role in the biology of the cancer and uncovering its molecular profile are crucial steps needed to advance accurate screening, early detection, and treatment strategies.

Dr. Salami’s team is using a combination of molecular profiling tools including spatial transcriptomic profiling to perform multi-region characterizations of prostate cancer and lymph node metastases specimens. This effort includes specimens from patients with germline alterations such as BRCA1/2, CHEK2, ATM, and others. They will also profile RNA and DNA from urine and compare with prostate specimens. Data will be analyzed to identify mutations, alterations, gene fusions and other transcripts to pinpoint the dominant cancer nodule that leads to metastasis. Additionally, the effects of pathogenic germline alterations on the tumor microenvironment will be analyzed.

To date, Dr. Salami’s team has performed spatial transcriptomic profiling of 11 patients with prostate cancer and pathogenic germline alterations associated with aggressive disease.

Using Spatial Transcriptomics to Understand Precursors to Pancreatic Cancer

A collaborative team of Eileen Carpenter, M.D., Ph.D., assistant professor of gastroenterology and hepatology; Marina Pasca Di Magliano, Ph.D., the Maud T.

Lane Professor of Surgical Immunology; and Timothy Frankel, M.D., the Maud T. Lane Professor of Surgical Oncology, is using spatial analysis to study the mechanisms that cause certain pancreatic lesions to transform to cancer.

These lesions remain the only identifiable precursor to pancreatic cancer. Unfortunately, there is limited research and information on which lesions will progress to malignancy. This is because it is rare for scientists to obtain tissue from a healthy pancreas to compare to cancerous tissue. It can also be difficult to find and extract cells from the lesions.

“We wanted to study precancerous pancreatic lesions, which are present, but make up a very small portion of the entire healthy pancreas, which is akin to looking for a needle in a haystack,” says Dr. Carpenter. “Because the single cell sequencing pipeline does not allow for histological examination of the tissue, the only way for us to really hone down on the molecular features of these pancreatic lesions was to turn to spatial transcriptomics, and that’s where NanoString came into play.”

In partnership with Gift of Life Michigan, Drs. Carpenter, Pasca Di Magliano, and Frankel collected pancreatic tissue from 30 healthy adult organ donors for whom no suitable recipient was identified.

Using a combination of single-cell RNA sequencing and spatial transcriptomics, the team provided the first-ever characterization of the microenvironment of the adult human pancreas and of sporadic PanIN lesions. They found that PanIN cells were remarkably similar to cancer cells, but the environment around the lesions is markedly distinct, which suggests that the environment is restraining the lesions from becoming cancerous.

These findings can help to set the stage for further studies on pancreatic cell microenvironments and factors within the cell that could prevent or promote cancer growth.

Evan Keller, Ph.D.

Eileen Carpenter, M.D., Ph.D. Marina Pasca Di Magliano, Ph.D.

New Immunotherapy Against Triple-Negative Breast Cancer

Despite the recent success of cancer immunotherapy, less than 30% of patients respond to these promising treatments. In this project, James Moon, Ph.D., the J. G. Searle Professor of Pharmaceutical Sciences, has developed a novel approach for activating the host immune responses against advanced cancer.

STING, which stands for stimulator of interferon genes, is a protein that helps to induce a body’s response to cells that are infected with viruses, mycobacteria, and other pathogens. As a mediator in the immune system, STING is considered one of the key regulators that could help to increase positive responses to immunotherapy.

Given the critical role of the STING pathway in cancer immunity, many pharmaceutical companies are racing to establish their discovery pipelines for drugs that can alter and activate STING molecules. This approach has shown great potential for treating infection and cancer.

Dr. Moon is working to develop the next generation of STING activating medications with potent anti-tumor properties. He is also focused on ensuring that these drugs have acceptable safety profiles. His innovative approach is based on his research team’s recent discovery that adding the nutritional metal ion manganese to these STING activators boosted STING’s tumor-fighting capability up to 77-fold.

Dr Moon’s team has demonstrated the potency and safety of this approach in animal models and anticipates they will soon be able to initiate a phase I clinical study to examine the effectiveness in cancer patients.

Karen and Mitchell Padnos Emerging Investigators

Inspired by the work of the Forbes Institute, donors

Karen and Mitchell Padnos established the Padnos Emerging Investigators within the institute. The program provides three-year awards to earlycareer faculty members to pursue imaginative new concepts and approaches to cancer research with high potential for clinical impact.

Calista Harbaugh, M.D., an assistant professor of surgery, was recently selected as the first Padnos Investigating Scholar. With support from the program, she has established a mentorship team, submitted for external funding, built her research team, and established a line of preliminary investigation.

James Moon, Ph.D.

Calista Harbaugh, M.D.

Examining Cell Interactions and Ecosystems

Arvind Rao, Ph.D., associate professor in computational medicine and bioinformatics, is developing methodologies to look at tumor architectures and microenvironments using a variety of multiomics single cell and spatial technologies. Similar to ecosystems found in nature, these tumor microenvironments have predators, prey, species, and habitats. There are different immune cells, inflammatory cells, immunosuppressive cells, and tumor cells all existing and interacting in the same space. Dr. Rao’s work is trying to determine why tumors develop this way and what their architecture means for the subsequent biology of the tumor — the way a tumor evolves will impact how it responds to drug treatment or other therapies.

People have the same types of cells, but in different configurations. Dr. Rao’s team has observed that some configurations can lead to a lower grade of cancer, but others can lead to more aggressive forms. By helping to build a better understanding of the biology behind the spatial organizational properties and process of tumor cell development, this work could help researchers and physicians to more effectively anticipate the progression of a patient’s cancer and use more targeted and effective approaches for treatment.

“The Forbes Institute has been a critical catalyst in terms of bringing likeminded people together. We can take a multidisciplinary approach to these problems and bring all our expertise to the table, and then the Forbes Institute provides the umbrella for us to do some really transformational science by combining our capabilities.”

— Arvind Rao, Ph.D.

Dr. Harbaugh’s team has received institutional review board approval and initiated work in two main areas. The first is establishing measures of oncologic quality which can be captured in claims data, such as accreditation status of hospitals and guideline-concordant practice.

The second is exploring quality variation across the state of Michigan among the hospitals in the Michigan Surgical Quality Collaborative (MSQC). This work has examined quality metrics for colorectal cancer operations across the 69 MSQC hospitals and analyzed outcomes from a two-year quality improvement project focused on complete cancer resection, one potential technical quality target.

“The ability to use these funds to protect my academic time, establish mentorship, and build a team amplify the impact we can have with this work. I have strong aspirations to improve cancer care for all patients regardless of who they are or where the live. I deeply appreciate the support provided by the Padnos award which will help me to build the skill set I need to become an independently funded investigator to continue this line of work.”

— Calista Harbaugh, M.D.

Arvind Rao, Ph.D.

Overcoming Treatment Resistance In Newly Diagnosed And Recurrent Glioblastoma

Glioblastoma is a deadly incurable brain cancer. With the support of the Forbes Institute for Cancer Research, Daniel Wahl, M.D., Ph.D., associate professor of radiation oncology and associate professor of neurosurgery, has made discoveries in the laboratory and the clinic that could improve prospects for patients with this disease.

Dr. Wahl’s laboratory team has found that purine metabolism promotes glioblastoma growth, stemness, invasiveness, and treatment resistance. The purine synthesis inhibitor, mycophenolate mofetil (MMF), improves radiation and temozolomide efficacy in preclinical glioblastoma models.

Dr. Wahl then moved these studies into the clinic. His team has made the first measurements of purine metabolism in human brain cancer and recently published interim results from his phase 0/1 clinical trial where he administered MMF combined with chemoradiation in 30 recurrent glioblastoma patients. The trial showed that this treatment approach has been well tolerated in glioblastoma patients with preliminary promising evidence of intracranial target engagement and improved patient survival. This study has now prompted a larger randomized phase 2/3 trial, which will be conducted across dozens of cancer centers across the United States.

Forbes Scholars in the News

Read these stories and more — visit “News and Impact” at rogelcancercenter.org/forbesinstitute

“Is lung cancer treatment working? This chip can tell from a blood draw,” Sunitha Nagrath, Ph.D.

“Metabolite tells cells whether to repair DNA,” Daniel Wahl, M.D., Ph.D.

“Hungry for more: Metabolism pathways make tumors sensitive or resistant to treatments,” Deepak Nagrath, Ph.D.

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

A Brand New Treatment For Patients — And A Possible Boost For Immunotherapy

Clifford Cho, M.D., the C. Gardner Child Professor of Surgery and the vice chair of the U-M Department of Surgery, recently guided a clinical trial on histotripsy — a process that uses focused ultrasound to disrupt target tissue — that determined the procedure was effective and safe for liver tumors.

This led to an expedited FDA approval for the histotripsy device, which is now being used by Dr. Cho and colleagues to treat patients. The Rogel Cancer Center is one of only a few institutions in the country currently using this technology.

In addition to this promising new treatment, Dr. Cho’s lab is focused on improving cancer immunotherapy by making it more effective to use on a variety of cancers. The cancers he treats most commonly, cancers of the liver and pancreas, are notoriously resistant to immunotherapy.

Dr. Cho’s team has found that histotripsy elicits an immune response that can help a patient’s immune system destroy tumor cells. Histotripsy is also changing blood flow within tumors. The oxygen level of tumors is normally very low, which helps cancers. But histotripsy provides a sudden restoration of oxygen in tumors. That seems to be a critical first step that precedes a lot of inflammatory and immune events, and could stimulate beneficial immune responses in patients.

Another discovery that has come from this work is that partially treating a tumor with histotripsy can open up that tumor and significantly increase the amount of chemotherapy that gets into the tumor.

“Our Forbes Institute grant was a game changer for us. When we wrote our application for it, our work really was in its earliest steps. For a higher risk concept like this, I would have had a hard time getting funding. All the data we generated were made possible because of this Forbes award and we really are super appreciative for the support from the institute.” —

Clifford Cho, M.D.

“Hitting the mark: Circulating biomarkers, a new frontier in cancer care, brings both hope and unease to the clinic,” Sunitha Nagrath, Ph.D.

“Gene therapy for brain tumor shows promising early results in humans,” Sriram Venneti, M.D., Ph.D.

“Study finds improved survival for incurable brain tumor, providing ‘a crack in the armor,’” Sriram Venneti, M.D., Ph.D., and Daniel Wahl, M.D., Ph.D.

“Study shows new approach to target deadly form of prostate cancer,” Joshi Alumkal, M.D.

Clifford Cho, M.D.

A Promising Approach for Targeting a Deadly Form of Prostate Cancer

Joshi Alumkal, M.D., Wicha Family Professor of Oncology, is working to develop a new treatment for aggressive prostate and other cancers.

Using tissue samples and cell models from patients, Dr. Alumkal and his team zeroed in on the lysine specific demethylase 1 (LSD1), a protein involved in turning genes off and on in normal and cancer cells. LSD1 appears to be particularly important in certain aggressive forms of prostate cancer.

It was believed that LSD1 turns genes on and off by modifying the histone proteins around which the DNA is wound. However, drugs that block this function of LSD1 have been disappointing in clinical trials. Dr. Alumkal’s lab was the first to determine LSD1 has another function—acting as an escort to recruit key proteins to the DNA to turn genes on and off without modifying histones. This function of LSD1 appears particularly important in cancer cells, but there are no drugs to prevent LSD1 from carrying out this function.

“LSD1 functions as sort of a scaffold or a crossing guard to bring other proteins to the DNA where they act to turn genes on and off. If you can get rid of LSD1 in a cancer cell, then those proteins cannot get to the DNA—they are stuck on the wrong side of the street,” says Dr. Alumkal.

“Our studies strongly suggest that removing LSD1 from cancer cells would be much more effective than preventing it from modifying histone proteins.”

Joshi Alumkal, M.D.

Dr. Alumkal’s lab believes that previous clinical trials of LSD1 inhibitors were not successful because those drugs did not address the important “crossing guard” function of LSD1. His lab’s approach is focused on removing LSD1 in cells rather than just interfering with its ability to modify histones.

In a new Forbes Institute proposal, Dr. Alumkal has teamed up with Shaomeng Wang, Ph.D., the Warner-Lambert/ParkeDavis Professor of Internal Medicine, and professor of medicinal chemistry in the U-M College of Pharmacy. Dr. Wang is an expert in drug development and is partnering with Dr. Alumkal to develop a new approach to block LSD1 using a degradation technology called Proteolysis Targeting Chimera, or PROTAC for short. PROTACs are a way to hijack the normal cellular process for removing proteins to target specific proteins of interest for degradation.

This project will modify existing LSD1 inhibitors that have proven to be safe in patients but which did not have significant tumor suppressive effects—most likely because these drugs did not block LSD1’s crossing guard function. Drs. Alumkal and Wang will turn these LSD1 inhibitors into PROTACs with the hope of developing a much more effective treatment for tumors driven by LSD1, including lethal prostate cancers, leukemia, lung cancer, and breast cancer.

“The fact that we have identified important, previously unappreciated functions of LSD1 and that we have found a suitable LSD1 inhibitor to modify into a PROTAC gives me hope that we might be able to develop a brand new approach to target LSD1 more effectively that we eventually move to the clinic,” he said.

Forbes Scholars Recent Honors and Achievements

JOSHI ALUMKAL, M.D.

• Stephen Weiss Award for Excellence in Research by an Established Investigator, 2023

• Named as the inaugural Wicha Family Professor in Oncology, 2022

• Prostate Cancer Foundation Challenge Award, 2021

CLIFFORD S. CHO, M.D.

• Invited speaker at IEEE International Ultrasonics Symposium, 2021

TOMASZ CIERPICKI, PH.D.

• Frankel Innovation Initiative Award, 2023

• Received promotion to professor of pathology, 2022

EVAN KELLER, D.V.M., PH.D.

• Named as Richard and Susan Rogel Professor of Oncology, 2022

• Named the inaugural director of research cores in the U-M Office of the Vice President for Research, 2022

DAVID MARKOVITZ, M.D.

• Frankel Innovation Initiative Award, 2022

JAMES MOON, PH.D.

• Controlled Release Society Samyang Award in Honor of Sung Wan Kim, 2023

• The American Institute for Medical and Biological Engineering (AIMBE) Fellow, 2023

• Fellow of the Biomedical Engineering Society, 2022

• Biointerfaces Institute Innovator Award, 2022

DEEPAK NAGRATH, PH.D.

• Received promotion to professor of biomedical engineering, 2023

SUNITHA NAGRATH, PH.D.

• Elected to the College of Fellows at the American Institute for Medical and Biological Engineering, 2021

SRIRAM VENNETI, M.D., PH.D.

• Named Scientific Research Director for the Chad Carr Pediatric Brain Tumor Center at U-M, 2022

• Named as the inaugural Al and Robert Glick Family Research Professor in Pediatrics, 2021

DANIEL WAHL, M.D., PH.D.

• Received promotion to associate professor of radiation oncology, 2022

• Sontag Foundation Distinguished Scientist Award, 2021

Together, We Can Make a Difference

The Forbes Institute for Cancer Discovery was founded 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.

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

Regents of the University of Michigan: Jordan B. Acker, Michael J. Behm, Mark J. Bernstein, Paul W. Brown, Sarah Hubbard, Denise Ilitch, Ron Weiser, Katherine E. White, Santa J. Ono, (ex officio).

A Non-discriminatory, Affirmative Action Employe

©2024 Regents of the University of Michigan