Nurturing high-risk, high-reward ideas

Sunitha Nagrath’s research is of a few projects funded by the Rogel Cancer Center’s Forbes Institute for Cancer Discovery that was featured in a recent article. The full text can be found here.

by Nicole Fawcett
Rogel Cancer Center

Sunitha Nagrath, Ph.D., had never heard of ductal carcinoma in situ. But when the chemical engineer started talking to breast cancer clinicians, she saw a problem she could help solve.

Why were patients diagnosed with this very early, non-invasive form of cancer developing distant metastases 20 or 30 years later?

“There was a very provocative idea in the field that these cells come into the blood early on,” says Nagrath, professor of chemical engineering. “The tumor was removed early, so why are these cells re-emerging after 20 years? The cells have to come from the DCIS. But how do we connect the dots? If you look at blood from DCIS patients, do you find tumor cells in the blood?”

Nagrath had already published research findings about circulating tumor cells in the blood. She had developed microfluidic devices to sort the small number of tumor cells from the large number of white blood cells. She had the tools to begin to understand whether DCIS was shedding into the blood.

There was only one problem: Who would fund something this out-of-the-box and unproven?

“Whenever we present this work, people say, ‘That’s not even a cancer.’ Why does this cell appear in the blood? It’s very much stretching our imagination in terms of science,” Nagrath says.

“We could not go to traditional funding initially because it’s such a provocative idea. First, we had to convince people this is something you can find. Even though we had some preliminary data, it was not enough to for us to pursue NIH funding,” Nagrath says.

Mainstream federal funding agencies like the National Institutes of Health often require extensive preliminary data before funding a project. But the Forbes Institute for Cancer Discovery, a philanthropy-fueled institute within the Rogel Cancer Center, takes aim at high-risk, high-reward concepts, providing seed funding to take a promising, bold idea forward.

“The goal of the Forbes Institute is to fund bold ideas that may have a big clinical impact,” says Max S. Wicha, M.D., Madeline and Sidney Forbes Professor of Oncology and director of the Forbes Institute.

“We have a clear metric that is a little different from other funding mechanisms. For projects funded through the institute, we look down the road: Do they take ideas from the laboratory to the clinic to directly benefit cancer patients?”

The Forbes Institute was founded in 2016 with a $17.5 million gift from Madeline and Sidney Forbes. Sidney Forbes founded The Forbes Company, a nationally recognized developer, owner and manager of luxury shopping destinations, including the Somerset Collection in Troy, Michigan.

The institute fosters cross-disciplinary collaboration, encouraging partnerships among faculty from various disciplines across the University of Michigan campus. The goal is to fuel rapid development of innovative technology and new therapies.

Nagrath was one of the initial Forbes Scholars. She had some proof-of-concept data that found circulating tumor cells in the blood of patients with DCIS and single cell analysis that showed these cells came from DCIS. With one year of funding from Forbes, Nagrath and doctoral student Neha Nagpal took a deeper dive into these cells, isolating them and examining single cell RNA transcriptome to identify DCIS-specific markers.

Tumor dormancy is emerging as a crucial issue for several cancer types, notably breast cancer. A 2017 New England Journal of Medicine paper led by Rogel researcher Daniel Hayes, M.D., reported that women with hormone sensitive breast cancer still face a substantial risk of cancer returning or spreading even 20 years after a diagnosis.

“This is an important area because it is such a big clinical problem”” says Wicha, who now collaborates with Nagrath on this work. “Women with hormone receptor positive breast cancer are told they’re cured after their adjuvant therapy, but the fact is they have a risk of recurrence that remains for the rest of their lives. Up to now there’s been no real test for dormant tumor cells or therapies to get rid of these seeds of metastases before they start growing.”

Nagrath and Wicha’s goal is to develop tools to identify which patients are harboring potentially aggressive dormant cells and find a way to eliminate those cells before they become metastases.

With Nagrath’s assay, survivors could potentially get regular blood draws to analyze circulating tumor cells. Another novel idea, also funded through the Forbes Institute, involves an implantable scaffold device designed to catch these circulating cells. The scaffold, which is implanted under the skin, traps immune cells, which differ in healthy tissue and tumors. The circulating cells grow on the scaffold, creating a microenvironment similar to a metastasis.

“Our approach is unique in that the implant mimics a metastatic site,” says Lonnie Shea, Ph.D., Steven A. Goldstein Collegiate Professor of Biomedical Engineering. “The site is being prepared for the arrival of cancer cells, which occurs prior to the spread of disease.”

The team is using the scaffold to study how factors in the microenvironment influence tumor dormancy. In a 2023 study in Nature Communications, they found that in mice with the implanted scaffold, the scaffold microenvironment recruited circulating tumor cells, mimicking a lung metastasis. Immune cells that either block cancer or promote cancer are attracted into the scaffold or the lungs and establish either active or suppressive immune environments. In the active immune environments, tumors cells are dormant. In the suppressed immune environment, aggressive metastases grow. Monitoring and tracking cells within the scaffold could help identify aggressive metastases and dormant tumors.

Shea and Jacqueline Jeruss, M.D., Ph.D., professor of surgery, have applied for approval from the U.S. Food and Drug Administration to implant the scaffold device in people with breast cancer.

Rogel researchers are now teaming up with three other institutions to submit a large program project grant around tumor dormancy, applying the Nagrath assay and Shea scaffold to identify dormant cells, then developing metabolic and immune therapies to try to eliminate them. The project will involve obtaining tissue and blood samples from patients undergoing surgery for DCIS.

For Wicha, it’s a prime example of how the Forbes Institute can move the needle.

“Those first funds are hard to get if you have a really novel idea. The scaffold, for example, is not the kind of thing NIH would ever consider funding,” Wicha says. “With the Forbes Institute, we take a chance. We want new ideas that, if they work, will have a big impact.”