R37 MERIT Grant Winner Takes Aim at Immune System in Pancreatic Cancer
Article Summary
- Sylvester physician-scientist Dr. Jashodeep Datta is the principal investigator on a new $2.5 million NCI R37 MERIT grant.
- The grant funds a project investigating the tumor microenvironment in pancreatic cancer, which contributes to resistance to cancer treatment that combines chemotherapy and immunotherapy.
- The researchers will investigate the effects of disrupting this environment with an experimental drug that could set the stage for a clinical trial.
Researchers at Sylvester Comprehensive Cancer Center, part of the University of Miami Miller School of Medicine, will explore a new way to treat one of the deadliest tumor types, pancreatic cancer, with funding from a new grant.
Project leader Jashodeep Datta, M.D., anticipates that the $2.5 million award from the U.S. National Cancer Institute (NCI) may set the stage for a clinical trial at Sylvester, South Florida’s only NCI-designated cancer center.
Resistance to Conventional Cancer Treatment
The research project focuses on understanding a network of molecular and cellular interactions that creates an impenetrable fortress for pancreatic cancer, enabling it to resist conventional therapeutic approaches.
While the emphasis is on investigating the network’s underlying biology, the work also has potential clinical implications.
Dr. Datta and his colleagues will test whether disrupting the network can make tumors susceptible to treatment. One of their tools for disruption is an antibody that interferes with the network by inhibiting a molecule called TNFR2 (Tumor Necrosis Factor Receptor 2). If this antibody works in experimental systems, human trials could begin as early as 2026, testing it in combination with conventional chemotherapy and immunotherapy.
“My entire academic mission is focused on trying to improve chemoimmunotherapy sensitivity in pancreatic cancer by retraining the immune system, to try to make the drugs that we know work in other tumor types work better in this disease,” said Dr. Datta, a surgical oncologist and the DiMare Family Chair in Immunotherapy.
“The grant awarded to Dr. Datta formally recognizes the significant value of the scientific research he is conducting at Sylvester. This forward-thinking research seeks to ultimately improve outcomes for patients facing one of the most challenging cancers to treat,” said Sylvester Director Stephen D. Nimer, M.D., a Miller School professor of medicine, biochemistry and molecular biology, as well as executive dean for research and the Oscar de La Renta Endowed Chair in Cancer Research. “With his research colleagues, Dr. Datta is able to explore new areas in cancer research and provide important insights that will improve the lives of our patients.”
Targeting Cells That Foster Cancer
Cancer researchers typically put their focus on understanding cancer cells. But tumors live, and often thrive, in a milieu that also includes connective tissue and immune cells.
Dr. Datta thinks that targeting this milieu is one of the keys to thwarting pancreatic cancer. Pancreatic tumor cells are highly embedded within a matrix of immune cells and connective-tissue forming stromal cells — more than with almost any other type of cancer. These cells can create a tumor microenvironment that fosters and protects cancer cells and shields them from treatment.
“We have zoomed into the cell types that are often ignored, sometimes forgotten, but that are critically important,” said Dr. Datta.
Key cells in the pancreatic tumor microenvironment include immune cells called neutrophilic/granulocytic myeloid-derived suppressor cells (MDSCs) and stromal cells called cancer-associated fibroblasts (CAFs).
Previous work by Dr. Datta and others has shown that MDSCs help shield cancer cells from immune attack. The MDSCs do this in part by excluding T cells from the tumor microenvironment. Pancreatic CAFs, in turn, promote inflammation and the migration of MDSCs into the tumor microenvironment.
The structural and immune cells interact with each other and tumor cells through signaling molecules that direct their actions. In a recent publication, Dr. Datta and his colleagues identified a key molecular regulator in this process, TNFR2. Inhibiting TNFR2 activity disrupted the cellular network in experimental systems and improved sensitivity to chemotherapy.
More recently, they showed elevated TNFR2 signaling is associated with chemoimmunotherapy resistance in patients.
Disrupting the Network
The researchers are now further exploring their findings in cancer models and human tumor specimens. The grant funding will help them understand more precisely the interactions between the cells and molecules and assess the impact of TNFR2 inhibition.
Project aims include:
• Further dissecting the molecules involved in regulating the activity of MDSCs and CAFs in pancreatic cancer. MDSCs are known to produce TNF, a molecule that interacts with TNFR2 on the surface of CAFs. But a host of other cellular regulators also play a role, including molecules known to be targeted by existing drugs. Do these drugs affect MDSC activity in patients? That is just one question the researchers will address.
• Exploring how signaling between the MDSCs and CAFs contributes to chemoimmunotherapy resistance. For instance, what is the architecture of the cellular network in patients that drives resistance to chemoimmunotherapy — are these MDSC-CAF networks more abundant?
• Assessing whether TNFR2 inhibition prolongs survival in cancer models treated with standard chemotherapy and immunotherapy agents. How is the cellular milieu affected by the drugs?
Reaching Up and Out
R37 MERIT (Method to Extend Research in Time) awards are given to early-stage investigators who receive an exceptional grant score within the pay line for established investigators. The NCI awards the grants to investigators “whose research competence and productivity are distinctly superior and who are highly likely to continue to perform in an outstanding manner.” The award will run through 2031.
“This is a highly prestigious research grant and a true testament to the remarkable innovation and productivity Dr. Datta has demonstrated in his short time as a faculty member,” said Nipun Merchant, M.D., chief of the Division of Surgical Oncology at Sylvester and director of the Sylvester Pancreatic Cancer Research Institute. Dr. Datta joined Sylvester in 2019.
“This award not only underscores the unique nature of Dr. Datta’s work but also acknowledges the significant potential it holds for improving outcomes in one of the most lethal forms of cancer,” added Dr. Merchant.
Dr. Datta also recently gave scientific presentations about the ongoing research at a plenary talk at an American Association for Cancer Research conference focused on pancreatic cancer research and at the PanCAN Scientific Summit.
Broader Implications for TNFR2 inhibitors
Dr. Datta is hopeful that the research could lead in the near future to studies of TNFR2 inhibitors in patients at Sylvester, in combination with conventional chemotherapy and immunotherapy. The experimental drug, being developed by Boston Immune Technologies & Therapeutics, is already being tested in phase 1 clinical trials for a form of blood cancer.
The award may also lead to insights that are relevant to other tumor types similarly shielded by their microenvironment, such as glioblastoma, said Dr. Datta.
The work could even identify new ways to diagnose pancreatic cancer and detect it earlier. Cells in the blood, like MDSCs and their associated molecular biomarkers, may provide an early warning system.
The new grant builds on others awarded to researchers at the Sylvester Pancreatic Cancer Research Institute. These include a recent $660,000 project led by Dr. Datta and Sylvester physician-researcher Peter Hosein, M.D., to explore another approach to increasing the susceptibility of pancreatic tumors to immunotherapy drugs.
New approaches to treating pancreatic cancer are badly needed. The five-year survival rate is only 13%, and the disease is still the third-leading cause of cancer death in the U.S. There are a lot of unanswered scientific questions.
“We are just beginning to scratch the surface of understanding how immune and stromal cells interact in the tumor microenvironment in pancreatic cancer,” said Dr. Datta.
Tags: cancer research, chemoimmunotherapy, chemotherapy, Dr. Jashodeep Datta, immunotherapy, National Cancer Institute, NCI grant, Sylvester Comprehensive Cancer Center