Pancreatic Cancer Surgeon-Scientist Awarded DOD Funding

Sylvester researcher Jashodeep Datta, M.D., will study how to disrupt the tumor-permissive crosstalk between the immune system and fibroblasts in pancreatic cancer.

The U.S. Department of Defense recently awarded Dr. Datta, a surgical oncologist and cancer researcher at Sylvester Comprehensive Cancer Center, part of the University of Miami Miller School of Medicine, a highly competitive grant for an innovative study on pancreatic cancer.

Dr. Datta, the DiMare Family Endowed Chair in Immunotherapy and associate director of translational research at Sylvester’s Pancreatic Cancer Research Institute, is the recipient of the DOD Pancreatic Cancer Research Program Idea Development Award, a three-year, $800,000 federal grant from the Congressionally Directed Medical Research Program to pursue a new approach to tackling one of the deadliest types of cancer.

More than 64,000 people will be diagnosed this year with pancreatic cancer, and it will be fatal for 50,000, per the American Cancer Society’s estimates. National Cancer Institute research indicates that there has been a marked increase in the incidence of pancreatic cancer in the past several decades. The fourth leading cause of cancer mortality in the U.S., its etiology is poorly understood. With risk factors that include inherited and non-inherited pathways, the cancer remains difficult to detect and diagnose because symptoms do not present until the disease reaches later stages and there is no screening test. Moreover, pancreatic cancer is extremely tough to treat.

A Focus on New Approaches

In his laboratory at Sylvester, Dr. Datta is determined to find new immunotherapy approaches to target the defining hallmarks of treatment resistance in pancreatic cancer. His prior research includes significant studies on the genetic and molecular factors that affect patient responses to chemotherapy and immunotherapies, implicating a major role for the innate immune system in thwarting antitumor responses. Last year, he received a prestigious career development grant from the Pancreatic Cancer Action Network (PanCAN) to study how myeloid-derived suppressor cells, or MDSCs — a component of the innate immune system hijacked by tumors — promote treatment resistance by sustaining pro-tumorigenic inflammatory networks in pancreatic cancer.

“As a surgical oncologist and cancer immunology researcher, my ultimate goal is to target these critical elements of what makes pancreatic cancer so challenging to treat and bring these therapies to the patients’ bedside,” Dr. Datta said.

The DOD-funded study supports a new arm of his research program, and aims to advance the understanding of the signaling circuitry between MDSCs and pro-inflammatory cancer-associated fibroblasts (CAFs) in the tumor microenvironment; the latter have been shown to be a major driver of treatment resistance in pancreatic cancer. Moreover, Dr. Datta’s group will target this crosstalk between MDSCs and fibroblasts using a novel nanoengineering immunotherapy that specifically disrupts these signaling mechanisms selectively in MDSCs. These efforts will lay the groundwork for commercialization of this nanotechnology to improve chemosensitivity in pancreatic cancer patients.

“Pancreatic cancers are highly resistant to standard treatments due to these diverse and disparate factors in the tumor microenvironment,” said Dr. Datta, who is also an assistant professor of surgery at the Miller School. “This new study will focus on catalyzing the development of a bold nanoengineered immunotherapy to disrupt signaling connections between MDSCs and fibroblasts that helps drive tumor chemoresistance.”

Uncovering Novel Crosstalk in the Pancreatic Tumor Microenvironment

Dr. Datta’s proposed research will examine the precise mechanisms by which these immunosuppressive MDSCs, which can make up to 20-30% of a typical tumor, interact with CAFs in the dense stroma that surrounds pancreatic cancer cells. Importantly, Dr. Datta’s lab and others have shown that both MDSCs and pro-inflammatory skewness of CAFs limit the effectiveness of standard therapies in pancreatic cancer.

“The novelty of this study is that it will be one of the first examining the intricate communication links between these two players in the tumor microenvironment,” said Dr. Datta. “Activated MDSCs instigate pro-inflammatory signaling in CAFs. In turn, these CAFs act as cellular antennae that transmit such inflammatory cues that beckon more MDSCs to infiltrate tumors, sustain immunosuppression and promote therapy resistance in pancreatic cancer cells.”

Dr. Datta and his team want to deeply investigate the signaling cascades that underlie these MDSC-CAF networks and devise a cell-specific engineering approach to prevent the activation of this inflammatory pathway in MDSCs.

“It is important to have specific targets in specific compartments in the tumor microenvironment, because ‘shotgun’ therapies have mixed effects,” Dr. Datta said. “We hope to restrict our targeting strategies selectively to MDSCs and inhibit their activation while avoiding unwanted complications that can occur with standard treatments that can adversely impact helpful immune cells (e.g., T-cells) as well as non-cancerous cells in our bodies.”

This study will also aim to use high-dimensional tissue imaging to see whether the spatial relationships between ecosystems of MDSCs and CAFs can predict poor chemotherapy responses in patients receiving treatment at Sylvester.

“Another impactful aspect of this study is that we will investigate if increased density of these MDSC-CAFs neighborhoods in tumors from Black patients may explain the disturbing racial disparities associated with chemotherapy responses in this disease,” he added.

Nanoparticles to Target MDSCs

To achieve the study’s objectives, Dr. Datta is collaborating with co-investigator Shanta Dhar, Ph.D., assistant director of technology and innovation at Sylvester and associate professor of biochemistry and molecular biology at the Miller School. Much of Dr. Dhar’s research is on how to use nanoparticle-assisted targeted delivery of therapeutics in cancer, cardiovascular and neurodegenerative diseases. Nanoparticles are created through the manipulation of materials at atomic, molecular and macromolecular scales.

“We have been working together to design a nanoparticle that can penetrate the tumor and deliver a payload of medication right to these MDSCs,” she said. “It’s an exciting project because it looks at the problem of treatment resistance in pancreatic cancer from a completely different perspective. Rather than trying to penetrate the dense stroma surrounding the cells, we can target the key cells that generate pro-tumorigenic signaling cascades in the microenvironment.”

Dr. Dhar added that the nanoparticles consist of biodegradable polymers that can be reproduced at scale if this therapeutic approach proves to be successful.

“Hopefully, this study will be a great example of translational science, taking findings from the laboratory into development to help patients and families facing the challenge of pancreatic cancer,” said Dr. Dhar.

Tags: Congressionally Directed Medical Research Programs, Department of Defense, Dr. Jashodeep Datta, Dr. Shanta Dhar, pancreatic cancer, Pancreatic Cancer Action Network, Pancreatic Cancer Research Institute, Sylvester Comprehensive Cancer Center