Researchers with Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine have been awarded a grant from the U.S. Department of Defense (DoD)'s Congressionally Directed Medical Research Program to target chemotherapy resistance in pancreatic cancer.
The $800,000, three-year grant is the first DoD award to Sylvester to study pancreatic cancer, a disease characterized by extreme resistance to chemotherapy and other treatments and dismal survival rates.
Pancreatic ductal adenocarcinoma is the most common and aggressive form of this disease. It accounts for more than 90% of cases and leads to almost 500,000 deaths per year worldwide, according to the National Institutes of Health (NIH).
In the U.S., about 65,000 people will be diagnosed with pancreatic cancer this year, and more than 50,000 will die from it, per estimates from the American Cancer Society. Statistics from NIH indicate it is the third-leading cause of cancer death in this country, after lung and colorectal cancer, and the number of cases in the U.S. and Europe is expected to double over the next decade, due to rising rates of obesity and type 2 diabetes.
Pancreatic cancer remains difficult to diagnose because there are no good screening tests and its symptoms do not present until the disease has advanced to later stages. Additionally, it's highly resistant to standard treatments due to diverse and disparate factors in the tumor microenvironment."
Jashodeep Datta, M.D., associate director of Translational Research at Sylvester's Pancreatic Cancer Research Institute and principal investigator for the new study
Datta, who is also UM Miller's DiMare Family Endowed Chair in Immunotherapy and a surgical oncologist specializing in pancreatic and hepatobiliary cancers, says this DoD study will support a new arm of his research program that aims to advance knowledge of the intricate signaling circuitry between myeloid-derived suppressor cells (MDSCs) and pro-inflammatory cancer-associated fibroblasts (CAFs) within the pancreatic tumor microenvironment. MDSCs are a component of the innate immune system that becomes hijacked by tumors, and early data from the Datta lab reveals that their intimate relationship with CAFs are a major driver of treatment resistance in pancreatic cancer.
In the proposed study, Datta will examine the precise signaling mechanisms by which these MDSCs and CAFs interact using innovative preclinical mouse models and single-cell sequencing methodologies. Then, using high-dimensional tissue imaging, the study will determine if spatial relationships between ecosystems of MDSCs and CAFs correlate with poor chemotherapy responses in patients receiving treatment at Sylvester.
Lastly, Datta and his colleagues seek to target this crosstalk between MDSCs and CAFs using a novel nanoengineered immunotherapy that specifically and selectively disrupts signaling mechanisms in MDSCs. "Our study will focus on catalyzing development of a bold immunotherapy to disrupt signaling connections that help drive tumor chemoresistance," Datta explained.
"Our study will be one of the first to examine the intricate communication between these two players in the tumor microenvironment," he said. "Activated MDSCs instigate pro-inflammatory CAF signaling. In turn, CAFs act as cellular antennae that transmit 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 investigate the signaling cascades that underlie these MDSC-CAF networks and devise a cell-specific engineering approach to prevent activation of this inflammatory pathway.
He noted that it's important to have specific targets in the tumor microenvironment because "shotgun" therapies produce mixed effects. "We hope to restrict our targeting selectively to MDSCs and inhibit their activation while avoiding unwanted complications that can occur with current treatments," he explained. "We want to avoid adversely impacting helpful immune cells, such as T-cells, as well as other non-cancerous cells in our bodies."
Another key aspect of the study is their plan to investigate if increased density of MDSC-CAF "neighborhoods" in tumors from Black patients may explain the disturbing racial disparities associated with chemotherapy responses to the disease, Datta added.
Nanoparticles to target MDSCs
For this study, Datta will collaborate with co-investigator Shanta Dhar, PhD, assistant director of Technology and Innovation at Sylvester and associate professor of biochemistry and molecular biology. Dhar's research focuses on nanoparticle-assisted delivery of therapeutics for cancer and cardiovascular and neurodegenerative diseases.
"We have been working together to design a nanoparticle that can penetrate the tumor and deliver a medication payload right to the MDSCs," Dhar said. "It's exciting because we're approaching the problem of tumor resistance from a different perspective."
Rather than trying to penetrate the dense stroma surrounding the cells, she explained, they will target the key cells that generate pro-tumor signaling cascades in the microenvironment.
Equally important, the nanoparticles used for therapeutic purposes are biodegradable polymers that can be reproduced at scale for wide application if this approach proves successful, Dhar added.
"Hopefully, this study will be a great example of translational science, taking laboratory findings into development of effective treatments to help patients and families facing the daunting challenge of pancreatic cancer," Dhar concluded.