Pancreatic cancer is a leading cause of cancer-related deaths. The development of drugs targeting mutant KRAS, the oncogenic driver of most pancreatic cancers, has led to much optimism for improved treatments. However, tumor recurrence driven by heterogeneous cancer cell responses to these drugs remains a major challenge. Some cancer cells die, while surviving cells can halt their proliferation or continue to proliferate in the presence of drug, all of which can occur within the same tumor and dictate the overall response to treatment. Dr. Ratnayeke [HHMI Fellow] is studying the mechanisms that underlie these heterogeneous responses using mouse models of pancreatic cancer and single-cell genomics to map cellular states to their drug responses. Understanding these mechanisms will inform combination and precision therapies with mutant KRAS-targeting drugs to tune tumor responses in beneficial directions. Dr. Ratnayeke received his PhD from Stanford University, Stanford and his BS from the University of Texas at Austin, Austin.
Dr. Roman [Leslie Cohen Seidman Quantitative Biology Fellow] aims to develop mathematical tools to determine which genes are associated with resistance to chemotherapy. Given genomic information from pancreatic cancer patients whose tumors are resistant or sensitive to chemotherapy, this tool will identify genes that distinguish the two populations. These genes can then be explored as potential drug targets that can sensitize chemotherapy-resistant tumors to treatment.
Dr. Roman’s research relies on the use of information theory to improve the ability of neural networks to find genes whose RNA expression distinguishes chemotherapy-sensitive from resistant patients. Another research direction is to leverage prior knowledge, accumulated over decades about gene-gene interactions in the laboratory, to inform the architecture of the neural networks or use large foundation models training on millions of cells to study cancer.
Pancreatic cancer remains unresponsive to current chemotherapy and immunotherapy treatments. However, with the recent development of mRNA vaccines and drugs that target cancer cell mutations, there is hope for a new generation of immune-based therapies. The ability of adaptive immune cells, called cytotoxic T cells, to kill cancer cells is central to anti-tumor immunity. Using mouse models of human pancreatic cancer, Dr. Fraschilla [Merck Fellow] plans to identify the flags presented by cancer cells that enable T cells to recognize them as foreign and kill them. One category of flags that label cancer cells as foreign may be proteins from bacteria that prefer to replicate within the tumor environment. This investigation of cancer cell targets will inform the development of future vaccines to treat cancer and prevent tumor regrowth or metastases. Dr. Fraschilla received her PhD from Harvard University, Cambridge and her BS from Emory University, Atlanta.
The innate immune system is the body's first line of defense against pathogens. The innate immune sensor MDA5 detects nucleic acids derived from pathogenic genomes or damaged cells and drives the production of cytokines, an important signaling molecule in the immune inflammatory response. MDA5 can be aberrantly activated by host nucleic acids, however, leading to autoimmune activation. Hyperactive MDA5 alleles are associated with the development of autoimmune diabetes. Dr. Van Dis [Robert Black Fellow] aims to define the innate immune signaling pathways that initiate autoimmune diabetes to better understand immune activation pathways in the pancreas and guide the development of novel immunotherapies for pancreatic cancer. Dr. Van Dis received his PhD from the University of California, Berkeley and his BA from Carleton College, Northfield.
Pancreatic cancer develops in the midst of intense scarring and fibrous connective tissue (fibrosis). The architects of this scarring are cells called fibroblasts, known to fuel cancer growth and promote treatment resistance. Dr. Delitto's research is focused on the interface between cancer-induced fibrosis and the immune system. He has shown that fibroblasts play a significant role in shielding cancer cells from immune cells. By altering how fibroblasts sense tissue damage, Dr. Delitto has uncovered a mechanism that reactivates the immune system to fight the tumor. He aims to further develop these findings into a novel immunotherapy regimen for pancreatic cancer.
Dr. Zheng [Connie and Bob Lurie Fellow] is developing small molecules that selectively inhibit the protein K-Ras(G12D). Pancreatic ductal adenocarcinoma (PDAC) is the most lethal common cancer due to the infrequency of early diagnosis and the lack of targeted or immune therapies. A high percentage (>90%) of PDAC patients harbor KRAS mutations, with the majority expressing the K-Ras(G12D) missense mutation. Despite extensive drug discovery efforts across academia and industry, there are no approved drugs directly targeting oncogenic K-Ras(G12D). K-Ras lacks an apparent surface topology for reversible small molecule binding, leading to its notorious characterization as “undruggable.” Dr. Zheng is searching for small molecules that form a permanent bond with the mutant protein at its missense site and inhibit its interaction with effector proteins.
Current pancreatic cancer chemotherapies are not effective, and targeted therapies are only applicable in about 5% of cases. Furthermore, pancreatic cancers cause immune cell stress, limiting the success of immunotherapies in this disease. Using animal models and tumor samples from pancreatic cancer patients, Dr. Escobar-Hoyos has discovered that changes in RNA splicing, a process that controls protein diversity in cells, are crucial for pancreatic cancer development, therapy resistance, and disruption of anti-tumor immunity. She plans to dissect the molecular role of RNA splicing in pancreatic cancer, which likely drives the disease's lethality. She seeks to develop a novel anti-RNA splicing therapy with dual action-a targeted therapy against tumor cells coupled with an immunotherapy to restore immune cell anti-tumor activity-to more effectively treat pancreatic cancer patients.
Obesity is a major risk factor for over a dozen cancer types, including pancreatic cancer, the third leading cause of cancer-related death in the United States. Despite the rising prevalence of obesity worldwide, surprisingly little is known about how it promotes cancer development. Using animal models that closely mimic human pancreatic cancer, Dr. Muzumdar showed that obesity could provoke abnormal signals sent by the hormone-producing cells of the pancreas to their neighboring tumor-forming cells. With this project, he aims to understand how these hormones are induced and act to drive cancer formation in obesity. Targeting pancreatic hormone signaling could provide a new approach for the prevention and treatment of pancreatic cancer and other obesity-associated cancers.
Dr. von Diezmann is a biophysicist who studies how cells regulate the pathway used to repair broken DNA. Errors in specific DNA repair pathways are an early step in the development of many cancers, such as with defects in homologous recombination for breast, ovarian, and pancreatic cancers. The Diezmann lab uses high-resolution microscopy techniques to visualize the process by which DNA breaks are designated for specific repair fates, working primarily in live meiotic nuclei of the model organism C. elegans. By elucidating the mechanisms by which protein assemblies form and transmit information along chromosomes and throughout the nucleus, her lab will help provide a foundation for the development of novel chemotherapies based on modulating the DNA damage response.
