Pancreatic cancer is a devastating disease with limited treatment options. New strategies are urgently needed, but few actionable therapeutic targets are known. By systematically testing diverse molecules against pancreatic cancer cells combined with gene knockout studies, Dr. Corsello [Leslie Cohen Seidman Clinical Investigator] has identified a starting point to simultaneously activate inflammatory signaling and cell death pathways. He will determine the efficacy and underlying molecular mechanism of this approach, and potential immunotherapy combinations, using patient-derived tumor models. His goal is to accelerate the development of more effective and less toxic therapies for pancreatic cancer.

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.

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. Evavold [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. Evavold received her PhD from Harvard University, Cambridge and her BS from Emory University, Atlanta.

A majority of pancreatic cancer cases harbor a mutation in the KRAS gene, which is involved in cancer initiation, progression, and chemotherapy resistance. Drugs targeting KRAS mutations are often met with resistance due to limited drug penetration into the tumor. Since pancreatic cancer progression involves increased tissue stiffening, KRAS signaling might be controlled by tissue stiffness. Dr. Jain is studying the mechanisms that underlie tissue stiffness-dependent KRAS signaling at the molecular level. Understanding these mechanisms will uncover new ways to block aberrant KRAS signaling or reduce the effects of tissue stiffness on cancer progression, ultimately informing new combination therapies with KRAS-targeting drugs. Dr. Jain received his PhD from the National University of Singapore, Singapore and his BTech and MTech from Indian Institute of Technology, Kanpur.

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.

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.

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.

Cancer cachexia, characterized by progressive muscle wasting and weight loss in cancer patients, is a common and multifaceted syndrome that negatively impacts patient quality of life. Cachexia has no available treatments to date, due to insufficient knowledge about the underlying mechanisms. Cachexia is particularly prominent in pancreatic cancer patients. Previous work from the Vander Heiden lab has identified that there is diminished secretion of pancreatic enzymes due to the pancreatic cancer, which contributes to tissue wasting because breakdown of muscle tissue can release amino acids into circulation. Dr. Zhang is interested in understanding whether amino acids released from muscle are fueling tumor growth or sustaining the host organism. Specifically, as circulating amino acids are often used by the liver to produce glucose, Dr. Zhang wants to study how liver glucose metabolism is affected in pancreatic cancer cachexia. This work seeks to improve the quality of life of cancer patients by reducing cachexia while seeking to understand how cancer impacts the whole-body metabolism of the host. Dr. Zhang received his PhD from University of Texas Southwestern Medical Center, Dallas, his MS from Carleton University, Ottawa, and his BScH from Queen’s University, Kingston.

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.