Targeting Nuclear Necroptosis Pathway in Pancreatic Cancer Microenvironment
Abstract
Scientific Objective and Rationale: Pancreatic cancer in 2022 remains one of the most devastating cancers irrevocably affecting the lives of nearly 50,000 Americans including Service Members, Veterans, and their Families. Unfortunately, the poor survival of PDAC patients, in whom the number of diagnosed narrowly exceeds the number of deaths, is the result of limited treatment options. Pancreatic cancer patients typically do not benefit from immunotherapy, which has brought major improvements in longevity, quality of life, and cures in lung, colon, melanoma, and other major cancers. This failure of the current immunotherapy approaches is determined by what is called a cold or immune suppressive microenvironment in the pancreatic tumors, which prevents immune cells from entering the tumor tissue, and deactivates even the few immune cells that are present in the vicinity of cancer cells. Research Idea/Hypothesis: We designed an approach to overcome this challenging barrier of immunotherapy resistance in pancreatic cancer by imitating changes similar to those in severe viral infections. When there is an ongoing viral infection, such as flu virus, the immune cells recognize the viral genetic material because its nucleic acids are twisted in the opposite direction than in humans (called Z-nucleic acids). A specialized protein called Z-binding protein 1, or ZBP1, is the critical sensor for such viruses. Once ZBP1 recognizes and binds Z-DNA, it triggers an all-out cascade leading to formation of holes in the membranes of cells, leading to a form of cell death called nuclear necroptosis (published in Cell (2020) and Nature (2022) by the Balachandran lab). We will target with a drug a specific subset of fibroblastic cells in the pancreatic cancer tissue microenvironment, called inflammatory fibroblasts, or iCAFs, which happen to express high level of ZBP1, and will push these iCAFs to execute nuclear necroptosis. What we ultimately aim to do next is to stimulate the immune system to kill pancreatic cancer cells. Remarkably, we found a drug called CBL0137 that can twist the cellular DNA in pancreatic tumors in the Z-form and to activate necroptosis. We hypothesized that nuclear necroptosis in iCAFs would send the danger signals to the immune cells and reinvigorate an immune attack on pancreatic cancer. Toward this objective, we will test why ZBP1 is expressed in pancreatic tissues because this will help us define the biomarkers for future patients selection (Aim 1). Secondly, we would like to test the efficacy of CBL0137 alone and in combination with immunotherapy drugs against the preclinical models of pancreatic cancer in mice (Aim 2). Relevance to Intent-Partnership: The proposed studies are the result of an ongoing and sustained collaboration between Dr. Siddharth Balachandran, who is an expert in nuclear necroptosis, and Dr. Igor Astsaturov, a physician-scientist with expertise in pancreatic cancer. The Balachandran lab will deploy unique research tools to study the effects of CBL0137 on nuclear necroptosis triggered by ZBP1. Dr. Astsaturov is a physician-scientist and a co-Director of the Greenberg Pancreatic Cancer Institute at Fox Chase. His laboratory and the clinical team will work synergistically with the Balachandran lab to deploy the necroptosis inducer, CBL0137, as a transformative immunotherapy tool in PDAC. Dr. Astsaturov s lab will contribute their expertise in pancreatic cancer preclinical models and analyses of PDAC TME using the cutting-edge single-cell genomics and spatial transcriptomics methods to define a subset of PDAC tumors, which will be highly vulnerable to nuclear necroptosis induction with CBL0137. Impact: We will make major advancements in the field of pancreatic cancer immunotherapy by: (1) nominating a subset of fibroblastic cells called inflammatory fibroblasts (iCAFs) as a new vulnerability target for immunotherapeutic exploitation through their high expression of Z
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310941
Entities
People
- Igor Astsaturov
Organizations
- United States Army