Grant: Joint Canada-Israel Health Research Program

Cellular senescence is a programmed response to oncogenic stress that aims to halt the expansion of cells with malignant potential. Senescent cells secrete inflammatory mediators that in the short term contribute to stop the proliferation of pre-cancerous lesions and recruit the immune system for their elimination. However, if these processes fail, senescent cells promote tumor progression by creating chronic inflammation and suppressing the immune response. In the pancreas, senescent cells can be observed in early premalignant lesions or after chemotherapy of grown tumors. Although the senescent response can initially halt tumor progression, in the long term, senescent cells contribute to resistance to therapy and tumor relapse. Our hypothesis is that eliminating senescent cells in the pancreas will prevent the progression of premalignant lesions into pancreatic adenocarcinoma and assist current chemotherapeutic approaches that are limited by the inflammatory mediators secreted by senescent cells. To prove our hypothesis, we will use animal models of pancreatic cancer to eliminate senescent cells in premalignant lesions or after chemotherapy. We will use a novel class of drugs developed in our laboratories to kill senescent cells (senolytics). First, we will use inhibitors of the BCL family of proteins to trigger cell death in senescent cells based on our results demonstrating that survival of senescent cells is dependent on these proteins. Second, we will treat mice with drugs inhibiting NAD salvage pathway, based on our preliminary data indicating that NAD levels are required for senescent cells viability. NAD is a coenzyme essential for cellular metabolism that its production is often increased in tumor cells. We will also use genome-engineering technologies based on the bacterial CRISPR system to identify new targets for developing new senolytic strategies. The research will provide a proof of concept for new modalities of treatment for pancreatic cancer.