Exploring the molecular mechanisms controlling CDK7i sensitivity in pancreas cancer. - PROJECT SUMMARY/ABSTRACT Pancreatic ductal adenocarcinoma (PDA) is projected to be the second leading cause of cancer deaths in the US by 2030. With no cost-effective screening or prevention measures, most newly diagnosed pancreas cancer patients present with locally advanced or metastatic disease, which carries a prognosis of less than one year. PDA is classified into classical and basal subtypes, with basal portending a worse survival. In preliminary data, we show that basal PDA is characterized by loss of the histone deacetylase sirtuin 6 (SIRT6) and inactivation of the Integrated Stress Response (ISR), which renders tumor cells more sensitive to CDK7 targeted therapies. SIRT6 has been recently shown to be a novel tumor suppressor in PDA, cooperating with oncogenic KRAS to drive an even more aggressive PDA. However, elucidating SIRT6’s role in modulating the ISR remains to be discovered. Here we propose three specific aims: (1) Identify how SIRT6 mechanistically affects ATF4 stability (2) Characterize the in vivo efficacy of CDK7i in clinically relevant PDA mouse models; and (3) Determine how DNp63 alters CDK7i sensitivity. This fellowship seeks support for the training of Dr. Adrianne Wallace-Povirk, a postdoctoral fellow at the Fred Hutchinson Cancer Center (Fred Hutch), toward her goal of pursuing an academic career in cancer research. To realize the scope of the proposed work, Dr. Wallace-Povirk will be sponsored by Dr. Sita Kugel, whose laboratory focuses on epigenetic dysregulation in pancreas cancer, and will also accelerate her research through collaborations with her co-mentor Dr. Andrew Hsieh (expert in translational regulation), Dr. Eric Collisson (recognized leader in pancreas subtyping research), Dr. Sunil Hingorani (a recognized leader in pancreas tumor biology and microenvironment), and Dr. Taran Gujral (expert in high- throughput drug screening design). Dr. Wallace-Povirk will benefit from the breadth of expertise and highly collaborative atmosphere at Fred Hutch, which houses leading research groups in pancreatic cancer and cancer therapeutics.
