Program Abstract - OverallThe goal for this renewal application is to a) elucidate oncogenic Kras (Kras*)-regulated metabolic pathwaysmediating pancreatic ductal adenocarcinoma (PDAC) tumor maintenance, b) define collateral metabolicdependencies, and c) establish how interventions targeting these processes influence tumor immunity, in orderto guide the design of clinical trials with existing drugs and to identify new therapeutic points of attack. Our P01program comprises 3 highly interdependent and collaborative projects and 4 essential cores with the goals ofconquering PDAC through targeting metabolic vulnerabilities in conjunction with immunotherapy. Project 1(DePinho with Draetta) has demonstrated that Kras* extinction in PDAC leads to pronounced tumor regressionthat involves critical functions of Kras* in metabolic reprogramming. We have also identified Kras*-extinctionresistant cells (KRCs), which show dramatic adaptive metabolic changes (in OXPHOS and autophagy)allowing survival upon Kras* inactivation. These studies thereby provide benchmarks for successfully targetingKras* in vivo and predicting resistance mechanisms that may be encountered in the clinic. Thus, the goal ofProject 1 is to kill the bulk Kras*-dependent tumor cells through identification of metabolic targets essential forKras*-mediated PDAC maintenance and to define methods to eliminate KRC through inhibiting autophagy andOXPHOS survival mechanisms. Project 2 (Bardeesy with Kimmelman and Cantley) has discovered that PDACis dependent on lysosome-dependent nutrient scavenging pathways for metabolic homeostasis and tumorgrowth, and has identified a transcriptional program that activates these processes. The goal of Project 2 is todecipher how lysosomal scavenging supports PDAC growth and how cancer cells can escape theirdependence on these processes, thereby informing improved therapeutic approaches. Project 2 will identifythe metabolic outputs of lysosomal mediated recycling pathways, establish which of these outputs play roles inPDAC growth, and explore metabolic escape pathways in order to identify novel therapeutic combinationssynergizing with lysosomal inhibition. Project 3 (Kalluri with Allison) has defined profound alterations in thetumor microenvironment, including a prominent CD8 T cell infiltration following Kras* extinction in PDAC.Project 3 will define the immune profiles throughout the genesis, regression and recurrence of PDAC and willdetermine the causal role of CD8 and CD4 cells in PDAC regression, as well as explore new opportunities totest the efficacy of checkpoint blockade therapy and assess the associated adaptive mechanisms underlyingimmune suppression. Furthermore, Project 3 will determine the direct impact of metabolically targeted therapyon tumor immunity and define effective methods to combine such therapies with immune checkpoint blockadetherapy. Highly innovative cores for Pathology (Maitra), Preclinical Therapeutics (Benes), Computation(Futreal), and an Administrative Core will enable these Projects.
Program Narrative ? (Genetics and Biology of Pancreatic Ductal Adenocarcinoma)Pancreatic cancer will be the second leading cause of cancer death in 15 years and remains incurable. Thisprogram project aims to identify therapeutic intervention points through various state-of-the-art technologiesand animal modeling. The goal remains to gain sufficient understanding of PDAC genetics and biology toinform the implementation of effective therapeutic combinations.
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