? Project 3 (The Functional Contribution of Tumor Immunity to PDAC) PDAC is marked by an extensive desmoplastic reaction/stroma consisting of myofibroblasts, extracellular matrix (ECM) and immune cells, and oncogenic Kras is a critical driver of PDAC genesis and maintenance. The functional importance of PDAC microenvironment and its various cellular constituent in oncogenic Kras dependent and independent PDAC maintenance remains an area of active investigation, but there is minimal knowledge addressing the role of oncogenic Kras in shaping tumor immunity, in particular the T cell response. The central mission of our P01 program is to collectively identify a range of novel Kras driven vulnerable nodes that can be inhibited as a treatment for this devastating disease. The inducible oncogenic Kras genetically engineered mouse model (GEMM) of PDAC indicated that tumor regression could be achieved via oncogenic Kras extinction, a process accompanied by depletion of oncogenic Kras dependent cancer cells and significant, albeit incompletely characterized, alterations in immune response. Studies from Projects 1 and 2 using this PDAC GEMM also offered mechanistic insights into spontaneous tumor relapse, which includes the presence oncogenic Kras extinction resistant cells (KRC) with distinct metabolic dependencies (OXPHOS), and the emergence of tumors with activation of YAP or other yet unidentified mechanism for PDAC maintenance. Projects 1 and 2 will focus on exploiting the metabolic vulnerabilities of cancer cells and the central hypothesis of Project 3 is that ?oncogenic Kras and its signaling surrogates have a causal effect on tumor immunity to facilitate cancer progression?. Knowledge of this oncogenic Kras driven circuitry may illuminate therapeutic points of intervention in the tumor microenvironment and offer an improved understanding of how to deploy checkpoint blockade therapies in combination with cancer cell-specific therapies targeting metabolic or salvage pathways. The study could inform combination treatment that includes checkpoint blockade therapies ? i.e., whether OXPHOS inhibition or autophagy inhibition can help or impede such immunotherapy strategies. The studies proposed by Project 3 are highly interconnected with studies proposed in Projects 1 and 2, and rely directly on all the Cores of this P01. Specifically, the integrated specific aims of Project 3 are to investigate Kras* dependent and independent immune response in PDAC (Aim 1), to determine the impact of targeting metabolic and salvage pathways on tumor immunity (Aim 2) and to identify novel strategies to enhance efficacy of checkpoint blockade immunotherapy in PDAC (Aim 3). This effort is integral to the overall P01 Program Goal of developing a mechanism-based rational combination strategy that can lead to meaningful therapeutic advances for PDAC patients.

Public Health Relevance

? Project 3 (The Functional Contribution of Tumor Immunity in PDAC) Oncogenic Ras is a key driver of PDAC pathogenesis and Project 3 will investigate the functional role of oncogenic Kras (Kras*) and its downstream effectors in the recruitment of immune cells that contribute to suppression of immune surveillance. Additionally, this project will identify the specific role of immune response in Kras* dependent PDAC, Kras* extinction associated regression and Kras* independent relapse. The impact of targeting such putative cancer cell autonomous pathways on tumor immunity will be explored with the goal of identifying an optimal opportunity to combine immune checkpoint blockade (immunotherapy) with Kras* dependent targets in clinic.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA117969-15
Application #
9904493
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2020-04-01
Budget End
2021-03-31
Support Year
15
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Type
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Lundquist, Mark R; Goncalves, Marcus D; Loughran, Ryan M et al. (2018) Phosphatidylinositol-5-Phosphate 4-Kinases Regulate Cellular Lipid Metabolism By Facilitating Autophagy. Mol Cell 70:531-544.e9
Hopkins, Benjamin D; Pauli, Chantal; Du, Xing et al. (2018) Suppression of insulin feedback enhances the efficacy of PI3K inhibitors. Nature 560:499-503
Biancur, Douglas E; Kimmelman, Alec C (2018) The plasticity of pancreatic cancer metabolism in tumor progression and therapeutic resistance. Biochim Biophys Acta Rev Cancer 1870:67-75
Chen, Yang; LeBleu, Valerie S; Carstens, Julienne L et al. (2018) Dual reporter genetic mouse models of pancreatic cancer identify an epithelial-to-mesenchymal transition-independent metastasis program. EMBO Mol Med 10:
Hill, Margaret A; Alexander, William B; Guo, Bing et al. (2018) Kras and Tp53 Mutations Cause Cholangiocyte- and Hepatocyte-Derived Cholangiocarcinoma. Cancer Res 78:4445-4451
Mendt, Mayela; Kamerkar, Sushrut; Sugimoto, Hikaru et al. (2018) Generation and testing of clinical-grade exosomes for pancreatic cancer. JCI Insight 3:
Patra, Krushna C; Kato, Yasutaka; Mizukami, Yusuke et al. (2018) Mutant GNAS drives pancreatic tumourigenesis by inducing PKA-mediated SIK suppression and reprogramming lipid metabolism. Nat Cell Biol 20:811-822
Anglin, Justin; Zavareh, Reza Beheshti; Sander, Philipp N et al. (2018) Discovery and optimization of aspartate aminotransferase 1 inhibitors to target redox balance in pancreatic ductal adenocarcinoma. Bioorg Med Chem Lett 28:2675-2678
Yang, Annan; Herter-Sprie, Grit; Zhang, Haikuo et al. (2018) Autophagy Sustains Pancreatic Cancer Growth through Both Cell-Autonomous and Nonautonomous Mechanisms. Cancer Discov 8:276-287
Santana-Codina, Naiara; Roeth, Anjali A; Zhang, Yi et al. (2018) Oncogenic KRAS supports pancreatic cancer through regulation of nucleotide synthesis. Nat Commun 9:4945

Showing the most recent 10 out of 134 publications