Defining the Impact of Kras Mutational Heterogeneity on the Tumor Microenvironment in Pancreatic Cancer
Abstract
Background: Pancreatic cancer is a deadly disease with very few effective treatment options. In fact, of those patients with stage IV pancreatic ductal adenocarcinoma (PDA), less than 11% survive more than 5 years. Immunotherapy is an exciting new therapy for cancer patients, but it has limited efficacy in PDA. Understanding why PDA tumors are resistant to immunotherapy will increase sensitivity to current treatments, improving patient outcomes. Tumors are not just cancer cells, but include many other cell types, including immune cells. A tumor s DNA makeup can profoundly influence the number and types of immune cells in the tumor microenvironment, but this association has not been well-defined in PDA. KRAS gene mutations are present in over 90% of pancreatic tumors, with the vast majority occurring as mutations in a single amino acid of the protein -- glycine 12. We have shown that different amino acid substitutions in KRAS glycine 12 can change cellular signaling and alter tumor development and progression. For example, we revealed that mice with a KrasG12D mutation in the pancreas develop widespread early-PDA lesions called PanINs at 12 weeks of age, while mice carrying a KrasG12R mutation in the pancreas show very little change from normal. In PDA patients, a tumor s KRAS mutation type is associated with varying clinical outcomes. For example, patients with KRASG12D tumor mutations have poorer prognoses than patients with WT KRAS or KRASG12R mutations. Several research studies have demonstrated that KrasG12D mutations in tumor cells can remodel the immune microenvironment, yet the effect of other cancer-associated Kras mutations common in human PDA (G12V, G12C, G12R) have not been explored. Our poor understanding of the different Kras mutations limits our ability to design and implement appropriate treatments. Building on our previous work demonstrating that cells with specific Kras mutations exhibit different behaviors, we hypothesize that tumors with specific Kras mutations will display distinct immune microenvironments. Our proposal will determine how specific Kras mutations modulate the tumor microenvironment and promote evasion of immune-based therapies. This application will address the following PCARP Focus Areas: 1. Understanding the relationship between oncogenic signaling and the tumor microenvironment that drives drug resistance and therapeutic response 2. New drug development targeted toward cancer sensitivity and resistance mechanisms including immune mechanisms of resistance Innovation: We do not understand how tumor DNA genotype shapes the surrounding immune cells in PDA, what signaling pathways underlie these changes, or how we can design personalized immune-based combination therapy. We are leveraging our combined expertise in tumor immunology, preclinical models, oncogenic Kras signaling, and CRISPR-based gene editing to address a poorly understood but important question. We will use cutting-edge CRISPR-based editing technologies in 3D tumor organoid models, combined with state-of-the-art transcriptomic profiling technologies to search for drug targets that render PDA tumors susceptible to therapy. Our proposed project is conceptually novel through a focus on understanding the molecular and immunologic differences driven by prevalent, yet distinct KRAS variants. This work may help explain why patients with KRASG12D mutant tumors have poorer prognoses than patients with KRASG12R, or KRASG12V mutant tumors, in addition to guiding the design of personalized therapies appropriate to patients based on genotype. Impact: KRAS mutational status (e.g., G12D, G12R, G12V) is associated with different clinical outcomes in PDA patients. Although tumor genetic sequencing (which includes KRAS) is currently recommended for all stage IV pancreatic cancer patients, KRAS mutation status is not currently used as a predictive biomarker for therapy selection. Our short-term goal is
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310728
Entities
People
- Lukas E Dow
Organizations
- United States Army
- Weill Cornell Medicine