A Novel Strategy of Targeting Transmembrane Protein to Improve KRAS-targeted Therapy

Abstract public domain (NIH RePORTER)

Project Summary/Abstract Pancreatic cancer is the most common form of pancreatic cancer and is currently incurable. Unraveling essential cellular reprograming required for PDAC development and progression, and further identifying new drug targets to treat the disease is crucial to impact the outcomes for patients with this devastating disease. In this application, we propose to study the function of transmembrane protein in regulating major nutrient supply routes by which cells scavenge “food” to fuel their growth. It stands to reason that targeting such transmembrane protein will block the nutrient supply of pancreatic cancer cells and result in cell death. Building on our strong expertise in study transmembrane proteins in pancreatic cancer cell survival and growth, the overarching objective of this proposed research is to gain a comprehensive understanding of the role of transmembrane protein in mediating the nutrient supply routes and evaluate the potential of such transmembrane protein as a targeting node for pancreatic cancer treatment. The major advantage of studying transmembrane proteins is their accessibility by therapeutic agents, such as antibodies. To achieve the translational potential of our study, we will further develop and characterize novel therapeutic agents direct target such membrane proteins in various new preclinical models of pancreatic cancer. Upon completion of the proposed research, we will have more complete knowledge of the extent to which pancreatic cancer is reliant upon transmembrane protein for nutrient salvage, how the nutrient supply machinery is regulated by transmembrane protein on the surface in pancreatic cancer, and whether targeting such membrane protein-mediated metabolic reprogramming may be potent to eradicate pancreatic cancer cells. Answering these questions will significantly impact our ability to determine whether a rational approach to therapeutically intervene in nutrient supply routes in pancreatic cancer exists. Furthermore, our research is significant because it may have broad implications for other types of human cancers depending similar nutrient supply mechanisms. In the short term, findings from this project will advance our understanding of the nutrient supply routes required to sustain pancreatic cancer cells and provide strong preclinical evidence for targeting the nutrient supply routes as therapeutic strategy in treating pancreatic cancer. In the long term, findings of our research are expected to guide the development of clinical trials for achieving clinical benefits for patients with pancreatic cancer. We believe that the results of our studies will have a positive impact on the general public in the United States, benefiting individuals affected by pancreatic cancer and potentially leading to improved outcomes and enhanced quality of life.

Public health relevance public domain (NIH RePORTER)

Narrative The development of resistance to mutant KRAS inhibitors is currently a major obstacle for the treatment of KRAS mutant cancers and the underlying mechanisms are not well-understood. The proposed research is relevant to public health because it will reveal a newly-identified mechanism that contributes to the efficacy of KRAS- targeted therapy, and success of this proposal will not only expand our knowledge of KRAS signaling and biology but also shed light on novel therapeutic strategies against KRAS mutated cancer to achieve durable therapeutic response.