Disrupting Collagen-Mediated Prosurvival Pathways in Pancreatic Cancer
Abstract
Topic Area: Pancreatic cancer. Focus Area: Gaps in cancer treatment. Scientific Objective and Rationale for the Proposed Project: Currently, there are no effective treatments for pancreatic cancer patients. Thus, new therapies are urgently needed to improve the dismal patient survival. Our objective is to investigate the therapeutic effectiveness of targeting a unique class of receptor proteins, known as Discoidin Domain Receptors (DDRs). DDRs are unique receptors because they mediate the communication between cancer cells and collagen, a fibrous protein that is a major component of the tumor microenvironment. DDRs are like electrical switches, referred to as kinase receptors, that turn on the cell’s intracellular machinery in response to external signals, which help the cells to adapt and thrive within the surrounding collagen-rich microenvironment. Pancreatic tumors promote the development of a very dense collagen scaffold, a process known as fibrosis, which eventually hardens the tissue and prevents the penetration of anti-tumor drugs. This is one of the reasons why pancreatic tumors are so resistant to cancer drugs and very difficult to treat. The idea is therefore to block DDRs so that the cross-talk between pancreatic cancer cells and the fibrotic collagen is impaired. Recent evidence shows that DDRs are also part of the mechanisms that allow cancer cells to escape the anti-tumor effect of new biological therapies, called drug resistance. We hypothesize that targeting DDRs alone or in combination with other drugs may promote therapeutic response in patients with fibrotic, drug-resistant tumors. In this application, we propose to use state-of-the-art preclinical models and reagents to address this hypothesis, including patient-derived tumor cells, a mouse cancer model that mimics the human disease, and a new drug that specifically targets DDR1. Ultimate Applicability of the Research: What types of patients will it help, and how will it help them? The completion of the project will define the role and potential therapeutic efficacy of two key proteins that mediate the communication of pancreatic cancer cells with the fibrotic, collagen-rich environment. We hope that drugs targeting the DDR receptors will overcome drug resistance by disrupting the pro-cancerous effect of the collagen scaffold and thus render pancreatic cancer more vulnerable to the action of other drugs. Targeting the DDR-collagen axis of malignancy will benefit patients who failed standard of care and their tumors become resistance to new alternative drugs, such as those targeting the most common mutations in pancreatic cancer. What are the potential clinical applications, benefits, and risks? At this junction, the type of research proposed here is preclinical basic research. The interim outcome of these studies will be defining the role and efficacy of targeting DDRs in preclinical models of pancreatic cancer and elucidate whether blocking DDRs will overcome drug resistance. Potential benefits include the availability of a promising drug targeting an important survival mechanism of pancreatic cancer cells that may reduce drug resistance and improve patient outcome. Risks may include development of anti-DDR resistance due the multiple and insidious mechanisms that pancreatic cancer cells can utilize to overcome killing. We are hopeful that our current and future research in this area and the collective effort of the scientific community will overcome these challenges and ultimately benefit pancreatic cancer patients. What are the likely contributions of this study to advancing the field of cancer research and/or patient care? We hope that the results of these studies will contribute to the research aimed at uncovering the signals from the fibrotic environment that promote tumor survival and impair treatment due to drug resistance. We also hope to bring awareness and new evidence on the importance of preclinical studies o
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810426
Entities
People
- Rafael Fridman
Organizations
- United States Army
- Wayne State University