Accelerating the Preclinical Testing of a Promising Targeted Therapeutic for Triple-Negative Breast Cancer
Abstract
Rationale: A subtype of breast cancer, called “triple-negative,” is the most aggressive type of breast cancer. Since triple-negative breast cancer is the most likely to recur after treatment, patients with this type of cancer currently have the poorest prognosis among breast cancer subtypes. Because these tumors do not express molecules on their cell surface that can be blocked by currently available drugs, triple-negative breast cancer patients have fewer treatment options than patients with other types of breast cancer, relying mainly on chemotherapy. Chemotherapy is initially effective in reducing triple-negative tumor growth, but these cancers are hard to completely eradicate and they typically spread (or metastasize) to locations such as the lung and bone, the ultimate cause of patient mortality. Therefore, effective new treatment strategies are desperately needed to treat these patients. We have identified a protein (Neuropilin-1/NRP1) that is very highly expressed specifically in triple-negative breast cancers and drives their growth by orchestrating the activation of multiple tumor-promoting pathways simultaneously. Specifically, we have discovered that NRP1 is highly expressed in an aggressive subtype of triple-negative breast cancer called “claudin-low,” which has the highest frequency of metastasis and poorest prognosis among all triple-negative breast cancer subtypes. Our experimental results have shown that inhibiting NRP1 with an existing NRP1-blocking drug, which is well-tolerated in humans, potently blocks triple-negative breast cancer growth. Due to its ability to control multiple mechanisms of tumor growth, we hypothesize that inhibiting NRP1 will control many of the resistance mechanisms that typically arise in response to current therapies. Objective: This project will test the ability of an existing drug to halt triple-negative breast cancer growth by blocking the function of NRP1 that is highly expressed on the cell surface of claudin-low tumor cells. The aim of this work is to exploit the dependence of triple-negative breast cancers on NRP1 for their growth, helping to accelerate the development of a new therapy for claudin-low breast cancer, providing patients with a new therapeutic option and increasing their chances of survival. The specific aims of this project are to: (1) Determine how NRP1 promotes tumor growth by identifying the pathways it activates in claudin-low tumor cells. (2) Understand what causes high NRP1 expression in claudin-low tumors and whether this causes tumors to be more aggressive. (3) Analyze NRP1 levels in a large repository of triple-negative breast cancer samples to more accurately predict which patients are more likely to benefit from NRP1-targeted therapy. (4) Test an inhibitor of NRP1 in preclinical studies of claudin-low breast cancer and test our hypothesis that combining NRP1 inhibiting drugs with standard chemotherapy agents will improve patient outcomes. This proposal addresses the Overarching Challenge to (1) identify what drives breast cancer growth and determine how to stop it; (2) identify why some breast cancers become metastatic (spread to other organs); and (3) revolutionize treatment regimens by replacing them with ones that are more effective, less toxic and impact survival. Successful outcomes of this project will accelerate translation of NRP1 inhibitors as novel targeted therapies in TNBC patients. The ultimate goal of this project is to provide new information that can be exploited to design better treatments for women with triple-negative breast cancer. At the end of this project, we will have identified important pathways that drive tumor growth and predict poor patient survival. We will have tested an inhibitor of NRP1 in blocking tumor progression. We anticipate this project will also reveal the prognostic value of NRP1, helping to identify patients more likely to respond well to NRP1-targeting therapy. In the medium te
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010647
Entities
People
- Brett Hollier
Organizations
- Queensland University of Technology
- United States Army