Predicting Sensitivity of Breast Tumors to Src-Targeted Therapies through Assessment of Cas/Src/BCAR3 Activity
Abstract
Rationale: This is an extraordinary time for breast cancer research and treatment. We are learning more every day about the complexity of breast cancers, the pathways that drive tumor growth and metastasis, and drugs that should at least in theory inhibit those pathways. Coupled with better approaches for screening and early detection, these advances have positively impacted both the quality of life and prognosis of scores of people with breast cancer. Despite this progress, however, there remain a number of confounding issues that have prevented even greater successes in the clinic. Thus, as we embrace the explosion in knowledge and new targeted therapies, we are at the same time constantly being challenged to develop methods for determining which tumors will respond to these drugs and which combinations of drugs will produce the most benefit for the patient. For breast cancer, this requires detailed knowledge of the intracellular signaling pathways that drive tumor growth and metastasis of specific molecular breast tumor subtypes. Goal of the Project: The objective of this project is to develop a simple and reproducible approach for determining the response of breast cancers to a class of drugs that inhibit a molecule called Src. This molecule is upregulated in multiple breast tumor subtypes and functions as a driver of aggressive tumor behaviors. While Src inhibitors have shown some activity in breast cancer patients, their lack of consistent efficacy has been somewhat surprising in light of the fact that elevated Src activity is a feature of many breast cancers and multiple breast cancer subtypes. Our goal at the end of the grant period is to be poised to begin clinical trials that will couple dasatinib treatment with other targeted therapies in patients who have a high probability of benefitting from the Src-targeted therapy. Specific Aims: This proposal is focused on a signaling node comprised of three molecules that, together, function to activate Src and in so doing, promote aggressive tumor cell behaviors. Because of the central role played by Src in this process, dasatinib and other Src inhibitors should be effective in short-circuiting this pathway. However, there is currently no clinically tractable method for identifying tumors whose proliferation, metastasis, and therapeutic responses are driven by this pathway. Interestingly, one of the molecules that contribute to this signaling node and thus controls Src activity is not present in normal breast tissue but is significantly upregulated in breast cancers irrespective of whether they express estrogen receptor (ER), progesterone receptor (PR), or Human Epidermal Growth Factor Receptor-2 (HER2). We hypothesize that this molecule, called breast cancer antiestrogen resistance-3 (BCAR3), can be used to distinguish tumors that will likely respond to Src inhibition from those that will be resistant. To test this hypothesis, we propose to (1) determine whether BCAR3 serves as a predictor of sensitivity to the Src inhibitor dasatinib and assess the extent to which it is expressed in breast tumors defined by pathological criteria such as tumor grade and ER, PR, HER2 status; (2) understand how the three molecules that function as a critical signaling node contribute to the ability of Src to function as a driver of breast tumor growth and metastasis; and (3) determine if collaboration between these proteins and EGFR or HER2 pathways contributes to therapeutic resistance to drugs like trastuzumab and lapatinib that target these receptors. Overarching Challenges: Based on data in support of the signaling pathway described above functioning as a driver of tumor cell proliferation, survival, invasion, tumor growth, metastasis, and therapeutic response, this proposal addresses two overarching challenges: (1) identify what drives breast cancer growth; determine how to stop it and (2) eliminate the mortality associated with metastatic breast cancer Impac
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510306
Entities
People
- Amy Bouton
Organizations
- United States Army
- University of Virginia