Targeting MYC and LYN Crosstalk to Disrupt Breast Cancer Metabolism
Abstract
Receptor triple-negative breast cancers (TNBC) represent a particularly aggressive subset of human cancers that are associated with poor clinical outcome, including early tumor recurrence and distant metastasis. Unlike other subtypes of breast cancer, no targeted therapies for TNBCs currently exist for clinical use. As such, chemotherapy, with its lack of specificity and associated toxicities, remains the mainstay of therapy. Also, this aggressive cancer type disproportionately afflicts patients of African ancestry and can thus be considered a contributor to health disparities for this minority patient population. The overall challenge that this proposal seeks to address is to identify what drives breast cancer growth and determine how to stop it. Our labs have sought to identify the unique properties of TNBC tumor cells, allowing us to develop novel therapies. The two partnering Principal Investigators have independently discovered that TNBCs, unlike other breast cancer subtypes, utilize fat as an energy source, which drives the aggressive growth of this tumor type. We have discovered that blocking fatty acid oxidation, the process whereby fat is converted to energy, markedly diminishes TNBC tumor growth. We have also uncovered that this switch towards fat utilization can regulate the activity of known oncogenic SRC family kinases. In particular, LYN, one such SRC family kinase, has been found by our lab and others to be critical for the tumorigenic properties of TNBCs. Activated LYN, for its part, can stabilize and activate signaling by the MYC transcription factor. MYC is overexpressed or amplified in the majority of TNBC tumors, and activation of MYC signaling is associated with poor patient outcome and early metastasis. Thus, we have discovered that both MYC and LYN are critical for TNBCs growth and survival. Moreover, coordination between MYC and LYN cancer genes drives the unique metabolic reprogramming of TNBC tumor cells and permits their aggressive growth and metastasis. We propose to break this metabolic addiction by targeting MYC and LYN pathways together. We propose to use a variety of human primary tumor samples, patient-derived xenograft models, and transgenic models of TNBC to determine which currently existing, or currently in clinical trials, therapeutics can be used in combination to kill TNBCs. If successful, the proposed studies should lead us to rapidly translate our findings to early phase clinical trials.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810713
Entities
People
- Andrei Goga
Organizations
- United States Army
- University of California, San Francisco