Grant: Project Grant

BACKGROUND: Breast cancer can be sub-divided into distinct molecular subtypes, including triple negative breast cancer (TNBC), which is associated with the poorest patient outcomes. Unlike other breast cancer subtypes (luminal, Her2+ breast cancer) that have targeted therapeutic agents, TNBCs are treated by surgery, radiation and chemotherapy. GPNMB is a cell surface molecule that promotes tumor growth, invasion and metastasis in human and murine mammary carcinoma models. However the precise molecular mechanisms by which GPNMB induces these effects are largely unknown. Interestingly, we have shown that GPNMB is most highly expressed in TNBC. CDX-011 is a GPNMB-targeted antibody-drug conjugate that has shown robust clinical activity in late-stage clinical trials for breast cancer. Data from clinical trials with CDX-011, as a single agent, reveals that response rate is directly linked to tumoral GPNMB expression. Our preliminary results show that TNBC cells treated with chemotherapy agents, such as Doxorubicin, or targeted inhibitors (MEKi) display increased GPNMB levels. Thus, we hypothesize that that treatment-induced up-regulation of GPNMB will sensitize TNBC cells to CDX-011. OBJECTIVES: We will 1) elucidate intrinsic mechanisms that promote GPNMB-induced breast tumor growth and metastasis, 2) determine how therapeutic stress induces GPNMB expression in TNBCs and 3) assess the efficacy of combining chemotherapy or MAPKi with CDX-011 for treating TNBCs. SIGNIFICANCE: These studies will provide important information regarding how GPNMB promotes breast tumor growth and metastasis. We will also devise effective combination therapy strategies involving CDX-011 that may increase the efficacy of current therapies used to treat TNBC. The research proposed in this application will produce the necessary data to support clinical trials to test such therapeutic combinations.