437 Novel Targeting of Semaphorin 7a-Mediated Survival Signaling in ER+ Breast Cancer to Mitigate Therapy Resistance

Abstract

OBJECTIVES/GOALS: Estrogen receptor-positive (ER+) breast cancers (BC) comprise >70% of all BC and cause the most BC-related deaths in women worldwide. Despite available therapies against ER+ BC, recurrence often arises due to development of endocrine therapy resistance. Thus, our goal is to identify novel biomarkers that could serve as therapeutic targets for ER+ BC. METHODS/STUDY POPULATION: We have identified a neuroimmune molecule, Semaphorin 7a (SEMA7A), as a potential biomarker for endocrine therapy resistance, relapse, and poor survival in ER+ BC patients. SEMA7A promotes tumor growth, angiogenesis, epithelial-to-mesenchymal transition, metastasis, and endocrine therapy resistance in our pre-clinical models. Specifically, using in vivo models we have shown that SEMA7A+ MCF7 tumors result in lung metastases that do not respond to fulvestrant, in part via downregulation of ER, posing the need to identify novel, druggable targets for SEMA7A+ ER+ BC patients. SEMA7A is a membrane-bound protein that can inhibit tumor cell death via integrin-mediated PI3K/Akt pro-survival signaling. Thus, we hypothesized that SEMA7A+ ER+ BC may be sensitive to PI3K inhibition in combination with fulvestrant. RESULTS/ANTICIPATED RESULTS: Our preliminary studies confirmed that high SEMA7A expression associates with increased phospho-Akt levels and decreased apoptosis of tumor cells in forced suspension conditions. We also observed that human MCF7 ER+ SEMA7A overexpressing (OE) cells are sensitive to the PI3K (P110ï ¡ï€©ï€ inhibitor, Alpelisib. Also, the combination of Alpelisib with fulvestrant inhibited tumor cell viability in MCF7 cells, which was further enhanced in the SEMA7A OE counterparts. The combination also decreased proliferation and tumor sphere formation. There are currently no therapies that directly target SEMA7A, and here I propose an innovative hypothesis that PI3K inhibition will block SEMA7A signaling. DISCUSSION/SIGNIFICANCE: The role of SEMA7A has been studied in several cancer types, but its function in ER+ BC remains less well understood. In future studies, we will explore the mechanisms by which SEMA7A signals in the cell and to promote tumor cell survival. Delineating these mechanisms will help optimize treatment combinations to improve BC patient survival.