Abstract B074: Novel targeting of semaphorin 7a-mediated endocrine therapy resistance in an immune competent ER+ breast cancer model

Abstract

Abstract Estrogen receptor-positive (ER+) breast cancer (BC) comprises over 70% of all breast cancers and is the leading cause of BC-related deaths in women worldwide. Despite available therapies against ER+ BC, recurrence inevitably arises primarily due to therapeutic resistance. Our objective is to improve treatment strategies for patients with ER+ BC by studying the therapeutic targeting potential of semaphorin-7a (SEMA7A)-mediated endocrine therapy resistance in an immune competent model of ER+ breast cancer. It is known that SEMA7A, a neuronal guidance protein that is dysegulated in several cancer types, confers poor prognosis and survival in BC patients, is regulated by ER, activates integrin-mediated PI3K/AKT signaling and promotes resistance to the ER-targeted therapies. In the normal mammary gland, SEMA7A binds β1- and a6-integrin to activate pathways including pro-survival PI3K/AKT signaling, which is known to promote tumor cell survival and multi-drug resistance. Using reverse phase protein array we identified differential expression between empty vector (EV) or SEMA7A-overexpressing (OE) MCF7 cells. SEMA7A OE cells had increased survival signaling proteins (pAKT, pS6K, pPTEN, pFAK, pSrc, pmTOR). Other protein types upregulated included cell adhesion (E-Cadherin), signal transduction (ITGB1, STAT3, ITGB4, NFkB, ILK1) and regulation of cell death/survival (BCL2, RB1, Annexin1). We validated that SEMA7A-induced signaling activates AKT in ER+ BC cells, and that inhibition of PI3K via alpelisib (Novartis) and GCT-007 (Global Cancer Technology) reduces tumor growth in vitro and in vivo in a MCF7/NCG xenograft model. Our preliminary studies show that SEMA7A OE tumors in NCG mice respondly poorly to fulvestrant, while EV tumors are sensitive. Further, PI3K inhibition by alpelisib or GCT-007 rendered SEMA7A OE, fulvestrant-resistant tumors sensitive to treatment in this model (n=5/group). Our lab has also created an anti-SEMA7A monoclonal antibody (SmAb) that directly targets SEMA7A. Our results show that SmAb inhibits tumor growth in triple negative mouse BC mouse models, but is less effective in immunocompromised models. Since our data show that SmAb restores anti-tumor immunity, we sought to inhibit the SEMA7A-integrin-PI3K/AKT pathway in an immune competent ER+ model. Therefore, utilized a novel syngeneic ER+ preclinical model comprised of TC11 murine tumor cells, which express SEMA7A, and FVB/N mice. Mice were treated with tamoxifen, and after tumors did not respond, PI3K inhibitors were initiated, which slowed tumor growth but did not achieve full regression. Our findings show that the addition of either PI3K inhibitor (alpelisib or GCT-007) to tamoxifen was more effective than tamoxifen alone. Future studies will investigate the combinations with SmAb and identify immune-related effects after PI3K/SEMA7A inhibition. If effective, our studies would suggest that ER+ SEMA7A+ patient tumors should be considered for PI3K/SEMA7A-targeted therapies. Citation Format: Rachel N Steinmetz, Lyndsey S Crump, Traci R Lyons. Novel targeting of semaphorin 7a-mediated endocrine therapy resistance in an immune competent ER+ breast cancer model [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr B074.