Targeting Semaphorin 7a signaling in preclinical models of estrogen receptor-positive breast cancer.

Estrogen receptor-positive (ER+) breast cancer (BC) comprises over 70% of breast cancers and is the leading cause of BC-related deaths in women worldwide. Despite available therapies targeting ER in BC, recurrence occurs in many patients due to therapeutic resistance. Semaphorin 7a (SEMA7A) is a biomarker associated with poor prognosis and endocrine therapy resistance for BC patients. Survival analyses of ER+ BC patients on endocrine therapy confirm early recurrence in patients with SEMA7A+ tumors. Thus, we aim to establish novel treatment strategies to improve outcomes for patients with ER+ SEMA7A+ BC. In this paper we investigate the mechanisms by which SEMA7A promotes resistance to endocrine therapy and its potential as a therapeutic target for ER+ BC. Our studies suggest that SEMA7A binds to integrins β1 and β4 and activates AKT mediated pro-survival signaling via its RGD domain. Using syngeneic ER+ models, tumors in were treated with PI3K inhibitors (20mg/kg alpelisib; 10mg/kg GCT-007), alone or in combination with tamoxifen (0.5 mg/100uL peanut oil), which resulted in decreased tumor growth. Tumors were also treated with a combination of an anti-SEMA7A antibody (SmAbH1) (100-250mg/kg) and fulvestrant (83mg/kg), compared to single agents. Our results demonstrate that direct inhibition of SEMA7A via SmAbH1 significantly reduces tumor growth of SEMA7A+ tumors, and the combination with fulvestrant may be even more effective. Our studies suggest that patients with ER+SEMA7A+ tumors should be candidates for PI3K-targeted therapies or anti-SEMA7A-based therapy. TRANSLATIONAL RELEVANCE: Our studies propose inhibition of a novel target in estrogen receptor-positive (ER+) breast cancer (BC) with an anti-Semaphorin 7a (SEMA7A) monoclonal antibody (SmAbH1). We show efficacy of SmAbH1 as a single agent and in combination with endocrine therapy in preclinical models. We also show that targeting of SEMA7A signaling, including the use of well-known and novel PI3K inhibitors, could be an effective treatment strategy for patients with SEMA7A+ BC, particularly in combination with standard of care. Our mechanistic studies detail the cellular signaling pathway activated by SEMA7A and support the further investigation of these novel drug combinations for clinical use. Further, SEMA7A is a biomarker for poor prognosis and decreased patient survival, posing the need for a clinical diagnostic test for SEMA7A levels in BC patients, which we are currently developing.