GCT007

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 against ER+ 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 (ITGB1, ITGB4) and activates AKT cell survival signaling via its RGD domain. Using a syngeneic ER+ model, TC11 tumors in FVB/N mice were treated with PI3K inhibitors (20mg/kg alpelisib; 10mg/kg GCT-007), alone or in combination with tamoxifen (0.5 mg/100uL peanut oil). TC11 tumors were also treated with a combination of an anti-SEMA7A antibody (SmAb H1) (100-250mg/kg) and fulvestrant (83mg/kg), compared to single agents. In vivo studies were validated in a second syngeneic ER+ model; SSM2 cells and 129SV-E mice. Our results demonstrate that direct inhibition of SEMA7A via SmAb H1 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.