Abstract PO3-09-05: Potential novel treatments for high-risk subsets of breast cancer in postpartum and African American women
Authors: Traci Lyons, Lyndsey Crump, Rachel Steinmetz, Kelsey Kines, Heather Fairchild, Alan Elder
Journal: Cancer Research (2024)

Abstract Semaphorin 7a (SEMA7A) is a neuroimmune molecule first recognized for its roles in axonal guidance and inflammation. More recently, SEMA7A has emerged as a driver of tumor progression in multiple types of cancer including lung, glioblastoma and breast. Our studies have focused on the roles of SEMA7A in promoting tumor cell growth and survival as well as invasion and metastasis in mouse models including xenograft and syngeneic. Using patient samples and datamining we have shown that SEMA7A can predict for recurrence in women with postpartum breast cancer (PPBC), or breast cancers diagnosed within 10 years of recent childbirth, and SEMA7A mRNA expression in TCGA is highest in young and African American (AA) women with BC, who typically have poor prognosis. Additionally, our analysis of the Cancer Genome Atlas (TCGA) breast cancer (n=593) and METABRIC cohorts (n=2,136) revealed that SEMA7A is increased in invasive disease and in the top 9% and 27% of upregulated genes (p=1.09E-19&amp;p=0.009), respectively. Additionally, ~1.2 (TCGA) and ~1.1 (METABRIC) fold increases in SEMA7A mRNA conferred significantly decreased 5-year survival rates (p=0.009&amp;p=0.002) and SEMA7A was in the top 4% of mRNAs upregulated in patients who died within 5 years of diagnosis 20,24-26. Cumulatively, these results suggest that identifying therapeutic vulnerabilities of SEMA7A+BC, or direct targeting of SEMA7A, could improve prognosis for these high-risk populations. We have identified several targets in pre-clinical models of SEMA7A+BC that include clinically available, FDA approved drugs, as well as novel inhibitors that exhibit efficacy. In published studies, we have shown that venetoclax, a Bcl-2 inhibitor, reverses ER+SEMA7A+BC resistance to endocrine therapy in mouse models. In unpublished studies, we have extended our observations in ER+SEMA7A+BC to show that alpelisib and a novel PI3K kinase inhibitor, GCT-007, both inhibit growth of human and mouse mammary tumor cells. Furthermore, in models of ER-SEMA7A+BC where we have shown cells to be resistant to chemotherapy, we have utilized age matched cell lines from AA and CA women to dissect the downstream pro-survival signaling that is mediated by SEMA7A and we have shown that anti-PD-1 and anti-PD-L1 therapies are efficacious in reducing tumor growth in vivo. Finally, we have developed a novel monoclonal antibody-based therapy that directly targets SEMA7A signaling via pro-survival pathways and inhibits tumor growth in vivo and in vitro. Collectively our results suggest that SEMA7A+BC should be identified clinically, and alternative treatments advised for this high-risk subset of breast cancer. Citation Format: Traci Lyons, Lyndsey Crump, Rachel Steinmetz, Kelsey Kines, Heather Fairchild, Alan Elder. Potential novel treatments for high-risk subsets of breast cancer in postpartum and African American women [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-09-05.