Abstract 3639: Combinatorial therapy for triple negative breast cancer
Authors: Wang Yangyang , Patel Shalin S. , Cong Juan , Zhang Nan , Qi Yuan , Sabbatino Francesco , Isakoff Steven , DeLeo Albert B. , Ferrone Soldano , Wang Xinhui 
Published: May 2015

Abstract
In the US, about 10-20% of breast cancers are found to be triple-negative breast cancer (TNBC). In comparison to other types of breast cancer, TNBC is biologically more aggressive and more prevalent in younger women. Recent molecular analysis of TNBC has suggested that these tumors might be enriched with cancer initiating cells (CICs). According to the cancer stem cell theory, CICs play a major role in disease recurrence and metastatic spread, the two major causes of patient morbidity and mortality. Therefore, an effective therapy must both eliminate differentiated and CICs in TNBC, and counteract the escape mechanisms utilized by tumor cells to avoid destruction. We have designed a novel strategy which combines cell- and antibody-based immunotherapy with metronomic chemotherapy. The molecules selected as targets of T cell- and monoclonal antibody (mAb)-based immunotherapy are aldehyde dehydrogenase 1A1 (ALDH1A1) and chondroitin sulfate proteoglycan 4 (CSPG4). The latter is also expressed on activated tumor-associated pericytes. Immunodeficient SCID mice were orthotopically inoculated with TNBC MDA-MB-231 cells (1 million cells per mouse) and then subjected to the combinatorial treatment. Tumor volume was monitored twice weekly, and primary tumors were collected at the time of sacrifice and digested for mammosphere assays. Next, we examined the anti-tumor efficacy of the combinatorial therapy on tumor recurrence and survival using a post-surgery model. Immunodeficient SCID mice were orthotopically inoculated with MDA-MB-231 cells and on day 80, when the average tumor diameter reached 0.8 cm, all primary tumors were surgically removed. Mice were then subjected to the combinatorial treatment. The combinatorial treatment effectively inhibited primary tumor growth by 71.2%, which is significantly higher than that inhibited by the individual agents or any combination of two agents. Furthermore, the cells digested from primary tumors removed from mice treated with the combinatorial treatment formed less mammospheres (2) than those (at least 15) from any other groups. Importantly, the mice in the combinatorial treatment group exhibited only 20% tumor recurrence in comparison to 100% recurrence in all other groups by day 143. Moreover, the combinatorial treatment effectively prolonged the survival of mice after surgical removal of the primary tumors. By day 155, mice in the combinatorial treatment group exhibited 80% survival, in comparison to 0% survival in any other groups by day 143. Our findings strongly indicate that the combination of the CSPG4-specific mAb 225.28, ALDH1A1-specific CD8+ T cells, and metronomic chemotherapy with cyclophosphamide effectively targets both differentiated and CICs in TNBC, resulting in inhibition of both primary tumor growth and post-surgery tumor recurrence, and in prolonging post-surgery survival of mice orthotopically inoculated with TNBC cells. Thus, our described approach may provide a novel therapy for TNBC.
Citation Format: Yangyang Wang, Shalin S. Patel, Juan Cong, Nan Zhang, Yuan Qi, Francesco Sabbatino, Steven Isakoff, Albert B. DeLeo, Soldano Ferrone, Xinhui Wang. Combinatorial therapy for triple negative breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3639. doi:10.1158/1538-7445.AM2014-3639