Abstract 4741: Inhibition of TNBC cell growth by CSPG4-specific mAb 225.28 with a Sonic Hedgehog pathway inhibitor.

Abstract

Abstract In the US, about 10-20% of breast cancers are found to be triple-negative breast cancer(TNBC). Because of the lack of estrogen receptor (ER) and progesterone receptor (PR) expression, and human epidermal growth factor receptor 2 (HER2) amplification, TNBC does not benefit from the currently available targeted therapies. Furthermore, recent molecular analysis of TNBC cell lines and lesions has suggested that these tumors might be enriched with cancer initiating cells (CICs). This possibility is consistent with the failure of conventional therapies to control disease progression, because according to the cancer stem cell theory, CICs play a major role in disease recurrence and metastatic spread, the two major causes of patient mortality. These findings and the lack of curative therapy for any TNBC patient with metastatic disease emphasize the need to develop effective novel therapies for this type of breast cancer. To address this need, we have developed a combinatorial immunotherapy, which eliminates both differentiated TNBC cells and TNBC CICs. The tumor antigen we have selected as a target is chondroitin sulfate proteoglycan (CSPG)4, since this membrane bound tumor antigen is expressed at high levels on both differentiated TNBC cells and TNBC CICs. CSPG4 plays a crucial role in the biology of TNBC cells, since it is involved in ERK and FAK signaling pathways which are associated with TNBC cell proliferation and migration. Furthermore, it is upregulated on activated pericytes in the tumor microenvironment. CSPG4-specific mAb 225.28 inhibits TNBC cell growth and migration. Moreover, it inhibits signaling pathways associated with TNBC cell growth and survival. It also can selectively inhibit neoangiogenesis in the tumor microenvironment, contributing to the elimination of TNBC cells, even those that do not express CSPG4. To enhance the targeting of TNBC CICs, immunotherapy is combined with the administration of an inhibitor (cyclopamine/ LDE225) of the Sonic Hedgehog Homolog (SHH) pathway which is activated in TNBC cells and, especially in TNBC CICs. Inhibition of TNBC CIC growth by mAb 225.28 is around 10%, but is enhanced up to about 70% when mAb 225.28 is combined with a SHH pathway inhibitor. Our in vitro findings strongly suggest that targeting CSPG4 with mAb 225.28 in combination with a SHH inhibitor may represent an effective strategy to eliminate differentiated TNBC cells and TNBC CICs. Citation Format: Yangyang Wang, Francesco Sabbatino, Soldano Ferrone, Xinhui Wang. Inhibition of TNBC cell growth by CSPG4-specific mAb 225.28 with a Sonic Hedgehog pathway inhibitor. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4741. doi:10.1158/1538-7445.AM2013-4741