Abstract 2712: ISC-4, a novel inhibitor of hedgehog-Gli signaling, inhibits growth of CSC and CTC of melanoma patients

Abstract

Abstract Melanoma is one of the most aggressive cancers, and its incidence and mortality rate are on rise since no treatment options are available for metastatic disease. Recent evidences from in vitro and in vivo studies have demonstrated that aberrant reactivation of the Sonic Hedgehog (SHH) signaling pathway regulates genes that promote cellular proliferation in various human cancer stem cells (CSC) 36118-45. In melanoma cells, RAS-MEK and AKT signaling has also been shown to regulate the nuclear localization and transcriptional activity of Gli-1. Therefore, the agents that inhibit activation of Gli transcription factors have emerged as promising novel therapeutic drugs for pancreatic cancer. Through extensive structure-activity studies in our laboratory, based on naturally occurring isothiocyanates (ITCs) and their isosteric selenium analogs, we have recently identified phenylbutyl isoselecynate (ISC-4) as a promising agent that significantly retarded melanoma tumor growth without any systemic toxicity. We demonstrate here the effect of ISC-4 on the proliferation of CSC and 36118-45CTC (circulating tumor cell) cells isolated from a melanoma patient. ISC-4 treatments resulted in a dose-dependent inhibition of SHH signaling (SMO, PTCH-1, Gli1, Gli2, and Gli3) and induced significant growth inhibition of CSC and CTC cells. The data demonstrate that Hh signaling regulates proliferation of CSC and CTC of human melanoma and treatment with agents like ISC-4 might be a novel approach to prevent growth and metastasis of human melanoma. Citation Format: Arun K. Sharma, Jitesh Jani, Cristian Sharma, Patrick Cleary, Michael Sharma, Shruthi Satish, Esteban Gomez, Michael Prez, Natalee Amezcua, Mariam Navel, Deepkamal N. Karelia, Dhimant Desai, Shantu Amin, Jay Sharma. ISC-4, a novel inhibitor of hedgehog-Gli signaling, inhibits growth of CSC and CTC of melanoma patients. [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 2712. doi:10.1158/1538-7445.AM2014-2712