Abstract 5566: CARP-1 functional mimetics (CFMs): a novel class of small molecule inhibitors (SMIs) of medulloblastoma cell growth.

Abstract

Abstract Medulloblastomas (MBs) are an aggressive class of intracranial pediatric tumors. Current multimodality treatments for MBs include surgery, ionizing radiation, and chemotherapy. Toxic side effects of therapies coupled with high incidence of recurrence and the metastatic spread warrants development of more effective, less toxic therapies for this disease. CARP-1/CCAR1 is a peri-nuclear phospho-protein that is a co-activator of the cell cycle regulatory anaphase promoting complex/cyclosome (APC/C) E3 ligase. CARP-1 functional mimetics (CFMs) are a novel class of small molecule compounds that interfere with CARP-1 binding with APC/C subunit APC-2, and suppress growth of a variety of cancer cells in part by promoting apoptosis. Here we investigated MB growth inhibitory potential of the CFM-1, 4, and 5, and found that CFMs inhibit growth of MB cells. CFM suppression of MB cell growth involved elevated CARP-1 expression, activation of pro-apoptotic stress-activated protein kinase (SAPK) p38, and apoptosis. Gene-array-based analysis of the CFM-4-treated Daoy MB cells indicated down-regulation of a number of key cell growth and metastasis-promoting genes including cell motility regulating small GTP binding protein p21Rac1, and extracellular matrix metallopeptidase (MMP)-10. Moreover, CFM-4 treatment stimulated expression of a number of growth inhibitory and apoptosis-inducing molecules such as neurotropin (NTF)3, while knock-down of NTF3 interfered with MB growth inhibitory effects of CFM-4. CFMs also attenuated biological properties of the MB cells by blocking their abilities to migrate, form colonies in suspension, and invade through the matrix-coated membranes. Together our data support anti-MB properties of CFM-4, and provide a proof-of-concept basis for further development of CFMs as potential anti-cancer agents for MBs. Citation Format: Abdelkader E. Ashour, Shazia Jamal, Vino Cheryan, Ahmed M. Alafeefy, Edi Levi, Adi L. Tarca, Lisa A. Polin, Arun K. Rishi. CARP-1 functional mimetics (CFMs): a novel class of small molecule inhibitors (SMIs) of medulloblastoma cell growth. [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 5566. doi:10.1158/1538-7445.AM2013-5566