Abstract B03: Synergistic control of GBM growth by MEK and PI3kinase signaling in a RAS-driven preclinical orthotopic model for human glioblastoma multiforme

PI3K, RTK/RAS, and Rb signaling are commonly altered in human GBM. We utilized a genetically engineered mouse (GEM) model for GBM, designated “TRP,” that expresses GFAP-T121 to suppress Rb (T), the KrasG12D mutation (R), and is heterozygous for a PTEN null allele (P), to develop an efficient and tractable orthotopic mouse model for GBM treatment preclinical evaluation. The orthotopic brain tumors presented linear foci of necrosis with peudopalisading by neoplastic cells described in human GBM, and were highly proliferative, invasive, and vascular. Immunohistochemistry analysis of TRP orthotopic tumors identified markers characteristic of human GBM, and tumor progression was readily examined by serial MRI. Both PI3K and MAPK pathway inhibitors inhibited growth of TRP GEM-derived primary tumor cells, but did not result in significant apoptosis. However, when GBM derived cells were treated with a combination of pathway inhibitors such as BKM120 (a pan-PI3K inhibitor currently in clinical trials for solid tumors) and PD0325901 (a MEK inhibitor), potency was enhanced with a substantial increase in cell death. Analysis of downstream targets revealed a synergistic effect on target downregulation in the PI3K pathway. In the orthotopic GBM model, the PI3K/MAPK targeted combination delayed tumor growth by increasing GBM cell apoptosis and resulted in significantly increased survival. Taken together, our results validate this new orthotopic model for the assessment of targeted therapeutic regimens for human GBM, and show that the feedback loops and incomplete pathway suppression, observed in vivo with targeted single agents, can be overcome with a combination treatment strategy. Citation Format: Rajaa El Meskini, Anthony Iacovelli, Alan Kulaga, Michelle Gumprecht, Philip Martin, Maureen Baran, Deborah Householder, Terry van Dyke, Zoe Weaver Ohler. Synergistic control of GBM growth by MEK and PI3kinase signaling in a RAS-driven preclinical orthotopic model for human glioblastoma multiforme. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr B03. doi: 10.1158/1557-3125.RASONC14-B03