Abstract A08: IGF1R as a key target in high risk, metastatic medulloblastoma

Abstract

Abstract The risk or presence of metastasis in childhood medulloblastoma represents a substantial cause of morbidity and mortality. Relatively little has been known about the molecular mechanisms of medulloblastoma dissemination throughout the cerebrospinal axis. To determine potential interventions that address both metastasis and tumor growth, we examined the expression of cytokines and growth factors in the CSF of metastatic medulloblastoma patients that were also present in the conditioned media of metastatic, MYC amplified medulloblastoma cell lines and/or cell culture models of the leptomeninges. The presence of IGF1, the IGF-sequestering protein Igfbp3, which can be cleaved by metal metalloproteases (MMP) and the serine protease tPA, and the presence of corresponding protease modulators TIMP1 and SerpinE1/PAI-1, led us to explore the bioactivity of IGF1 in medulloblastoma. IGF1 led not only to receptor phosphorylation but also increased migration and increased relative cell growth. A tumor cell viability screen of 60 clinically-related compounds prioritized IGF1R inhibitors. Our findings support a model whereby medulloblastoma tumor cells actively migrate, rather than arrive passively, to the leptomeningeal cell surface and provide a rationale for exploring IGF1R as a target for therapeutics in future clinical trials. Citation Format: Matthew N. Svalina, Ken Kikuchi, Jinu Abraham, Sangeet Lal, Monika A. Davare, Jennifer L. Peckham, Yoon-Jae Cho, Melanie Jackson, Daniel J. Guillaume, Nathan R. Selden, Darell D. Bigner, Kellie J. Nazemi, Sarah C. Green, Christopher L. Corless, Sakir Gultekin, Brian P. Rubin, Randall Woltjer, Charles Keller. IGF1R as a key target in high risk, metastatic medulloblastoma. [abstract]. In: Proceedings of the AACR Special Conference: Advances in Brain Cancer Research; May 27-30, 2015; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2015;75(23 Suppl):Abstract nr A08.