Abstract IA27: A kinase inhibitor targeted to mTORC1 drives regression in glioblastoma

Abstract

Abstract San Francisco, San Francisco, CA. Glioblastoma (GBM), the most common primary brain tumor, numbers among the most aggressive of cancers. Although signaling from PI3K and AKT to mTOR is dysregulated prominently, we show here that blockade of these upstream targets affects mTOR activity minimally in glioma. Direct targeting using allosteric inhibitors (rapamycin) blocked mTORC1 incompletely, while we also show here that mTOR active site inhibitors (TORKi) have short residence times, limiting their efficacy preclinically. We therefore tested the third-generation mTOR inhbitior RapaLink-1 a TORKi to the mTORC1-specific binding domain of rapamycin, for activity in GBM. RapaLink-1 interacted with FKBP12, an abundant mTOR interacting protein, enabling accumulation of RapaLink-1 in tumor cells. RapaLink-1 showed better efficacy and durability than rapamycin or a TORKi, potently blocking cancer-derived, activating mutants of mTOR. RapaLink-1 drove regression of intracranial xenografts in-vivo, improving survival compared with earlier-generation inhibitors. Our studies re-establish mTOR as a central target in glioma, trace the failure of existing drugs to incomplete/nondurable inhibition of mTORC1, and offer a new class of mTORC1 inhibitors with improved potency and durability. Citation Format: QiWen Fan, Ozlem Aksoy, Robyn Wong, Shirin Ilkhanizadeh, Chris Novotny, William Gustafson, Albert Tuong, Geraldine Cayanan, Erin Simonds, Daphne Haas-Kogan, Joanna Phillips, Theo Nicolaides, Theo Nicolaides, Masanori Okaniwa, Kevan Shokat, William A. Weiss. A kinase inhibitor targeted to mTORC1 drives regression in glioblastoma. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr IA27.