TGF-β signals through the type I and type II TGF-β receptors (TGFβRI and TGFβRII) to phosphorylate the SMAD proteins. In normal tissues, this signaling axis provides a growth inhibitory signal. However, in some cancers, TGF-β is often secreted at high levels and has been implicated in tumor invasion, angiogenesis and decreased immune surveillance. Recent work in GBM indicates that TGFβ may promote aggressive proliferation if the tumor cells are able to express Platelet Derived Growth Factor in response to TGFβ. Indeed, in glioblastoma patient samples, high pSmad2 levels are related to increased proliferation as well as reduced progression-free and overall patient survival. These data strongly implicate aberrant TGFβ signaling in human glioblastoma (GBM) and provide strong rationale to target this pathway for therapeutic intervention. Indeed, phase 1 and 2 clinical trials in GBM patients have begun using the recently developed small molecule inhibitor of TGFβR1 (LY2157299 monohydrate) alone and in combination with lomustine (CCNU). Herein, we show, in GBM cell lines, that LY2157299 monohydrate blocks signaling through the heteromeric TGFβ receptor complex to reduce levels of active, phosphorylated SMAD. Similarly, CCNU treatment of these same GBM cell lines also blocks Smad phosphorylation. In combination, CCNU and LY2157299 monohydrate more effectively block Smad phosphorylation than either agent alone. Furthermore, in U87MG and CRL-2611 human glioblastoma xenografts, oral dosing of LY2157299 monohydrate significantly enhanced the efficacy of CCNU (lomustine). Taken together, these preclinical data support the exploration of LY2157299 monohydrate in combination with CCNU for glioblastoma therapy.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C201.