Abstract 3255: MLN0128, an investigational selective TORC1/2 kinase inhibitor, demonstrates potent antitumor activity in preclinical models of soft tissue sarcoma.

Abstract

Abstract Sarcomas, cancers of mesodermal origin, represent a heterogenous group of malignancies with limited treatment options currently available. The mammalian target of rapamycin (mTOR), a serine-threonine protein kinase, consists of two distinct multi-protein complexes, TORC1 and TORC2, which regulate protein synthesis, cell proliferation, and metabolism. Rapamycin, a TORC1 inhibitor, and its analogs (rapalogs) have been disappointing in sarcoma clinical studies but inhibitors of TORC1/2 kinase have the potential of resulting in better outcomes. MLN0128, an investigational potent small molecule TORC1/2 inhibitor, has shown promising results in preclinical studies of breast and other cancer types. We tested the in vitro anti-proliferative activity of MLN0128 in a panel of sarcoma cell lines including malignant peripheral nerve sheath tumor, synovial, Ewing's and osteosarcoma. Our results indicate that when compared to rapamycin, MLN0128 is highly efficient in blocking proliferative activity of all the sarcoma cell lines tested at nanomolar concentrations irrespective of the tumor subtype. We also carried out western blot analysis to test the efficacy of MLN0128 in blocking TORC1/2 signaling pathway. Inhibition of TORC1 pathway by rapamycin in sarcomas has been shown to release negative feedback inhibition of receptor tyrosine kinases like IGF1-R and activate AKT (p-AKT). Our data suggest that MLN0128, unlike rapamycin, effectively blocks both the phosphorylation of S6 and 4EBP1, the downstream substrates of TORC1, and specifically inhibits AKT phosphorylation at Ser473, the downstream substrate of TORC2. This superior in vitro activity of MLN0128 may be attributed to its apparent improved TORC1 inhibition. Taken together, our data supports further clinical research of MLN0128 in sarcoma. Targeting TORC1/2 pathways using MLN0128 either alone or in combination with inhibitors of receptor tyrosine kinases could provide a new therapeutic approach in this disease. Citation Format: Parag Patwardhan, Shyamprasad Vasudeva Deraje, William D. Tap, Elisa De Stanchina, Gary K. Schwartz. MLN0128, an investigational selective TORC1/2 kinase inhibitor, demonstrates potent antitumor activity in preclinical models of soft tissue sarcoma. [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 3255. doi:10.1158/1538-7445.AM2013-3255