The mammalian target of rapamycin (mTOR) protein kinase plays a central role in regulating cell proliferation and cell survival. The PI3K/AKT signaling pathway that activates mTOR is frequently altered in many human cancers. mTOR exists as multi-protein complexes with distinct signaling functions. Complexes containing mTOR and RAPTOR (mTORC1) phosphorylate S6K and 4E-BP1 and are rapamycin sensitive. Whereas, complexes that contain mTOR and RICTOR (mTORC2) phosphorylate AKT and 4E-BP1 and are insensitive to rapamycin treatment. OSI-027 is a selective small molecule dual inhibitor of both mTORC1 and mTORC2 kinase activity with biochemical IC50 values of 22 nM and 65 nM, respectively. In the MDA-MB 231 breast carcinoma xenograft model, a single 65 mg/kg oral dose of OSI-027 resulted in significant inhibition of 4E-BP1 phosphorylation (>70%) up to 16 h in tumor tissue. At 24 h post-dose, 59% inhibition of phospho-4E-BP1 was observed with a corresponding plasma OSI-027 concentration of 2.2 μM. Consistent with its ability to inhibit mTORC2 in vitro, a single dose of 65 mg/kg also resulted in significant inhibition of phospho-AKT (Ser473) for up to 8 hours with slow recovery thereafter. Such extended target suppression at 65 mg/kg was associated with significant efficacy corresponding to 100% tumor growth inhibition (TGI) with 19% regression in the MDA-MB 231 xenograft model when dosed for 14 consecutive days. In comparison, a lower dose of 25 mg/kg resulted in only 39% TGI which corresponded with a shorter duration of pharmacodynamic effects in vivo. In particular, at the 25 mg/kg dose, inhibition of 4E-BP1 phosphorylation was observed only up to 8 h in tumor tissue with return to predose levels by 16 h which corresponded with plasma drug concentrations of <0.1 µM. These data suggest that maximal anti-tumor efficacy may require plasma levels sufficient to chronically suppress phospho-4E-BP1 in tumor tissue. In addition to significant efficacy in MDA-MB 231 breast carcinoma model, OSI-027 demonstrated robust anti-tumor activity in several different human xenograft models representing different histologies, including colon carcinomas, non-small cell lung carcinomas and ovarian carcinomas. These preclinical studies indicate that OSI-027, a dual mTORC1/2 kinase inhibitor, may show broad spectrum anti-tumor activity, including superior efficacy compared to mTORC1-selective rapalogs against some human cancers. OSI-027 is currently being evaluated in Phase I clinical studies.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4486.