Abstract #3712: OXA-01, a novel potent mTORC1/TORC2 inhibitor displays improved anti-tumor activity in comparison to rapamycin, an mTORC1 selective inhibitor Free

The mammalian target of rapamycin (mTOR) protein kinase plays a central role in regulating cell proliferation and cell survival. The PI3K/AKT signaling pathways that activate mTOR are frequently altered in many human cancers. mTOR exists as multi-protein complexes, mTORC1 and mTORC2 with distinct signaling functions. OXA-01 is a selective small molecule inhibitor that potently inhibits both mTORC1 and mTORC2 kinase activity with IC₅₀ values of 29 nM and 7 nM, respectively. Rapamycin and its analogs, on the other hand inhibit only the mTORC1 signaling pathway. Although, rapamycin completely inhibits pS6 and partially inhibits p4E-BP1 which is downstream of mTORC1 signaling, it fails to inhibit pAKT (S473) in vitro, a downstream effector of mTORC2. In addition, in many cell types, rapamycin paradoxically induces phosphorylation of AKT (S473), downstream of mTORC2, suggesting a possible resistance mechanism for mTORC1 selective inhibitors. In contrast, OXA-01 completely abrogates both mTORC1 and mTORC2 signaling in various cancer cells tested in vitro. This profile was also extended to the in vivo setting. Specifically, OXA-01 dosed at 75 mg/Kg bid demonstrated significant and prolonged (up to 24 hr) inhibition of both p4E-BP1 and pAKT in the MDA-MB 231 human breast carcinoma xenograft model. Such extended target suppression was associated with significant efficacy corresponding to 100% TGI with 25% regressions. In contrast, rapamycin treatment at a dose of 20 mg/Kg qd resulted in only 79% TGI. This corresponded to only partial inhibition of p4E-BP1 in tumors. AKT phosphorylation was also evaluated following treatment with rapamycin with no inhibition observed up to 8 hr and only marginal inhibition seen at 24 hr. Overall, OXA-01 demonstrated broad anti-tumor activity in several different human xenograft models of various histologies. Furthermore, in GEO and Colo-205 colon xenograft models, OXA-01 demonstrated 100% TGI, whilst rapamycin treatment resulted in only 75% and 53% TGI, respectively. We believe this improved anti-tumor activity profile of OXA-01 versus rapamycin may be due to its dual mTORC1/TORC2 activity profile, resulting in more pronounced direct anti-tumor as well as anti-angiogenic effects by the mTOR kinase inhibitor. Indeed, the direct effects of OXA-01 and rapamycin on MDA-MB 231 tumor cell proliferation were determined in vivo by Ki67 staining. Only OXA-01 treatment efficiently reduced Ki67 staining in MDA-MB 231 tumors (65% inhibition, P<0.02 versus untreated control) while rapamycin had no significant effect. These data suggest that a dual mTORC1/2 kinase inhibitor, such as OXA-01, may have significant therapeutic utility compared to rapamycin and other mTORC1 selective inhibitors, warranting further clinical investigation of this novel class of anticancer agents.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3712.