Anti-Myeloma Activity of Selective PI-3K/PDK/mTOR Inhibitor BEZ235.

Abstract

Context: The PI3K-Akt-mTOR pathway has been a promising target for the treatment of multiple myeloma (MM). Major cytokine/growth factor receptor cascades (e.g. IGF-1/IGF-1R or IL-6/IL-6R) mediate, at least in part, their proliferative, anti-apoptotic or drug resistance effects through PI3K-Akt-mTOR activation and their downstream effectors. Therefore blocking this signaling pathway at one, or preferably more, of its molecular levels is considered to have promising therapeutic potential for MM. The small molecular mass compound NVP-BEZ235 (Novartis Pharma, Basel Switzerland) allows a multi-targeted, yet selective, inhibition of the PI-3K/Akt/mTOR signaling axis at the level of PI-3K and mTOR and was tested in our pre-clinical MM models.Methods/Results: A panel of human MM cell lines was tested for their in vitro response to NVP-BEZ235 using MTT colorimetric survival assays. All MM cell lines tested exhibited dose- and time-dependent decrease of their viability upon exposure to NVP-BEZ235 (IC50= 25–800 nM for 24–48hrs), without evidence of potential cross-resistance between conventional or novel anti-MM agents and NVP-BEZ235. Indeed, MM cells highly sensitive (IC50 <25 nM) to NVP-BEZ235 (e.g. MM.1S, MM.1R, Dox40 and KMS-12-PE) included both lines known to be sensitive as well as others which are resistant to dexamethasone, cytotoxic chemotherapy, thalidomide and/or its immunomodulatory derivatives (IMIDs). A longitudinal assessment of viability of MM-1S and OPM-2 MM cells during a 48-hr incubation with pharmacologically relevant concentrations of NVP-BEZ235 (25– 400nM) showed rapid commitment to and induction of MM cell death. This result, coupled with the observation that normal donor peripheral blood mononuclear cells (PBMCs) were less sensitive (IC50 >800 nM) than all MM cell lines tested, suggest that this compound exhibits a rapid and tumor-selective effect at clinically relevant conditions. This observation is further supported by our preliminary in vivo studies which suggest anti-MM activity of the drug in a model of diffuse MM bone lesions in SCID/NOD mice. Optimization of dosing and schedule to improve overall survival of NVP-BEZ235 treated mice is ongoing. To provide a more comprehensive framework for possible clinical applications of NVP-BEZ235 for MM treatment, we evaluated a series of combinations of this agent with conventional (e.g. dexamethasone, doxorubicin) and novel (e.g. bortezomib, immunodulatory thalidomide derivatives) anti-MM agents. Given the very potent single-agent activity of NVP-BEZ235 at even low nM concentrations, formal statistical documentation of synergy was not observed, but encouragingly no evidence of antagonism with any of these anti-MM agents was observed, indicating that combinations of NVP-BEZ235 with the aforementioned anti-MM agents can be feasible in clinical settings.Conclusion: The dual PI3K/mTOR inhibitor NVP-BEZ235 induces MM cell killing at sub-μM concentrations, with significantly higher sensitivity of MM cells compared to normal tissues, suggesting that this kinase inhibitor merits further consideration for possible testing as treatment option for MM patients. Further in vitro and in vivo studies are ongoing to further support the translation of these observations to clinical trials in MM.