Abstract A237: The transcriptional signature of kinases inhibited by the multitargeted kinase inhibitor AS703569 is associated with inferior clinical outcome in multiple myeloma (MM), with promising anti-MM activity of AS703569 demonstrated in preclinical studies in vitro and in vivo
Authors: Delmore Jake , Cervi David N. , McMillin Douglas W. , Kastritis Efstathios , Jakubikova Jana , Klippel Steffen , Negri Joseph M. , Leutz Buon , Laubach Jacob , Rastelli Luca , Clark Ann , Sarno Samantha , Richardson Paul G. , Anderson Kenneth C. , Constantine Mitsiades 
Published: June 2012

Abstract
Multi-targeted kinase inhibitors, when associated with manageable toxicity, offer the therapeutically desirable option of targeting, through a single chemical entity, several pathways contributing to the molecular complexity and heterogeneity of neoplasias, such as multiple myeloma (MM). However, when multi-targeted agents have extensive and/or only partially overlapping known targets, it is difficult to prioritize them for further development. We hypothesized that the potential therapeutic relevance of a multi-targeted inhibitor may be reflected on the prognostic relevance of its targets' transcriptional signature. We applied this concept in the case of the orally bioavailable multi-targeted kinase inhibitor AS703569, which targets (IC50 in low nM range) all 3 Aurora kinase isoforms and diverse other kinases (e.g. cSRC, FGFR1, Flt3, Fyn, Lyn, Rsk1-3, Axl, et.c.) and evaluated the transcriptional signature of AS703569 kinase targets (with IC50 &lt;10 nM) in MM cells of patients receiving Bortezomib as part of Phase II/III trials. We observed that patients with high transcriptional signature of AS703569 targets had inferior progression-free and overall survival (p=0.005 and p=0.012, log-rank test) and also validated that, in a study of tandem autologous transplant, a subset of patients with high levels of this AS703569 target transcriptional signature also have inferior overall survival (p=0.032, log-rank test) compared to cases with low levels of the signature. These observations indicate that the kinome space targeted by AS703569 is enriched for targets associated with adverse clinical outcome in MM. In preclinical assays, we observed that AS703569 decreased the viability of MM cell lines and primary CD138+ MM tumor cells in time- and dose-dependent manner (IC50 values &lt;50 nM for the majority of cell lines tested), without evidence of cross-resistance with established anti-MM agents. Combinations of AS703569 with dexamethasone, doxorubicin, or bortezomib did not exhibit antagonism, suggesting that AS703569 can be incorporated in regimens with these established anti-MM drug classes. Interestingly, in vitro compartment-specific bioluminescence imaging (CS-BLI) assays showed that against MM cells which respond to stromal cells with increased proliferation and survival, the anti-MM activity of AS703569 is more pronounced when these MM cells are co-cultured with bone marrow stromal cells than in conventional cultures in isolation. This in vitro result that AS703569 can overcome protective effects of BSMCs on MM tumor cells was validated in vivo in orthotopic SCID/NOD model of diffuse MM bone lesions established by i.v. injection of MM-1S-GFP/Luc cells monitored by whole body bioluminescence imaging. AS703569 (50 mg/kg p.o. once weekly)-treated mice had longer overall survival than vehicle-treated mice (median 50.0 vs. 39.0 days, p=0.019, log-rank test). An alternative schedule of AS703569 at 16.7 mg/kg 3 times/week also resulted in longer overall survival (median 54.0 days, p=0.023). These data suggest that AS703569 merits further studies towards potential clinical trials in MM, especially given the adverse outcome associated with the molecular signature of its targets.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A237.