Abstract B192: Preclinical characterization of BMS-833923 (XL139), a hedgehog (HH) pathway inhibitor in early clinical development

Abstract

Abstract Background: Aberrant HH pathway signaling has been implicated in human malignancies ranging from semi-malignant tumors of the skin to highly aggressive cancers of the brain, lung, pancreas, breast, prostate, and lymphohematopoietic lineages. Dysregulation of this pathway contributes to uncontrolled proliferation, invasion, metastasis, evasion of apoptosis, and resistance to chemotherapy. Results: BMS-833923 is a potent inhibitor of SMO, a GPCR-like 7-transmembrane receptor that is a critical regulator of the HH pathway. In vitro, BMS-833923 inhibits the expression of downstream effectors in the HH pathway (GLI1 and PTCH1) in cell lines that express wild-type SMO and those which express activated mutant forms of SMO (IC50 values of 6–35 nM). In FACS-based binding assays, BMS-833923 inhibits BODIPY cyclopamine binding to SMO in a dose-dependent manner with an IC50 of 21 nM. Prior work has demonstrated that HH pathway blockade inhibits the in vitro clonal expansion of multiple myeloma (MM) precursor cells in both established cell lines and in clinical samples from patients with MM (Peacock et al 2007, PNAS 104:4048). Consistent with these observations, BMS-833923 inhibited the in vitro growth of MM clones and proportion of ALDH+ cancer stem cells derived from bone marrow samples from subjects with MM. Furthermore, BMS-833923 inhibited the clonogenic growth of multiple tumor cell lines derived from patients with hematological malignancies including CML, ALL and AML, suggesting that targeting the HH pathway may have broad therapeutic utility for patients with hematologic malignancies. In vivo pharmacodynamic studies show that BMS-833923 robustly inhibits HH pathway activity with a long duration of action after a single oral dose in medulloblastoma and pancreatic carcinoma xenograft models. The pharmacodynamic effects of BMS-833923 observed in these models translate into tumor growth inhibition at well-tolerated doses. These results are consistent with pharmacokinetic parameters demonstrated in nonclinical studies. Conclusions: BMS-833923 is an orally bioavailable, potent and selective inhibitor of the HH pathway as measured by in vitro cell-based assays and in vivo pharmacodynamic and efficacy models, supporting the clinical development of BMS-833923 in both hematological and non-hematological malignancies. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B192.