CHIR-258 Efficacy in a Newly Developed Preclinical Bone Marrow Model of t(4;14) Multiple Myeloma.

Multiple myeloma (MM) remains a fatal hematological malignancy due to the development of drug resistance to conventional high-dosage chemotherapy. It has been demonstrated that the bone marrow microenvironment, where MM cells preferentially home and grow, plays a crucial role in developing resistance to therapies for MM. Recent understanding of the molecular pathology of MM has provided novel therapeutic targets for treatment of this disease. The ectopic expression of FGFR3, which occurs in approximately 15–20% MM patients resulting from a t(4;14) chromosomal translocation and confers a particularly poor prognosis in clinic, has become an attractive therapeutic target for MM. CHIR-258 is a small molecule inhibitor of Class III, IV and V receptor tyrosine kinases, including FGFR, VEGFR and PDGFR (IC50s ~5–15 nM in kinase assays). It has been demonstrated that CHIR-258 inhibits FGFR3 autophosphorylation, downstream signaling and cell proliferation in FGFR3 mutant MM cells in vitro as well as induces apoptosis in FGFR3 positive primary myeloma cells (Trudel, et.al, Blood 2005). To evaluate the anti-myeloma efficacy of CHIR-258, we developed an in vivo MM model in which multi-organ MM lesions developed after tail vein injection of human KMS-11-luc cells stably transfected with luciferase. This cell line harbors the t(4;14) translocation and expresses constitutively active FGFR3 (Y373C mutation). Non-invasive bioluminescent imaging (BLI) was used to monitor the in vivo growth and dissemination of KMS-11-luc MM tumors. Early detection and serial imaging monitoring the growth of metastatic lesions was successfully captured by BLI in this model. Nearly all mice injected with KMS-11-luc tumor cells were found to develop MM lesions, which were mainly localized in spine, skull and pelvis. We examined CHIR-258 anti-myeloma efficacy in this model and found that daily oral administration of CHIR-258 at 20 mg/kg, a dose that was demonstrated to inhibit phosphorylation of ERK in KMS-11-luc tumors in vivo, resulted in a significant inhibition of tumor growth. Furthermore, this anti-tumor activity of CHIR-258 translated to a significant improvement of animal survival compared to vehicle treatment in this model. In vitro combination studies with dexamethasone and bortezomib in KMS-11 cells demonstrated synergistic and additive effects, respectively. The development of this KMS-11-luc in vivo model will allow further evaluation of CHIR-258 combination therapy with conventional or other molecularly targeted agents. These studies have provided further rationale for the ongoing clinical trials of CHIR-258 in MM.