Preclinical Validation of Novel Agents for Treatment of Multiple Myeloma Multiple Myeloma
Our research focus is on novel drug development for the treatment of mature B cell malignancies based on molecular targets. This encompasses drug discovery and pharmacological profiling of candidate compounds, pre-clinical studies to validate molecular and cellular targets, the establishment of appropriate animal models for drug testing, and the development of Phase I/II clinical trials.
Specifically, we have recently validated the tyrosine kinase, Fibroblast Growth Factor Receptor 3 (FGFR3) as therapeutic target for a subgroup of multiple myeloma patients that express this receptor on tumor surface. We in pre-clinical studies have further identified the small molecule inhibitor, CHIR-258 and a neutralizing anti-FGFR3 antibody, PRO-001 as active agents against FGFR3 expressing myeloma cells. As a direct result the first ever, clinical trial of FGFR3 inhibition in myeloma has been initiated.
Our efforts are now focused on the development and implementation of relevant biological endpoints to study this novel class of anti-tumor drugs in the context of clinical trials. In addition experiments to validate additional molecular targets in myeloma such as MMSET and the maf and cyclin family of genes are ongoing or currently development.
Selected References:Link to Pubmed Publications
Trudel, S., Ely, S., Farooqui, Y., Affer, M., Robbiani, D.F., Chesi, M., Bergsagel, P.L. Inhibition of FGFR3 induces terminal differentiation and apoptosis in t(4;14) myeloma. Blood, 103: 3521- 3528, 2004.
Trudel, S., Li, Z., Wek, E., Wiesmann, M., Chang, H., Chen, C., Reece, D., Heise, C. and Stewart, A.K. CIHR-258, a novel, multi-targeted tyrosine kinase inhibitor for the treatment of t(4;14) multiple myeloma. Blood, 105:2941-2948, 2005.
Chang, H., Stewart, A.K., Li, Z.H., Yi, Q.L., and Trudel, S. Immunohistochemistry accurately predicts FGFR3 overexpression and t(4;14) in multiple myeloma. Blood, 106:353-355, 2005.
Trudel, S., Li, Z.H., Rauw, J., Tiedeman, R.E., Wen. X.Y., Stewart, A.K. Pre-clinical studies of the pan-Bcl inhibitor obatoclax (GX015-070) in multiple myeloma. Blood, 109:5430-8, 2007.