Abstract 1020: VRC2, a novel bortezomib re-sensitizing compound for the treatment of multiple myeloma.

Abstract

Abstract The development of novel agents including the proteasome inhibitor bortezomib (Btz) has significantly improved treatment outcomes in multiple myeloma (MM). Despite these advances, resistance to therapy invariably emerges and MM remains an incurable disease. The objective of this study was to identify new therapeutic agents and combinations with the ability to overcome resistance to Btz in MM cells. We developed a high throughput drug screening (HTS) assay system to discover small molecules that selectively target Btz resistant MM cells as single agents and/or re-sensitize resistant cells to Btz. For HTS we used isogenic pairs of Btz sensitive (595 P) and resistant (595 VR) cells derived from iMycCα/Bcl-xL transgenic mouse model of MM. Cell viability was the HTS assay read-out, and 3 treatment groups (595 P, 595 VR, and 595 VR + Btz) were included to identify compounds with selective activity against Btz resistant cells as single agents, and compounds that restore Btz sensitivity in the presence of Btz. Our screening of multiple publically-available compound libraries identified several chemical structures with selective activity against Btz resistant cells. One compound in particular showed modest but significant selectivity for Btz resistant cells as a single agent, and most notably, exhibited potent Btz re-sensitizing activity when the 2 drugs were combined. We named this compound Velcade Re-sensitizing Compound 2, or VRC-2 for short. The Btz re-sensitizing activity of VRC-2 was confirmed using multiple human and mouse cell lines that had been selected for Btz resistance in vitro. IC50s for VRC-2 in normal mouse and human fibroblasts were 100-fold higher than that observed in MM cells, suggesting it may have a low toxicity profile in vivo. We are currently evaluating the activity of VRC-2 in animal models of MM, alone and in combination with Btz, and conducting molecular studies to identify its precise mechanism of action. This study establishes the proof-of-principal for our HTS approach and demonstrates the potential of VRC-2 in Btz refractory MM. Citation Format: Amriti Lulla, Holly Stessman, David Dicker, Brian Van Ness, Wafik El-Deiry, Nathan G. Dolloff. VRC2, a novel bortezomib re-sensitizing compound for the treatment of multiple myeloma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1020. doi:10.1158/1538-7445.AM2013-1020