Abstract 2628: BU32: A novel proteasome inhibitor for treatment of multiple myeloma and other types of cancer

Abstract

Abstract Background: Multiple myeloma (MM) is an incurable neoplasm characterized by devastating and progressive bone destruction. Standard chemotherapeutic agents have not been effective at significantly prolonging the survival of MM patients and these agents are typically associated with often severe, dose-limiting side effects. Proteasome inhibition provides an attractive approach to cancer therapy and may have application in the treatment of MM and also other types of cancers. However, results of recent clinical trials to evaluate the effect of the proteasome inhibitor bortezomib (Velcade®, also called PS-341) in MM patients have shown limited activity when used as a single agent. This underscores the need to find new and more efficacious proteasome inhibitors for treatment of MM. We have recently synthesized a novel proteasome inhibitor BU-32 and tested its growth inhibitory effects in different MM cells including RPMI8226 (human) and 5TGM1 (mouse) and other types of cancer cells. Methods and Results: In this study, we evaluate the efficacy of the novel proteasome inhibitor BU-32 (NSC D750499) using in vitro and in vivo MM models. BU-32 exhibits strong cytotoxicity in a panel of MM cell lines - RPMI8226 and 5TGM1. Furthermore, proteasome inhibition assay reveals that BU-32 potently inhibits the chymotryptic- and caspase-like activities of the 26S proteasome. Results from our studies using real-time PCR array analyses show that BU-32 effectively down-regulates an array of angiogenesis and inflammatory markers. We show from Annexin V FITC binding studies that BU-32, like bortezomib, induces apoptosis in different MM cell lines but the effect is more prominent in case of BU-32 treated cells. Studies using an in vivo MM model show significant effect and marked reduction in osteolytic bone lesions in radiography with 0.3 mg/kg body weight dose of BU-32. Further testing of BU-32 on pancreatic cancer and various hormone regulated cancers like ovarian and prostate are currently under way. Preliminary cell viability studies on these cancer cell lines indicate BU-32 is highly effective against other cancer cells also. Annexin V FITC binding analyses show that BU-32 drug induces apoptosis to these cell lines. These studies elucidate that BU-32 is a most promising candidate drug for clinical trial as a novel treatment modality for MM and other types of cancer. Conclusion: Our results suggest that BU-32 might be a potential chemotherapeutic agent with promising antitumor activity for the treatment of MM and other types of cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2628.