CRM1 INHIBITORS SENSITIZE MULTIPLE MYELOMA CELLS TO TOPOISOMERASE II AND PROTEASOME INHIBITORS

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 DESCRIPTION (provided by applicant): Multiple myeloma (MM) accounts for about 10% of all hematologic malignancies, with estimated numbers of new cases and deaths for 2014 in the US at 24,050 and 11,090, respectively. Significant increases in response and survival have been seen over the last several years, largely due to the introduction of highly effective immunomodulatory agents, proteasome inhibitors, and the expanded use of high-dose chemotherapy and autologous stem cell transplant. Notwithstanding these significant advances, MM remains an incurable disease, and patients ultimately die from progressive disease refractory to anti-myeloma therapy. There is clearly a need for additional effective therapies. In our lab, we have shown that high-density human MM cells demonstrate de novo resistance to DNA topoisomerase II (topo II) inhibitors by transporting topo IIa from the nucleus to the cytoplasm. We have shown that chromosomal maintenance region 1 (CRM1 or XPO1) protein binds the nuclear export signals (NES) of topo IIa and that knockdown of CRM1 or its inhibition with small molecules results in the nuclear retention of topo IIa and re-sensitization of MM cells to topo II inhibitors. KPT-330, one of a new class of CRM1 inhibitors, sensitizes high-density MM cells to doxorubicin (DOX) and to proteasome inhibitors (PI). Our central hypothesis is that molecules that disrupt CRM1 binding of protein-NES in human MM significantly sensitize MM cells to existing anti-MM drugs (thus far including DOX and PIs). Our goals are to further define the role of a specific CRM1i (KPT-330) in the treatment of MM in combination with other anti-MM agents using in vitro MM cell lines models, ex vivo MM patient cells, mouse models, and ultimately early-phase clinical trials in patients with relapsed/refractory disease. To address thi hypothesis and achieve these goals, we propose the following specific aims. Specific Aim 1: To optimize the interactions between the CRM1 inhibitor KPT-330 (Selinexor) and other anti-MM drugs using in vitro MM cell line models and ex vivo human MM cells. Specific Aim 2: To define the mechanisms of synergy between KPT-330 and other anti-MM drugs using MM cell lines and primary MM cells and to define biomarkers predictive of response to the drug combinations. Specific Aim 3: To confirm the most effective KPT-330/anti-MM drug combination(s) in vivo using mouse models of human MM. Specific Aim 4: To perform an early-phase trial of KPT-330 and pegylated liposomal doxorubicin in relapsed/refractory MM using the optimal administration schedule defined above. This application is highly innovative in that it explores the synergism between a first-in-class agent (CRM1 inhibitor) combined with known active agents in MM, including an initial early-phase trial with KPT-330 + PLD in relapsed/refractory MM. The Clinical Trials Office/Phase I Program will oversee the early-phase trials, while the Tissue Core will provide QA/QC for cell lines and oversee human tissue acquisition. The Biostatistics Core will help design the mouse studies and early-phase trials and provide the analyses of large datasets.