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

 描述（由申请方提供）：多发性骨髓瘤（MM）约占所有血液恶性肿瘤的10%，2014年美国新发病例和死亡人数估计分别为24，050例和11，090例。在过去的几年中，反应和生存率显着增加，主要是由于引入了高效的免疫调节剂，蛋白酶体抑制剂，以及扩大使用高剂量化疗和自体干细胞移植。尽管取得了这些重大进展，但MM仍然是一种无法治愈的疾病，患者最终死于抗骨髓瘤治疗难治性进行性疾病。显然需要额外的有效疗法。 在 我们的实验室，我们已经表明，高密度的人MM细胞表现出从头耐DNA拓扑异构酶II（topo II）抑制剂转运topo IIa从细胞核到细胞质。我们已经表明，染色体维持区1（CRM 1或XPO 1）蛋白结合的核输出信号（内斯）的拓扑异构酶Ⅱ a和CRM 1的敲低或其抑制与小分子的结果在核保留拓扑异构酶Ⅱ a和重新致敏的MM细胞拓扑异构酶Ⅱ抑制剂。KPT-330是一类新的CRM 1抑制剂，可使高密度MM细胞对阿霉素（DOX）和蛋白酶体抑制剂（PI）敏感。我们的中心假设是，在人MM中破坏CRM 1与蛋白质-NES结合的分子显著地使MM细胞对现有的抗MM药物（迄今为止包括DOX和PI）敏感。我们的目标是使用体外MM细胞系模型、离体MM患者细胞、小鼠模型以及最终在复发性/难治性疾病患者中进行的早期临床试验，进一步确定特定CRM 1 i（KPT-330）与其他抗MM药物联合治疗MM的作用。为了解决这一假设并实现这些目标，我们提出了以下具体目标。具体目标1：使用体外MM细胞系模型和离体人MM细胞优化CRM 1抑制剂KPT-330（Selinexor）与其他抗MM药物之间的相互作用。具体目标二：使用MM细胞系和原代MM细胞确定KPT-330与其他抗MM药物之间的协同作用机制，并确定预测药物组合反应的生物标志物。具体目标3：使用人MM的小鼠模型在体内确认最有效的KPT-330/抗MM药物组合。具体目的4：使用上文定义的最佳给药方案在复发性/难治性MM中进行KPT-330和聚乙二醇化脂质体多柔比星的早期试验。 该应用程序是高度创新的，因为它探索了一流的药物（CRM 1抑制剂）与已知的MM活性药物组合之间的协同作用，包括在复发性/难治性MM中使用KPT-330 + PLD的初始早期试验。临床试验办公室/I期项目将监督早期试验，而组织核心将为细胞系提供QA/QC并监督人体组织采集。生物统计学核心将帮助设计小鼠研究和早期试验，并提供大型数据集的分析。

 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.