Development of Small Molecule Crm-1 Inhibitor for Pancreatic Cancer Therapy

描述（由申请人提供）：胰腺癌是一种致命的疾病，每30分钟就夺去2名美国人的生命（年死亡率为33,000美元）。标准化疗和新开发的靶向治疗的失败使总体生存率（<5%）的改善停滞不前，这表明迫切需要新的治疗策略。根据本RFA的目标，即确定潜在的分子靶点，并测试新的治疗策略，我们打算研究其治疗潜力

DESCRIPTION (provided by applicant): Pancreatic cancer is a deadly disease that takes two American lives every 30 minutes (annual mortality >33,000). Failure of standard chemotherapies and newly developed targeted therapies has stagnated any improvement on the overall dismal survival (<5%) indicating that newer strategies for the management of this disease are urgently needed. In line with the goals of this RFA i.e. to identify potential molecula targets, and to test new therapeutic strategies, we intend to investigate the therapeutic potential of targeting CRM-1 (chromosome region maintenance 1) by our newly developed selective inhibitors of nuclear export (SINE) in pancreatic cancer. CRM-1 is a member of the importin superfamily of nuclear transport receptors, recognizing proteins bearing a leucine-rich nuclear export sequence (NES) and is the major receptor for the export of proteins out of the nucleus. Among the target of CRM-1 is the tumor suppressor protein (TSP) prostate apoptosis response-4 (Par-4). Earlier we had proposed Par-4 as a potential therapeutic target in pancreatic cancer since downregulation of this TSP has been directly linked to poor overall survival. Nuclear exclusion of Par-4 by CRM-1 renders the cancer cells resistant to apoptosis. Our preliminary findings demonstrate that SINE (KPT-185 and clinical candidate KPT-251) can lock Par-4 in pancreatic cancer cell nucleus by inhibiting CRM-1 that leads to cancer cell selective apoptosis and anti-tumor effects. To our surprise normal cells did not respond SINEs and this emerges to be mechanistically co-related to low Par-4 expression and insignificant Par-4 phosphorylation due to low protein kinase A (PKA). Hence we hypothesize that targeted inhibition of CRM-1 is an attractive strategy to guide TSPs (specifically Par-4) in the nucleus, inducing pancreatic cancer specific apoptosis. Based on our provocative initial findings and to test our hypothesis we propose 1. To establish whether there is a direct relationship between Par-4 nuclear localization and growth inhibitory and apoptosis inducing activity of KPT-185 and KPT-251 in a panel of pancreatic cancer cell lines with differential PKA and Par-4 expression and establish whether knockdown of PKA can cause resistance to KPT-mediated killing through Par-4 and other mechanisms. 2. Assess the in vivo efficacy of KPT- 251 (clinical candidate at MTD) in animal xenograft mice models developed from pancreatic cell lines with differential Par-4 expression (high Par-4 PKA vs low Par-4 PKA). Impact: CRM-1 is a druggable target in pancreatic cancer, however, currently there is no existing drug targeting this detrimental nuclear exporter. Earlier attempts to develop CRM-1 inhibitor were not successful as exemplified by the failure of the natural product Leptomycin B in a single clinical trial due to severe toxicity. Sinc then the field has not witnessed any serious attempts to develop newer classes of CRM-1 inhibitors that could be used clinically for the treatment of pancreatic cancer. Our newly developed KPT-SINE's are highly specific, orally active drugs with excellent pharmacokinetic parameters and hold promise against deadly pancreatic cancer.