Evaluating a parthenolide analogue as a new bladder and kidney cancer therapy

描述（由申请人提供）：在标题为“Evaluating a parthenaldehyde analogue as a new bladder and kidney cancer therapy”的本申请中，详细描述了证明二甲基氨基parthenaldehyde（DMAPT）作为这些癌症类型的新疗法的计划。DMAPT是倍半萜内酯小白菊的氨基类似物。后者是从植物Tenacetum Parthenium中提取的，并被列入世界卫生组织传统医学系统药典。然而，其不良的药学性质限制了其临床应用。DMAPT减轻了孤雌菊的生物利用度问题，同时保持相同的作用机制。从本质上讲，孤雌激素和DMAPT都产生短暂的氧化应激，同时阻断保护途径，核因子κ B（NF？B）。因此，这种药物具有新的作用机制，并有可能改善肾癌或膀胱癌患者的护理。然而，在进行临床试验之前，需要定义DMAPT作为单一药剂以及组合的体内活性，以评估其是否可以增强这些癌症类型中的标准抗癌疗法。成功完成本R 03申请中提出的工作也将实现计划公告- PA-09-168的两个目的，因为它将（i）为R 01资助申请提供必要的数据，以资助临床试验的进行，以及（ii）推进补充和替代医学的科学。后者将通过显示植物产品的简单修饰可以克服固有的不良药物特性并促进否则会失败的药剂的临床开发来实现。 还值得注意的是，已经开发了用于转移性膀胱癌和肾癌的主动全身疗法。然而，只有少数患者在这些标准疗法下获得长期缓解，几乎所有患者都将在两年内死于癌症。因此，迫切需要改进治疗。DMAPT在不久的将来成为膀胱癌和/或肾癌新药的潜力得到了以下事实的支持：目前正在英国进行的血液恶性肿瘤1期临床试验中对其进行评估，并且已经证明了良好的药物特性，有利的毒性特征和药效学（PD）活性的证据。因此，从这项资助中提出的工作中积累的知识将在不久的将来指导DMAPT在膀胱癌和肾癌中的临床开发。 公共卫生相关性：二甲基氨基parthenaldehyde是天然产品parthenaldehyde的氨基类似物，具有增强的生物利用度。该申请详细介绍了在体内模型中评估DMAPT作为单一药物以及与标准疗法组合用于膀胱癌和肾癌的计划，目的是指导临床试验设计。如果成功，这项工作有可能改善膀胱癌和/或肾癌患者的护理。

DESCRIPTION (provided by applicant): In this application entitled "Evaluating a parthenolide analogue as a new bladder and kidney cancer therapy" a plan to credential dimethylaminoparthenolide (DMAPT) as a new therapy for these cancer types is detailed. DMAPT is an amino analogue of the sesquiterpene lactone parthenolide. The latter is extracted from the plant Tenacetum Parthenium and is listed in the WHO pharmacopeia of Traditional Medical Systems. However, its poor pharmaceutical properties have limited its clinical applicability. DMAPT has mitigated the bioavailability concerns of parthenolide while maintaining the same mechanism of action. In essence, both parthenolide and DMAPT generate brief oxidative stress while concurrently blocking the protective pathway, nuclear factor kappa B (NF?B). This agent therefore has a novel mechanism of action and has the potential to improve the care of patients with kidney or bladder cancer. However, prior to conducting clinical trials there is a need to define the in vivo activity of DMAPT both as a single agent as well as in combination to assess whether it can enhance standard anti-cancer therapies in these cancer types. Successful completion of the work proposed in this R03 application will also fulfill two purposes of Program Announcement - PA-09-168 as it will (i) provide essential data for an R01 grant application to fund the conduct of a clinical trial and (ii) advance the science of Complementary and Alternative Medicine. The latter will be achieved by showing that simple modifications of a botanical product can overcome inherent poor pharmaceutical properties and facilitate the clinical development of an agent that would have otherwise failed. It is also of note that active systemic therapies have been developed for metastatic bladder and kidney cancer. However, only a few patients have long term remissions with these standard therapies and nearly all patients will have died of their cancer by two years. Therefore, there is an urgent need for improved therapy. The potential for DMAPT to be a new agent for bladder and/or kidney cancer in the near future is bolstered by the fact it is currently being evaluated in an ongoing phase 1 clinical trial in hematological malignancies in the United Kingdom and has already demonstrated good pharmaceutical properties, a favorable toxicity profile and evidence of pharmacodynamic (PD) activity. Therefore, the knowledge accumulated from the work proposed in this grant will guide the clinical development of DMAPT in bladder and kidney cancer in the near future. PUBLIC HEALTH RELEVANCE: Dimethylaminoparthenolide is an amino analogue of the natural product, parthenolide and has enhanced bioavailability. This application details the plans to assess DMAPT in bladder and kidney cancer in in vivo models as a single agent and in combination with standard therapies with the goal to guide clinical trial design. If successful, this work has the potential to improve the care of patient with bladder and/or kidney cancer.