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

评估小白菊内酯类似物作为一种新的膀胱癌和肾癌治疗方法

• 批准号: 8207261
• 负责人: CHRISTOPHER J SWEENEY
• 金额: $ 8.32万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-01 至 2013-05-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8207261
• 关键词: Agonist; Angiogenesis Inhibitors; Angiogenic Factor; Antineoplastic Agents; Applications Grants; Benchmarking; Biological; Biological Availability; Biological Factors; Bladder; Bladder Diseases; Botanicals; CXCL12 gene; CXCR4 Receptors; Cancer cell line; Caring; Cell Line; Cells; Cisplatin; Clear Cell; Clinical; Clinical Trials; Clinical Trials Design; Complementary and alternative medicine; Conduct Clinical Trials; Data; Development; Disease remission; Evaluation; FDA approved; Funding; Future; Genetic Transcription; Goals; Grant; Growth Factor; Hematologic Neoplasms; Immunosuppressive Agents; In Vitro; Inflammatory; Interleukin-6; Kidney; Kidney Diseases; Knowledge; Lactones; Lead; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Mediating; Medical; Modification; Molecular; Mus; Mutation; NF-kappa B; NIH Program Announcements; New Agents; Oxidative Stress; Pathway interactions; Patient Care; Patients; Peptide Hydrolases; Pharmacodynamics; Pharmacologic Substance; Pharmacopoeias; Phase I Clinical Trials; Plant Extracts; Production; Property; Renal Cell Carcinoma; Renal carcinoma; Residual Tumors; SDZ RAD; Science; Series; Sesquiterpenes; System; Systemic Therapy; Toxic effect; Tumor Necrosis Factor Receptor; United Kingdom; Up-Regulation; Work; Xenograft procedure; analog; arm; cancer therapy; cancer type; chemokine; clinical application; cytokine; improved; in vivo; in vivo Model; mTOR Inhibitor; novel; parthenolide; public health relevance; research study; resistance mechanism; tumor

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.

描述(由申请人提供)：在这份题为“评估一种巴特内酯类似物作为一种新的膀胱癌和肾癌疗法”的申请中，详细介绍了一项证明二甲氨基苯丙内酯(DMAPT)作为一种治疗这些癌症类型的新疗法的计划。DMAPT是倍半萜内酯的氨基类似物。后者是从植物田纳香中提取的，被列入世界卫生组织《传统医疗系统药典》。然而，其较差的药学性质限制了其临床应用。DMAPT在保持相同作用机制的同时，减轻了对巴豆内酯生物利用度的担忧。本质上，菊内酯和DMAPT都会产生短暂的氧化应激，同时阻断保护途径--核因子-kappaB(NFkappaB)。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，有必要确定DMAPT作为单一药物以及联合使用的体内活性，以评估它是否可以加强这些癌症类型的标准抗癌治疗。R03申请中建议的工作的成功完成也将实现计划公告的两个目的-PA-09-168，因为它将(I)为R01拨款申请提供必要的数据，以资助临床试验的进行和(Ii)促进补充和替代医学的科学。后者的实现将通过展示对植物产品的简单修改可以克服固有的糟糕的药学特性，并促进本来会失败的药物的临床开发。同样值得注意的是，对于转移性膀胱癌和肾癌，已经开发出积极的系统治疗方法。然而，只有少数患者可以通过这些标准疗法获得长期缓解，而且几乎所有患者都将在两年前死于癌症。因此，迫切需要改进治疗方法。DMAPT在不久的将来成为一种治疗膀胱癌和/或肾癌的新药物的潜力得到了这样一个事实的支持：它目前正在英国进行血液恶性肿瘤的1期临床试验，并且已经显示出良好的药学特性、良好的毒性和药效学(PD)活性的证据。因此，这项资助工作所积累的知识将在不久的将来指导DMAPT在膀胱和肾癌的临床开发。 公共卫生相关性：二甲氨基帕索内酯是一种天然产物巴特内酯的氨基类似物，具有更高的生物利用度。这项申请详细说明了在活体模型中评估DMAPT治疗膀胱癌和肾癌的计划，作为单一药物并与标准治疗相结合，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。