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: 8028806
• 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 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8028806
• 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; 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）：在题为“评估小白菊内酯类似物作为新的膀胱癌和肾癌疗法”的申请中，详细介绍了将二甲基氨基小白菊内酯（DMAPT）认定为这些癌症类型的新疗法的计划。 DMAPT 是倍半萜内酯小白菊内酯的氨基类似物。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。但其较差的药学特性限制了其临床应用。 DMAPT 减轻了小白菊内酯的生物利用度问题，同时保持了相同的作用机制。本质上，小白菊内酯和 DMAPT 都会产生短暂的氧化应激，同时阻断保护途径核因子 kappa B (NF?B)。因此，该药物具有新颖的作用机制，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，需要确定 DMAPT 作为单一药物以及组合药物的体内活性，以评估它是否可以增强这些癌症类型的标准抗癌治疗。成功完成本 R03 申请中提出的工作还将实现计划公告 - PA-09-168 的两个目的，因为它将 (i) 为 R01 拨款申请提供基本数据，以资助临床试验的进行；(ii) 推进补充和替代医学的科学发展。后者将通过证明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物的临床开发来实现。 还值得注意的是，针对转移性膀胱癌和肾癌已经开发出积极的全身疗法。然而，只有少数患者通过这些标准疗法获得长期缓解，几乎所有患者都会在两年内死于癌症。因此，迫切需要改进治疗。 DMAPT 在不久的将来成为治疗膀胱癌和/或肾癌的新药的潜力受到以下事实的支持：目前正在英国正在进行的一项针对血液恶性肿瘤的 1 期临床试验中对 DMAPT 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 (PD) 活性的证据。因此，从本次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：二甲氨基小白菊内酯是天然产物小白菊内酯的氨基类似物，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 作为单一药物并与标准疗法相结合的计划，旨在指导临床试验设计。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。