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

基本信息

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
项目类别：
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

项目摘要

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）：在本申请中，标题为“将parthenolide类似物作为一种新的膀胱和肾脏癌症疗法评估”，详细介绍了鉴定二甲基氨基苯甲酰乙烯酚（DMAPT）作为这些癌症类型的新疗法的计划。 DMAPT是倍半萜烯内酯parthenolide的氨基类似物。后者是从植物骨parthenium中提取的，并在传统医学系统的WHO Pharmacopeia中列出。但是，其不良的药物特性限制了其临床适用性。 DMAPT减轻了Parthenolide的生物利用度问题，同时保持了相同的作用机理。本质上，parthenolide和DMAPT都会产生短暂的氧化应激，同时阻止保护途径，即核因子Kappa B（NF？b）。因此，该药物具有一种新颖的作用机理，并且有可能改善肾脏或膀胱癌患者的护理。但是，在进行临床试验之前，需要定义DMAPT作为单一药物的体内活性以及组合，以评估它是否可以增强这些癌症类型中的标准抗癌疗法。在本R03申请中提出的工作的成功完成还将实现计划公告的两个目的-PA-09-168，因为它将（i）为R01赠款申请提供基本数据，以资助临床试验的行为，并且（ii）促进补充和替代医学的科学。后者将通过证明对植物产品的简单修改可以克服固有的较差药物特性并促进原本可能失败的药物的临床发育。还要注意的是，已经为转移性膀胱和肾癌开发了主动的全身疗法。但是，只有少数患者对这些标准疗法有长期的减免，几乎所有患者都会死于两年。因此，迫切需要改善治疗。在不久的将来，DMAPT成为膀胱和/或肾癌的新药物的潜力是由目前在英国血液学恶性肿瘤中正在进行的1期临床试验中进行评估的事实，并且已经证明了药物良好的特性，这是一种有利的毒性和有利的毒性和药物学（PD）的证据。因此，本赠款中提出的工作中积累的知识将在不久的将来指导膀胱和肾癌中DMAPT的临床发展。公共卫生相关性：二甲基丙二酰苯甲酰胺是天然产物的氨基类似物，parthenolide，具有增强的生物利用度。本应用程序详细介绍了在体内模型中评估膀胱和肾脏癌的DMAPT的计划，并与标准疗法结合使用标准疗法以及指导临床试验设计的目标。如果成功，这项工作有可能改善膀胱和/或肾癌患者的护理。