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Treatment of Melanoma with wild-type P53 and detectable S100B using pentamidine:

使用喷他脒用野生型 P53 和可检测的 S100B 治疗黑色素瘤：

基本信息

批准号：
7642487
负责人：
EDWARD A. SAUSVILLE
金额：
$ 31.13万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7642487
关键词：
Age Apoptosis Apoptotic Basic Science Binding Binding Proteins Biochemical Biological Assay Calcium-Binding Proteins Carboplatin Clinical Clinical Research Computer Assisted Cutaneous Dacarbazine Diagnostic Disease Documentation Down-Regulation Drug usage Excision FDA approved Family Goals Induction of Apoptosis Infection Interferons Interleukin-2 Laboratories Leishmania Melanoma Cell Mutation Nodal Outpatients Pathway interactions Patients Pentamidine Pharmaceutical Preparations Phase II Clinical Trials Pneumocystis Principal Investigator Protein Isoforms Proteins Protozoan Infections Recovery Refractory Relapse Research Personnel Science Serum Site Skin Small Interfering RNA Structure System TP53 gene Therapeutic Trans-Activators Transactivation Treatment Protocols Visceral anticancer activity base chemotherapy drug discovery exhaust experience in vivo Model melanoma neoplastic cell oncology public health relevance research clinical testing response small molecule tissue culture tumor

项目摘要

DESCRIPTION (provided by applicant): Basic science observations in the laboratory of Co-Investigator David Weber have demonstrated that S100B is a Ca2+binding protein that also binds to wild type (wt) p53 in primary melanoma cells. When targeted downregulation of S100B is accomplished by siRNA, recovery of p53 function ensues, with induction of apoptosis. This suggests the hypothesis that small molecules directed at the interaction of S100B and p53 might have clinical value in melanoma patients with wt p53 and expression of S100B. Co- Investigator Weber engaged collaborators to conduct a computer assisted drug discovery screen based on the known structure of S100B which defined that pentamidine, a clinically available FDA approved agent for treatment of protozoal infections could potently disrupt the p53-S100B interaction. The current Quick Trials application therefore seeks to partner the laboratory expertise of Co-Investigator Weber with the clinical experience of Principal Investigator Edward Sausville to conduct a phase II clinical trial in which patients with metastatic and/ or refractory malignant melanoma who are shown to express wtp53 and detectable S100B in their tumor cells will be treated with a well tolerated, outpatient regimen of pentamidine (days 1-5 for two of four weeks) for two cycles, followed by clinical reassessment. The primary endpoint will be to determine the response rate of relapsed and/or refractory melanoma that has previously been defined to express detectable S100B and to have wtp53, using RECIST criteria. The second goal of the application is to follow the effect of pentamidine on p21 expression in tumors, as a marker of p53 transactivator function, and S100B levels in tumor (also reflecting transactivation by p53) and in serum, as correlative indicators of drug effect on this pro-apoptotic pathway. Correlative science will benefit from the enormous expertise and established background of the Weber laboratory in S100B assays and expression systems. PUBLIC HEALTH RELEVANCE: The result of this clinical study will be important scientifically, as it will allow a clinical test with a readily available drug of an important therapeutic goal in oncology, namely "re- awakening" of p53 function with a readily available drug molecule. From a clinical and patient perspective, patients with advanced melanoma have essentially no consistently useful chemotherapeutic approaches, and so the documentation of clinical utility would provide options heretofore not available to these patients.

描述(申请人提供)：联合调查员David Weber的实验室中的基础科学观察表明，S100B是一种钙离子结合蛋白，也与原代黑色素瘤细胞中的野生型(Wt)P53结合。当通过siRNA实现S100B的靶向下调时，P53功能随之恢复，并诱导细胞凋亡。这提示针对S100B和P53相互作用的小分子假说在Wt P53和S100B表达的黑色素瘤患者中可能具有临床价值。联合调查员韦伯聘请合作者进行了一项计算机辅助药物发现筛选，该筛选基于S100B的已知结构，该结构定义了临床上可用于FDA批准的用于治疗原虫感染的五烷双胺可以有效地扰乱P53-S100B的相互作用。因此，当前的Quick Trials应用程序寻求将联合调查员韦伯的实验室专业知识与首席调查员爱德华·索斯维尔的临床经验相结合，进行II期临床试验，在该试验中，肿瘤细胞中表达wtp53和可检测到S100B的转移性和/或难治性恶性黑色素瘤患者将接受耐受性良好的门诊方案(为期四周中的两周，第1-5天)，为期两个周期，然后进行临床重新评估。主要终点将是确定复发和/或难治性黑色素瘤的应答率，该黑色素瘤之前已被定义为表达可检测到的S100b和wtp53，使用RECIST标准。该应用的第二个目标是跟踪作为P53反式激活功能标志物的五烷双胺对肿瘤中p21表达的影响，以及作为药物作用于这一促凋亡途径的相关指标的肿瘤中S100B水平(也反映P53反式激活)和血清中S100B水平的影响。相关科学将受益于韦伯实验室在S100B分析和表达系统方面的丰富专业知识和成熟的背景。公共卫生相关性：这项临床研究的结果将具有重要的科学意义，因为它将允许对肿瘤学中一个重要治疗目标的现成药物进行临床测试，即利用现成的药物分子重新唤醒P53功能。从临床和患者的角度来看，晚期黑色素瘤患者基本上没有始终如一的有效化疗方法，因此临床实用文献将提供迄今为止这些患者无法获得的选择。