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（由申请人提供）：共同研究器实验室的基础科学观察大卫·韦伯（David Weber）证明，S100B是一种Ca2+结合蛋白，在原发性黑色素瘤细胞中也与野生型（WT）p53结合。当靶向S100B的靶向下调是通过siRNA完成的，随着凋亡的诱导，随后恢复了p53功能。这表明，针对S100B和p53相互作用的小分子可能在WT p53和S100B表达的黑色素瘤患者中具有临床价值。联合研究者Weber聘请合作者根据已知的S100B结构进行计算机辅助药物发现筛查，该结构定义了五达米二碱（一种临床上可用的FDA批准的药物，用于治疗原生动物感染的药物，可能会严重破坏p53-S100B的相互作用。因此，当前的快速试验申请旨在将共同投资者Weber的实验室专业知识与首席研究员Edward Sausville的临床经验相合道，以进行II期临床试验，在该试验中，在该试验中，具有转移性和/或耐火性恶性黑色素瘤的患者被证明会表现出WTP53的wtp53，并在其肿瘤细胞中表现出可容忍的S100B（可容忍）（py）（可容忍）（p）） 1-5在四个星期中的两个）进行两个周期，然后进行临床重新评估。主要终点是使用RECIST标准确定以前已定义为表达可检测到的S100B并具有WTP53的复发和/或难治性黑色素瘤的响应率。该应用的第二个目标是遵循五氨基氨酸对肿瘤中p21表达的影响，作为p53反式激活函数的标记，以及在肿瘤中的S100B水平（也反映了p53的反式激活）和血清中的S100B水平，作为药物对这种促脑毒化途径的相关指标。相关科学将受益于S100B分析和表达系统中韦伯实验室的巨大专业知识和既定背景。公共卫生相关性：这项临床研究的结果将在科学上很重要，因为它将允许使用肿瘤学重要的治疗目标的易于使用的药物进行临床测试，即p53功能“唤醒”具有易于使用的药物分子。从临床和患者的角度来看，患有晚期黑色素瘤的患者基本上没有一贯有用的化学治疗方法，因此临床实用程序的文献记录将提供这些患者无法获得的选择。