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：

• 批准号: 7529101
• 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
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7529101
• 关键词: Age; Apoptosis; Apoptotic; Basic Science; Binding; Binding Proteins; Biochemical; Biological Assay; CDKN1A gene; Calcium-Binding Proteins; Carboplatin; Clinical; Clinical Research; Computer Assisted; Cutaneous; Dacarbazine; Diagnostic; Disease; Documentation; Down-Regulation; Drug usage; End Point; Excision; 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; Public Health; Rate; Recovery; Refractory; Relapse; Research Personnel; Science; Serum; Site; Skin; Small Interfering RNA; Structure; System; TP53 gene; Therapeutic; Trans-Activators; Transactivation; Treatment Protocols; United States Food and Drug Administration; Visceral; Week; anticancer activity; base; chemotherapy; day; drug discovery; exhaust; experience; in vivo Model; melanoma; neoplastic cell; oncology; oncoprotein p21; research clinical testing; response; small molecule; tissue culture; tumor

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（由申请方提供）：共同研究者大卫韦伯实验室的基础科学观察结果表明，S100 B是一种Ca 2+结合蛋白，也与原发性黑色素瘤细胞中的野生型（wt）p53结合。当通过siRNA实现S100 B的靶向下调时，p53功能的恢复增强，并诱导细胞凋亡。这表明了这样的假设，即针对S100 B和p53相互作用的小分子可能在具有野生型p53和S100 B表达的黑素瘤患者中具有临床价值。共同研究者Weber聘请合作者基于S100 B的已知结构进行计算机辅助药物发现筛选，其定义了喷他脒（一种临床上可用的FDA批准的用于治疗原生动物感染的药剂）可以有效地破坏p53-S100 B相互作用。因此，目前的快速试验申请旨在将合作研究者韦伯的实验室专业知识与主要研究者爱德华·索斯维尔的临床经验合作，进行II期临床试验，其中转移性和/或难治性恶性黑色素瘤患者显示在其肿瘤细胞中表达wtp 53和可检测的S100 B，喷他脒门诊方案（第1-5天，共2周，共4周），持续2个周期，然后进行临床再评估。主要终点将是确定复发性和/或难治性黑色素瘤的缓解率，这些黑色素瘤先前已被定义为表达可检测的S100 B并具有wtp 53，使用RECIST标准。本申请的第二个目的是跟踪喷他脒对肿瘤中p21表达的影响，作为p53反式激活因子功能的标志物，以及肿瘤中S100 B水平（也反映了p53的反式激活）和血清中S100 B水平，作为药物对该促凋亡途径作用的相关指标。相关科学将受益于韦伯实验室在S100 B检测和表达系统方面的丰富专业知识和既定背景。公共卫生相关性：该临床研究的结果在科学上将是重要的，因为它将允许用容易获得的药物进行临床测试，该药物具有肿瘤学中的重要治疗目标，即用容易获得的药物分子“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持续有用的化疗方法，因此临床效用的文献将提供迄今为止这些患者不可用的选择。