Exploration of a Mutant p53 Reactivating Compound

突变型 p53 重新激活化合物的探索

基本信息

批准号：
8883424
负责人：
Darren Richard Carpizo
金额：
$ 15.9万
依托单位：
RBHS -CANCER INSTITUTE OF NEW JERSEY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-16 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8883424
关键词：
Acetylcysteine Address Affinity Alleles Antineoplastic Agents Apoptosis Apoptotic Area Binding Buffers California Cancer Institute of New Jersey Cancer Model Cellular biology Chelating Agents Chemistry Clinic Clinical Clinical Trials Comprehensive Cancer Center Computer Simulation Copper DNA Binding Domain Data Development Development Plans Developmental Therapeutics Program Diamide Discipline Doctor of Philosophy Dose Drug Kinetics Drug Targeting Educational workshop Enrollment Environment Erinaceidae Family Funding Future Genes Genetically Engineered Mouse Goals Health Human Instruction Ions Iron K-Series Research Career Programs Knowledge Laboratories Laboratory Research Lead Left Los Angeles MDM2 gene Malignant Neoplasms Malignant neoplasm of pancreas Mediating Memorial Sloan-Kettering Cancer Center Mentors Mentorship Metals Methodology Modeling Molecular Molecular Biology Mus Mutate Mutation Normal Cell Olives - dietary Operative Surgical Procedures Outcome Oxidation-Reduction Patients Pharmaceutical Preparations Pharmacodynamics Pilot Projects Post-Translational Protein Processing Principal Investigator Property Protein p53 Proteins RNA Interference Reducing Agents Research Research Design Research Project Grants Research Support Resectable Residencies Running Scientist Source Structural Biologist Structure Surgical Oncologist Surgical Oncology TP53 gene Techniques Technology Testing Therapeutic Thiosemicarbazones Training Transgenic Mice Tumor Suppressor Proteins United States United States National Institutes of Health Universities Xenograft procedure Zinc anti-cancer therapeutic cancer cell career career development chelation design drug development experience hepatobiliary cancer in vivo inhibitor/antagonist killings mouse model mutant novel pre-clinical preclinical study professor programs protein folding research study restoration screening translational clinical trial tumor growth zinc-binding protein

项目摘要

DESCRIPTION (provided by applicant): TP53 is the most commonly mutated gene in human cancer for which no effective targeted anti-cancer drug exists. We identified NSC319726 (726) as a mutant p53 reactivating compound, and a lead compound for mutant p53 targeted drug development [1]. Prior evidence indicated that the effects of 726 were allele-specific, by restoring wildtype structure and function to the third most common p53 mis-sense mutant (p53-R175H). This effect was dependent on the zinc-chelating and redox modulating properties of 726. The p53 protein binds a single zinc ion, which is necessary for proper p53 structure and function. The p53-R175H mutation impairs the protein from binding zinc causing it to mis-fold and lose transcriptional function. The mechanism of 726 mutant p53 reactivation is unknown. We provide preliminary data that describe a novel "dual" mechanism where 726 restores wild-type structure to the p53-R175H using a zinc-metallochaperone function to provide an optimal concentration of zinc to facilitate proper folding. We also demonstrate that the redox modulating properties of 726 function to transactivate the newly conformed p53-R175 and induce an apoptotic program. We also demonstrate that this zinc-metallochaperone function applies to other p53 mis-sense mutants with impaired zinc binding. In this K08 Career Development Award, Dr Darren Carpizo and his collaborators plan to explore this compound in two major directions. Aim #1 is to dissect the molecular mechanism by which the compound reactivates the p53-R175 mutant protein and other p53 zinc-binding mutants. Aim #2 is conduct pre-clinical studies of the compound to evaluate its potential for clinical development as a mutant p53 targeted anti-cancer drug. Dr. Carpizo is a surgical oncologist specializing in hepatobiliary and pancreatic cancers currently appointed as an assistant professor of surgery at The Cancer Institute of New Jersey (CINJ), an NCI designated Comprehensive Cancer Center. He has obtained formalized training in research at the University of California at Los Angeles, earning a PhD in molecular and cell biology during his general surgical residency training. Dr. Arnold Levine whose laboratory discovered the p53 tumor suppressor and Dr. Joseph Bertino, an internationally recognized expert in the field of Developmental Therapeutics in cancer, are currently mentoring him. Dr. Carpizo's immediate and long term career goals are to 1) Build an independent NIH Research Project Grant supported research program focusing on pancreatic cancer, 2) Become a leader of a dedicated group of clinicians and scientists that focus on pancreatic cancer at an NCI designated Comprehensive Cancer Center and 3) To develop a niche of Developmental Therapeutics within the broader discipline of Surgical Oncology. The Career Development Plan designed by Dr. Carpizo and his Mentor/Co-Mentor will accomplish these goals with three major components: 1) Laboratory research: The candidate will execute the research plan outlined above under the mentorship of Drs. Levine and Bertino. He will receive further instruction from several collaborators including Dr. Stewart Loh, a biochemist who will conduct biophysical experiments with NSC319726. Dr. Gaetano Montelione, an NMR structural biologist who will attempt to use NMR techniques to study drug-p53-R175 protein interactions and Dr. Ken Olive, a molecular biologist who runs a NIH funded pancreatic cancer laboratory with expertise in the transgenic mouse model of pancreas cancer that will be used to test NSC319726. Dr. Carpizo will also receive specialized instruction in using RNAi technologies in mouse cancer modeling from Dr. Scott Lowe, (Memorial Sloan-Kettering cancer center). 2) Experience in Translational Clinical Trials: Dr. Carpizo will gain experience in translational clinical trials through the conduct of small pilot study designed to study the mechanism of action of the Novartis Hedgehog inhibitor (LDE-225) in patients with surgically resectable pancreas cancer. Dr. Carpizo is the principal investigator of this clinical trial that is being funded by Novartis. Dr. Bertino will mentor him through the conduct of this trial. 3) Didactics: Dr. Carpizo will take attend several courses at Cold Spring Harbor including 1) Advanced Sequencing Technologies, and 2) Mechanisms and Models of Cancer and 3) Workshop on Pancreatic Cancer.

描述（申请人提供）：TP53是人类癌症中最常见的突变基因，目前尚无有效的靶向抗癌药物。我们确定 NSC319726 (726) 是一种突变型 p53 重新激活化合物，也是突变型 p53 靶向药物开发的先导化合物 [1]。先前的证据表明，726 的作用是等位基因特异性的，通过恢复第三种最常见的 p53 错义突变体 (p53-R175H) 的野生型结构和功能。这种效应取决于 726 的锌螯合和氧化还原调节特性。p53 蛋白结合单个锌离子，这对于正确的 p53 结构和功能是必需的。 p53-R175H 突变会损害蛋白质与锌的结合，导致其错误折叠并丧失转录功能。 726 突变体 p53 重新激活的机制尚不清楚。我们提供了描述一种新颖的“双重”机制的初步数据，其中 726 使用锌金属伴侣功能恢复 p53-R175H 的野生型结构，以提供最佳浓度的锌以促进正确折叠。我们还证明 726 的氧化还原调节特性可反式激活新构象的 p53-R175 并诱导细胞凋亡程序。我们还证明这种锌金属伴侣功能适用于其他锌结合受损的 p53 错义突变体。在本次 K08 职业发展奖中，Darren Carpizo 博士和他的合作者计划从两个主要方向探索这种化合物。目标#1 是剖析该化合物重新激活 p53-R175 突变蛋白和其他 p53 锌结合突变体的分子机制。目标#2 是对该化合物进行临床前研究，以评估其作为突变型 p53 靶向抗癌药物的临床开发潜力。 Carpizo 博士是一位专门研究肝胆癌和胰腺癌的外科肿瘤学家，目前被任命为新泽西州癌症研究所 (CINJ) 的外科助理教授，该研究所是 NCI 指定的综合癌症中心。他在加州大学洛杉矶分校接受了正式的研究培训，并在普通外科住院医师培训期间获得了分子和细胞生物学博士学位。 Arnold Levine 博士（其实验室发现了 p53 肿瘤抑制因子）和 Joseph Bertino 博士（国际公认的癌症发展治疗领域专家）目前正在指导他。 Carpizo 博士的近期和长期职业目标是 1) 建立一个独立的 NIH 研究项目拨款支持的研究计划，重点关注胰腺癌，2) 成为 NCI 指定的专注于胰腺癌的临床医生和科学家专门小组的领导者综合癌症中心和 3) 在更广泛的肿瘤外科学科中开发发育治疗学的利基市场。 Carpizo 博士及其导师/共同导师设计的职业发展计划将通过三个主要组成部分来实现这些目标： 1) 实验室研究：候选人将在 Carpizo 博士的指导下执行上述研究计划。莱文和贝尔蒂诺。他将接受几位合作者的进一步指导，其中包括生物化学家 Stewart Loh 博士，他将使用 NSC319726 进行生物物理实验。 Gaetano Montelione 博士是一位 NMR 结构生物学家，他将尝试使用 NMR 技术来研究药物 - p53-R175 蛋白质相互作用；Ken Olive 博士是一位分子生物学家，负责管理 NIH 资助的胰腺癌实验室，在转基因小鼠模型方面具有专业知识将用于测试 NSC319726 的胰腺癌。 Carpizo 博士还将接受 Scott Lowe 博士（纪念斯隆-凯特琳癌症中心）关于在小鼠癌症建模中使用 RNAi 技术的专门指导。 2) 转化临床试验经验：Carpizo 博士将通过开展小型试点研究获得转化临床试验经验，该研究旨在研究诺华 Hedgehog 抑制剂 (LDE-225) 在可手术切除的胰腺癌患者中的作用机制。 Carpizo 博士是这项由诺华资助的临床试验的首席研究员。贝尔蒂诺博士将指导他完成本次试验。 3) 教学：Carpizo 博士将参加冷泉港的几门课程，包括 1) 高级测序技术、2) 癌症机制和模型以及 3) 胰腺癌研讨会。