Targeted Development of Platinum Drugs

铂类药物的靶向开发

基本信息

批准号：
8294609
负责人：
ZAHID H SIDDIK
金额：
$ 32.79万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-01 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8294609
关键词：
Address Advanced Malignant Neoplasm Affinity Animal Model Apoptosis Apoptotic Biological Models Cell Death Cells Cisplatin Clinical Complex DNA DNA Damage Defect Development Disease Down-Regulation EP300 gene Engineering Epithelial Gene Targeting Genes Histocompatibility Testing Ionizing radiation Lead MAPK8 gene MAPKAPK2 gene MDM2 gene Malignant Neoplasms Malignant neoplasm of ovary Malignant neoplasm of testis Mesothelioma Modality Modeling New Agents Non-Small-Cell Lung Carcinoma Paclitaxel Pathway interactions Patients Pharmaceutical Preparations Phenotype Phosphorylation Phosphorylation Site Phosphotransferases Platinum Play Post-Translational Protein Processing Protein p53 Proteins Refractory Regimen Regulation Relapse Reporting Resistance Rewards Role Satraplatin Series Signal Transduction Site Solid Structure Structure-Activity Relationship Suppressor-Effector T-Lymphocytes Survival Rate TP53 gene Testing Therapeutic Transactivation Transducers Work advanced disease analog antitumor agent base chemotherapy crosslink cytotoxic design drug development improved killings mouse model mutant neoplastic cell novel oxaliplatin prevent response therapy resistant tumor

项目摘要

DESCRIPTION (provided by applicant): A major treatment modality in the advanced disease setting is chemotherapy, with cisplatin-based regimens playing significant roles in the cancer management strategy of a number of cancers, including ovarian cancer, mesothelioma and non-small cell lung cancer. However, the majority of advanced cancer cases relapse and fail therapy due to the onset of cisplatin resistance, and patients eventually succumb to their disease. The most recent advance about two decades ago was the inclusion of taxol to the platinum regimen, but this has only provided short-term incremental benefit without impacting the 5-year survival rate. Thus, cisplatin resistance is a significant drawback, and there is a desperate need to understand the causes of resistance, so new agents can be developed. A major understanding emerging from our work is that wild-type p53 features prominently in the resistance phenotype and this represents a major puzzle why the apoptotic function of p53 is being inhibited. Since many advanced and refractory cancer disease types include substantial numbers of tumors that harbor wild-type p53, there is reason to believe that a common defect in a key gene or pathway may be the cause of p53 failing to become functionally activated. Based on the strong relationship of mutual exclusivity, tumors with wild-type p53 are likely to have defective Chk2 expression, and this defect will impact post-translational modification of p53 that is essential for stabilization and stimulation of its function. Indeed, wild-type p53 in cisplatin-resistant tumor cells often demonstrates defective function. Since specific cancers have intrinsic affinity for platinum drugs, we hypothesize that defective Chk2 expression prevents stabilization and/or stimulation of wild-type p53 in cisplatin-resistant cancers, and that platinum analogs can be designed to activate an alternative kinase to maximally restore p53 inducibility and cytotoxic activity. We will address this hypothesis through three specific aims: 1) Characterize cisplatin resistance as related to defective Chk2 in tumor panels harboring wild-type p53; 2) Identify the kinase activated by platinum analogs that restores p53 function in cisplatin-resistant cells; and 3) Establish structure-activity relationships for lead optimization and identify an analog that maximally stabilizes and stimulates wild-type p53 in resistant Chk2-defective tumor cells. Based on mouse models, activation of wild-type p53 is sufficient to kill tumor cells, and this raises the potential that targeting cisplatin resistance through a mechanism-directed drug development approach will restore wild-type p53 function and significantly increase response and 5-yr survival rates.

描述（由申请人提供）：晚期疾病的主要治疗方式是化疗，基于顺铂的治疗方案在多种癌症的癌症管理策略中发挥着重要作用，包括卵巢癌、间皮瘤和非小细胞肺癌。然而，大多数晚期癌症病例由于顺铂耐药性的出现而复发并导致治疗失败，患者最终死于疾病。大约二十年前的最新进展是将紫杉醇纳入铂类治疗方案中，但这仅提供了短期增量益处，而不会影响 5 年生存率。因此，顺铂耐药性是一个显着的缺点，迫切需要了解耐药性的原因，以便开发新的药物。我们工作中得出的一个主要认识是，野生型 p53 在抗性表型中具有显着特征，这代表了 p53 凋亡功能为何受到抑制的一个主要难题。由于许多晚期和难治性癌症疾病类型包括大量含有野生型 p53 的肿瘤，因此有理由相信关键基因或通路中的常见缺陷可能是 p53 未能功能激活的原因。基于强烈的相互排他性关系，野生型p53的肿瘤很可能有缺陷的Chk2表达，这种缺陷将影响p53的翻译后修饰，而这对于稳定和刺激其功能至关重要。事实上，顺铂耐药肿瘤细胞中的野生型 p53 通常表现出功能缺陷。由于特定癌症对铂类药物具有内在亲和力，我们假设 Chk2 表达缺陷会阻止顺铂耐药癌症中野生型 p53 的稳定和/或刺激，并且铂类似物可以设计为激活替代激酶以最大限度地恢复 p53 诱导能力和细胞毒活性。我们将通过三个具体目标来解决这一假设：1）表征与含有野生型p53的肿瘤组中的缺陷Chk2相关的顺铂耐药性； 2) 鉴定铂类似物激活的激酶，可恢复顺铂耐药细胞中的p53功能； 3) 建立先导化合物优化的结构-活性关系，并鉴定一种能够最大程度地稳定和刺激 Chk2 缺陷型耐药肿瘤细胞中野生型 p53 的类似物。基于小鼠模型，野生型 p53 的激活足以杀死肿瘤细胞，这提高了通过机制导向的药物开发方法针对顺铂耐药性将恢复野生型 p53 功能并显着提高反应和 5 年疗效的潜力。存活率。