Targeted Development of Platinum Drugs

铂类药物的靶向开发

• 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
• 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

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）：晚期疾病环境中的主要治疗方式是化学疗法，基于顺铂的方案在许多癌症的癌症管理策略中起着重要作用，包括卵巢癌，间皮瘤和非小细胞细胞肺癌。但是，大多数晚期癌症病例复发和由于顺铂耐药的发作而导致的治疗，患者最终屈服于他们的疾病。大约二十年前的最新进展是将紫杉醇纳入白金方案，但这仅提供了短期增量收益而不会影响5年生存率。因此，顺铂耐药是一个重要的缺点，并且迫切需要了解抗药性的原因，因此可以开发出新的代理。从我们的工作中出现的一个主要理解是，野生型p53特征在抗性表型中突出，这代表了为什么抑制p53的凋亡功能的主要难题。由于许多晚期和难治性的癌症类型包括具有野生型p53的大量肿瘤，因此有理由相信，关键基因或途径中的常见缺陷可能是p53无法在功能上激活的原因。基于相互排他性的牢固关系，具有野生型p53的肿瘤可能具有有缺陷的CHK2表达，并且这种缺陷会影响p53的翻译后修饰，这对于稳定和刺激其功能至关重要。实际上，抗铂抗性肿瘤细胞中的野生型p53通常表现出功能缺陷。由于特定的癌症对铂药具有固有的亲和力，因此我们假设有缺陷的CHK2表达可防止抗铂耐药性癌症中野生型p53的稳定和/或刺激，并且可以设计铂类似物来激活一种替代性激酶，以最大程度地恢复P53的替代性p53构成p53构成症状和cytotox cytotoxic castoxox cantotox castoxox cantot cytoxox cantotox cantotox cistoxox actotox cistoxox cistoxox actoxox cistoxox actoxox actox oftoxox actox ofcotic castox cytoxox。我们将通过三个特定目的来解决这一假设：1）表征与野生型p53的肿瘤面板中的CISPLATIN耐药性有关； 2）鉴定由铂类似物激活的激酶，该铂类似物恢复了抗顺铂耐药细胞中的p53功能； 3）建立铅优化的结构 - 活性关系，并确定一个类似物，该类似物在耐药性CHK2缺陷肿瘤细胞中最大程度地稳定和刺激野生型p53。基于小鼠模型，野生型p53的激活足以杀死肿瘤细胞，这增加了通过机制指导的药物开发方法靶向顺铂耐药性的潜力，将恢复野生型p53功能，并显着提高反应和5年生存率。