Targeted Development of Platinum Drugs

描述（由申请人提供）：晚期疾病的主要治疗方式是化疗，基于顺铂的方案在许多癌症的癌症管理策略中发挥重要作用，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发生而复发和治疗失败，并且患者最终死于其疾病。大约20年前的最新进展是将紫杉醇纳入铂方案，但这只提供了短期的增量获益，而不会影响5年生存率。因此，顺铂耐药性是一个显著的缺点，迫切需要了解耐药性的原因，因此可以开发新的药物。从我们的工作中出现的一个主要的理解是，野生型p53的特点突出的抗性表型，这代表了一个主要的难题，为什么p53的凋亡功能被抑制。由于许多晚期和难治性癌症疾病类型包括大量携带野生型p53的肿瘤，因此有理由相信关键基因或途径中的常见缺陷可能是p53未能功能激活的原因。基于相互排斥的强烈关系，具有野生型p53的肿瘤可能具有缺陷的Chk 2表达，并且该缺陷将影响p53的翻译后修饰，这对于稳定和刺激其功能是必不可少的。事实上，顺铂耐药肿瘤细胞中的野生型p53常常表现出功能缺陷。由于特定的癌症具有固有的亲和力铂类药物，我们假设，缺陷Chk 2表达阻止稳定和/或刺激野生型p53在顺铂耐药的癌症，铂类似物可以被设计为激活一种替代激酶，最大限度地恢复p53诱导和细胞毒活性。我们将通过三个具体的目标来解决这一假设：1）在携带野生型p53的肿瘤组中表征与缺陷性Chk 2相关的顺铂抗性; 2）鉴定由铂类似物激活的激酶，该激酶恢复顺铂抗性细胞中的p53功能;和3）建立用于先导物优化的结构-活性关系，并鉴定最大限度地稳定和刺激野生型的类似物。在耐药Chk 2缺陷型肿瘤细胞中的p53。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靶向顺铂耐药性将恢复野生型p53功能并显着增加反应和5年生存率的可能性。 公共卫生相关性：晚期实体癌用基于顺铂的方案治疗，但反应不持久，高达90%的患者可能因肿瘤对治疗表现出耐药性而死亡。仍然携带正常凋亡野生型p53基因的癌症是最耐药的，我们将研究为什么p53不起作用，以允许合理的治疗方法出现。我们的机制为基础的战略将确定药物，将有潜力的治愈性疗法得以实现。

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. PUBLIC HEALTH RELEVANCE: Advanced solid cancers are treated with cisplatin-based regimens, but the response is not durable and up to 90% of the patients may die as the tumor demonstrates resistance to therapy. Cancers that still harbor the normally-apoptotic wild-type p53 gene are the most resistant, and we will investigate why p53 is not functioning to allow rational therapies to emerge. Our mechanism-based strategy will identify drugs that will have potential for curative therapies to be realized.