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，以顺铂为基础的方案在许多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的发作而复发和治疗失败，患者最终死于疾病。大约20年前的最新进展是将紫杉醇纳入铂金治疗方案，但这只提供了短期的增量益处，而不会影响5年生存率。因此，顺铂耐药是一个显著的缺点，迫切需要了解耐药的原因，以便开发新的药物。从我们的工作中出现的一个主要理解是野生型p53在抗性表型中具有突出的特征，这代表了p53的凋亡功能被抑制的主要谜团。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通路的共同缺陷可能是p53无法功能激活的原因。基于强互斥关系，具有野生型p53的肿瘤可能存在Chk2表达缺陷，这种缺陷会影响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，野生型p53在顺铂耐药肿瘤细胞中经常表现出功能缺陷。由于特定的癌症对铂类药物具有内在的亲和力，我们假设Chk2表达缺陷阻止了顺铂耐药癌症中野生型p53的稳定和/或刺激，并且铂类似物可以被设计为激活替代激酶，以最大限度地恢复p53的诱导性和细胞毒性活性。我们将通过三个具体目标来解决这一假设：1)在携带野生型p53的肿瘤组中，将顺铂耐药性与Chk2缺陷相关；2)鉴定由铂类似物激活的激酶，恢复顺铂耐药细胞中的p53功能；3)建立导联优化的构效关系，并确定在耐药chk2缺陷肿瘤细胞中最大限度地稳定和刺激野生型p53的类似物。根据小鼠模型，激活野生型p53足以杀死肿瘤细胞，这就提出了通过机制导向的药物开发方法靶向顺铂耐药将恢复野生型p53功能并显着提高应答和5年生存率的可能性。

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.