Mechanistic Studies on New Platinum Clinical Agents

描述(由申请人提供)：这项修订后的更新建议的直接意义是研究基于多(二/三)核基序的一系列临床相关的铂类抗癌药物的作用机制。这项工作源于这样一个基本原则：与临床使用的药物相比，为了获得真正不同的抗肿瘤活性，需要一种不同的识别和处理结构不同的DNA加合物的模式。这类药物与靶DNA的相互作用不同于以单核为基础的顺铂家族，而且确实不同于临床上使用的任何DNA损伤剂。一种名为BBR3464的药物进入人类第二阶段试验，证明了这种方法的有效性。随着这一进展，以顺铂为基础的抗肿瘤药物的范式发生了改变。这些药物的化学和生物学特征表明，它们应该被认为代表了一种全新的DNA修饰抗癌剂的结构类别。了解这些新的相互作用的性质以及它们是如何影响DNA功能的，以便充分发挥它们的临床潜力是很重要的。这项提议将研究我们实验室中出现的多核铂化合物形成的DNA加合物的独特方面，以及这些新结构形成的生物学后果。I期试验表明，在通常无法用顺铂治疗的癌症中，包括黑色素瘤、胰腺癌和肺癌的反应，都有明显的模式。目的复发性卵巢癌和非小细胞肺癌的II期疗效已得到证实。临床前研究表明，在BBR3464治疗后，p53突变肿瘤中的活性和对p53的诱导微乎其微。该项目的长期目标是了解一种独特的DNA加合物形成模式如何导致不同的细胞信号或“下游”效应，如蛋白质识别，以及这些事件是否可能导致真正的新的抗肿瘤活性模式。这是该项目的另一个长期目标，将这些化合物的细胞毒性作用置于导致细胞死亡的分子途径的背景下。铂类药物是抗癌药物军工厂中最强大的药物之一。阐明这类新型抗癌药物的作用机制将有助于设计出更好、更特异的癌症治疗药物。这些药物将与靶向药物结合使用，为癌症患者提供更好的治疗方案。与公共健康相关：铂类药物是抗癌药物武器库中最强大的药物之一。阐明这类新型抗癌药物的作用机制将有助于设计出更好、更特异的癌症治疗药物。这些药物将与靶向药物结合使用，为癌症患者提供更好的治疗方案。

DESCRIPTION (provided by applicant): The immediate significance of this revised renewal proposal is the study of the mechanism of action of a clinically relevant series of platinum-based anticancer agents based on a poly(di/tri)nuclear motif. The work stems from the fundamental tenet that to obtain a genuinely different profile of antitumor activity in comparison to clinically used agents, a different pattern of recognition and processing of structurally distinct DNA adducts is required. The interactions of this class of drugs with target DNA are distinct from the mononuclear-based cisplatin family and, indeed, unlike those of any DNA-damaging agent in clinical use. Proof of concept of the utility of this approach is given by the entry of one agent, BBR3464, to human Phase II trials. With this advance, the paradigm of cisplatin-based antitumor agents is altered. The chemical and biological features of these drugs argue that they should be considered representative of an entirely new structural class of DNA- modifying anticancer agents. It is important to understand the nature of these novel interactions and how they affect DNA function in order to exploit their full clinical potential. This proposal will study the unique aspects of the DNA adducts formed by the polynuclear platinum compounds that have emerged from our laboratory and the biological consequences of formation of these novel structures. The Phase I trials demonstrated a clear pattern of responses in cancers not normally treatable with cisplatin including responses in melanoma, pancreatic and lung cancer. Objective responses in Phase II have been verified in relapsed ovarian cancer and non-small cell lung cancer. Pre-clinical studies indicated activity in p53-mutant tumors and a minimal induction of p53 following BBR3464 treatment. It is the long-term goal of this project to understand how a unique pattern of DNA adduct formation may result in different cellular signaling or "downstream" effects such as protein recognition and whether such events may be dictated to lead to a genuinely new pattern of antitumor activity. It is a further long-term goal of this project to place the cytotoxic effects of these compounds into the context of molecular pathways leading to cell death. Platinum drugs are some of the most powerful agents in the cancer drug armamentarium. Elucidating the mechanism of action of this new class of anticancer agents will lead to design of better, more specific drugs for treatment of cancer. The drugs will be used in combination with targeted drugs to provide better treatment regimens for cancer patients. PUBLIC HEALTH RELEVANCE: Platinum drugs are some of the most powerful agents in the cancer drug armamentarium. Elucidating the mechanism of action of this new class of anticancer agents will lead to design of better, more specific drugs for treatment of cancer. The drugs will be used in combination with targeted drugs to provide better treatment regimens for cancer patients.