Mechanistic Studies on New Platinum Clinical Agents

描述（由申请人提供）：本修订更新提案的直接意义是研究基于多（di/tri）核基序的一系列临床相关铂基抗癌药物的作用机制。这项工作源于一个基本原则，即与临床使用的药物相比，为了获得真正不同的抗肿瘤活性，需要对结构不同的DNA加合物进行不同的识别和处理模式。这类药物与靶DNA的相互作用不同于单核顺铂家族，实际上也不同于临床使用的任何DNA损伤剂。一种药物BBR3464进入人体II期试验，证明了这种方法实用性的概念。随着这一进展，以顺铂为基础的抗肿瘤药物的范式被改变。这些药物的化学和生物学特性表明，它们应该被认为是一类全新结构的DNA修饰抗癌药物的代表。了解这些新相互作用的性质以及它们如何影响DNA功能是很重要的，以便充分利用它们的临床潜力。本提案将研究由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，有明确的反应模式。在复发的卵巢癌和非小细胞肺癌中，II期的客观反应已经得到证实。临床前研究表明，BBR3464治疗对p53突变肿瘤有活性，对p53的诱导作用最小。该项目的长期目标是了解DNA加合物形成的独特模式如何导致不同的细胞信号传导或“下游”效应，如蛋白质识别，以及这些事件是否可能导致真正新的抗肿瘤活性模式。该项目的另一个长期目标是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中最有效的药物之一。阐明这类新型抗癌药物的作用机制将有助于设计出更好、更有针对性的治疗癌症的药物。这些药物将与靶向药物联合使用，为癌症患者提供更好的治疗方案。公共卫生相关性：铂类药物是抗癌药物中最有效的药物之一。阐明这类新型抗癌药物的作用机制将有助于设计出更好、更有针对性的治疗癌症的药物。这些药物将与靶向药物联合使用，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.