The immediate significance of this 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 compoariosn to clinically used agents, disparate recognition and processing of structurally distinct DMA adducts is required. The interactions of this class of drugs with target DMA are distinct from the mononuclear-based cisplatin family and, indeed, unlike those of any DMA-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 DMA-modifying anticancer agents. It is important to understand the nature of these novel interactions and how they affect DMA function in order to exploit their full clinical potential. This proposal will study the unique aspects of the DMA 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 DMA adduct formation may result in different cellular signalling 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 targetted drugs to provide better treatment regimens for cancer patients.
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