The long-term objective of this collaborative research is to discover novel anti-cancer drugs that are useful against the major types of cancer. These are the colon, lung, breast, prostate and ovarian tumors. Together, these tumors comprise over 70% of human cancers. Cancer is a major cause of death in the USA: over 563,000 Americans die from the disease annually. At present, cancer is treated by surgery, X-ray, radiation, biological therapy and chemotherapy; these therapies are largely ineffective against the major tumors. There is a critical need to discover effective and selective anti-tumor drugs, but this research is severely limited by our lack of understanding of cancer. Our work focuses on the development of anti-tumor drugs that affect some of the more recently discovered targets and/or processes that are unique or present at different levels in tumors rather than normal tissue. The primary and secondary screens employed by the Oncology Research Program (ORP) at Novartis are aimed at potentially important protein targets involve din signal transduction, tumor suppression, transcription factors and the cell cycle. Singly or in various combinations, the gene for each of these proteins are mutated or deleted in the majority of common tumors. This approach is different from the more traditional """"""""cytotoxicity- based"""""""" cancer drug discovery programs. Compounds found to be active in the primary and secondary screens will be further examined according to Flow Charts established for each target. Compounds with the desired profile will then be evaluated in vivo against tumor tumors growing as xenografts in nude mice and following successful development enter into human clinical trials. The diversity of natural products has provided a rich source of novel anti- tumor agent classes, but it still appears to be underutilized. The diversity of marine organisms collected and extracted by our Academic Collaborators coupled with activity-guided assays aimed at unique targets supplied by Novartis will continue to provide a rich milieu of natural products for further evaluation. Combinatorial chemistry and partial and total synthesis efforts by Novartis will further create a series of analogous and derivatives that will enhance biological activity and physical properties of the lead structures. Active involvement of the structural biology unit and Novartis is expected to provide NMR and X-ray data on target molecules alone or complexed with natural product lead compounds which will allow optimization of properties of series of interest. The high throughput screening and secondary assays typically implemented for a given target provide rapid turnaround to direct drug development efforts and provide the basis is for selection for compounds that will be examined in in vivo models. The organization of these tools, assays and associated activity criteria provide an effective framework for drug discovery and development.
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