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 536,000 Americans due 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 involved in signal transduction, tumor suppression, transcription factors and the cell cycle. Singly or in various combinations, the genes 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 human 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 under-utilized. Combinatorial biosynthesis and combinatorial chemistry technologies may provide the means to produce additional compounds related to interesting natural products and to further explore SARs within series in ways not possible with traditional methods of isolation and semi- or total synthesis. Mixtures of compounds produced by these two alternative methods can be evaluated, fractionated according to primary assay activity, and pure compounds isolated and identified using established methods for natural product mixtures. The creation of libraries of highly complex unique""""""""natural product-like"""""""" molecules, the broad number of potentially relevant target proteins and associated high throughput screening capacity and well-designed secondary and in vivo evaluations provide an effective framework for cancer drug discovery and development.
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