Abstract ED05-02: Discovering new drugs to inhibit prostate cancer metastasis

Abstract

Abstract ED05-02 Cancer chemoprevention offers a unique drug discovery opportunity. This is because at its core, chemoprevention involves the interface between pharmacologic agents that induce perturbations in biological systems and early stage cancer biology. The molecular aberrations in early stage cancer are more limited than those in advanced stage cancer. This provides a more permissive environment for understanding the complex relationships between drug, pharmacologic target, and therapeutic result. Thus, agents with therapeutically relevant activity represent important investigative tools that can be used to reveal important underlying biology, to identify new pharmacologic targets, and to develop pathophysiologically relevant models. Initial agents can then serve as starting blocks for new chemical synthesis, and these new compounds in turn can be evaluated for bioactivity in relevant model systems. The same considerations in the field of chemoprevention that facilitate this conventional bench-to-man approach to drug discovery can also be applied to the more novel approach of beginning drug discovery endeavors in man. The impetus for undertaking such an approach stems from the facts that our preclinical models have severe restrictions in emulating the biology in man, that the transition from preclinical to clinical represents a frequent point of failure, that the time to drug approval is not improving, and that the cost of drug discovery continues to rise. With the advent of new methods that permit robust system-wide measurement of cell and molecular parameters on limiting amounts of tissue, a practical barrier to beginning drug discovery efforts in man is now being lifted. Here too, chemoprevention offers a unique opportunity. This is because chemopreventive agent candidates are relatively non-toxic, and because they are tested in well defined risk cohorts. Thus, taken together, it now becomes possible to prospectively administer relatively non-toxic agents to at risk cohorts, and to screen for cell and molecular effects in a target organ harboring a limited spectrum of molecular aberrations. By definition, the resultant findings will have direct relevance to man, as well as to relevant underlying biology. An example of how an integrated approach was pursued by a single research group will be provided, and will serve to highlight the efficiency of interfacing chemoprevention with drug discovery. In particular, a natural product that possesses anti-motility properties has fostered the elucidation of pathways which regulated prostate cancer cell motility, has led to the identification of a pharmacologically relevant target protein, and has provided the chemical scaffold which supported new agent discovery. By coupling administration of the natural product to man, with gene expression profiling of target cells in man, new regulators of prostate cell motility have been identified and then confirmed by in vitro studies. Citation Information: Cancer Prev Res 2008;1(7 Suppl):ED05-02.