This proposal represents a multifaceted program for studying drug development. The natural product, discodermolide has the potential to be an important antitumor drug, particularly in Taxol resistant tumors. The preclinical studies that were done in our laboratory were crucial for the clinical development of Taxol and we believe that meaningful research with discodermolide could pave the way for its clinical development. Today, there is an immense interest in "targeted therapies", utilizing small molecules and antibodies that target aberrant signaling pathways in cancer cells. However for many malignancies, standard cytotoxic-based therapies, some in combination with targeted therapies, will remain the mainstream. Discodermolide is a natural product with a chemical structure very different from Taxol, but whose mechanism of action has major similarities, but also has distinct and intriguing differences. Relative to Taxol, discodermolide-treated cells have a low propensity for developing acquired resistance. This is attributable to discodermolide's ability to induce accelerated senescence and undergo a prolonged state of proliferative arrest. It has taken us several years to develop a discodermolide-resistant cancer cell line and unlike Taxol-resistant cells, these do not have classic mechanisms of Taxol resistance, namely beta-tubulin mutations or overexpression of the ATP- dependent drug efflux pump, P-glycoprotein. It is likely that the unique properties of discodermolide are related to its ability to induce senescence and also to its initial characterization as an immunosuppressive agent. This proposal will focus on delineating the effect of disocodermolide on the molecular pathways involved in drug- induced senescence and how that relates to modulation of 4EBP and mRNA processing and translation. Although senescence in cancer cells is a recognized mechanism of suppressing tumor-growth, the possibility exists that senescent cells may contribute to tumorigenesis through the induction of several pathways involved in inflammation and extracellular remodeling (reviewed in [64]), and in the case of discodermolide, this may render some patients susceptible to the development of pulmonary fibrosis. Thus, a fundamental component of this proposal is specific aim 3 that details a comprehensive chemical-biological approach to selecting promising structural analogs of discodermolide that have modified senescent-inducing properties. These compounds ideally would retain the very potent and unique microtubule-binding properties of the parent compound that initially attracted our attention for the therapeutic development of this drug, while minimizing the potential for senescence. The co-P.I.'s have had many productive years working with natural products and drug development and have assembled a superb group of colleagues at Albert Einstein and a unique group of synthetic chemists as collaborators. PUBLIC HEALTH RELEVANCE: Taxol is efficacious in the treatment of numerous human malignancies, but many patients experience serious side effects and / or develop acquired resistance. This has motivated a search for Taxol-like drugs that have equal or superior therapeutic efficacy. The mechansim of action of another Taxol-like drug, discodermolide will be determined and different structural analogs will be tested for improved chemotherapeutic activity.
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