Studies in Mice to Improve Efficacy/Safety of Paclitaxel/Docetaxel with an Anti-I

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DESCRIPTION (provided by applicant): Inhibitor of differentiation (Id) genes and proteins play a significant role in tumor biology, and an anti-Id therapy in combination with a taxanes, a widely prescribed class of cytotoxic (paclitaxel/docetaxel, docetaxel or protein-bound paclitaxel) to treat cancer, is hypothesized to significantly improve the efficacy of the taxane without compromising safety while also providing additional anti-cancer activity. An effective Id1 inhibitor would potentially improve the efficacy of the taxanes by three distinct mechanisms: (i) preventing endothelial repair and thereby promoting the intrinsic anti-angiogenic effect of paclitaxel/docetaxel, (ii) lowering the anti-apoptotic environment of the tumor making it more susceptible to the cytotoxicity of paclitaxel/docetaxel and (iii) augmenting the cytotoxicity of paclitaxel/docetaxel by a direct anti-cancer effect. The goal of this proposal is to provide data to justify formal preclinical development and initial clinical evaluation of this therapeutic approach with an anti-Id1 small molecule. Experiments to be funded by the grant include xenograft studies in mice to establish the optimum dosing regimen for both the anti-Id agent and the taxanes. PUBLIC HEALTH RELEVANCE: Anti-microtubule taxanes like paclitaxel and docetaxel are widely prescribed cytotoxics to treat cancer. An effective Id1 inhibitor would potentially improve the efficacy of taxanes by three distinct mechanisms: (i) preventing endothelial repair and thereby promoting the intrinsic anti-angiogenic effect of taxanes, (ii) lowering the anti-apoptotic environment of the tumor making it more susceptible to the cytotoxicity of the taxanes, and (iii) augmenting the cytotoxicity of the taxanes by a direct anti-cancer effect. The goal of this proposal is to provide data to justify formal preclinical development and initial clinical evaluation of this therapeutic approach using an anti-Id1 small molecule.