Direct targeting of cancer invasion and metastasis using Withania root extracts

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DESCRIPTION (provided by applicant): Though clinicians can predict which patients are at risk for developing metastases, traditional therapies prove ineffective and metastatic disease is the primary cause of cancer patient death. We propose a novel anti- metastatic strategy to prevent metastases from occurring by perturbing a unique cell migration target-the vimentin cytoskeleton. Vimentin overexpression is found in nearly all invasive cancers in both basic and pre- clinical models, and is used as a clinical marker of cancer invasion. Functional studies show that vimentin is essential for cell migration but not viability, and overexpression leads to more aggressive and motile cancer cells. Here we present data showing that Withania somnifera root extracts (WRE) target vimentin to inhibit cancer cell motility and invasion while having negligible effects on cell viability at low doses. We test the hypothesis that WRE is an anti-metastatic and anti-invasive complementary alternative medicine (CAM) that disrupts vimentin function with limited toxicity. We propose comprehensive analysis of the anti-invasive and anti-metastatic efficacy of WRE in cell lines and a pre-clinical metastatic mouse model. We will employ cutting- edge live cell imaging to dissect the mechanism of how WRE inhibits vimentin function and cancer cell migration, as well as determine if WRE inhibits endothelial cell motility resulting in anti-angiogenic activity. Since all data show that vimentin disruption does not impact cell viability, this cell invasion inhibitor is aligned with the goals of CAM and chemoprevention. Ultimately, we envision that WRE can be a vimentin-targeting chemopreventative in high-risk metastatic patients. PUBLIC HEALTH RELEVANCE: Metastatic disease is the major cause of death in almost all cancer types; however, most treatments target the primary tumor and not the metastases. Here we take a chemopreventative approach to prevent cancer invasion and metastasis from ever occurring. We propose studies that investigate the efficacy of our novel compound, its mechanism of action, and pre-clinical activity.