In this study we investigate the translational potential of targeting Spleen Tyrosine Kinase (SYK) as a new regimen in developmental therapeutics in ovarian cancer. Ovarian cancer is one of the most aggressive types of women cancer and an effective therapy is an unmet need to improve the clinical outcome in patients at advanced stages. Our recent study demonstrates that ovarian cancer cells surviving paclitaxel treatment have higher levels of activated SYK. Inactivating SYK using gene knockdown, knockout and small compound inhibitors can re-sensitize resistant cells to paclitaxel by enhancing microtubule stability. This effect is presumably due to SYK inhibitor mediated de-phosphorylation of microtubule-associated proteins (MAPs), a mechanism distinct from paclitaxel-induced microtubule stability (binding the ?-tubulin). The above result indicates a potential use for combining paclitaxel and SYK inhibitors that have been tested in late-phase clinical trials (in autoimmune diseases and hematopoietic malignancies) in enhancing paclitaxel cytotoxicity. Our recent unpublished studies further suggest that SYK inhibition alone can also harness cancer cells by inhibiting their motility and invasion. Phospho-proteomic analyses in ovarian cancer cells demonstrate that in addition to the MAPs recently reported by us, actin-associated proteins, cortactin and cofilin, and survival signaling molecules, EGFR, ErbB2 and STAT3, are also substrates of SYK. Inactivation of these pathways may protect cells from chemotherapy-induced cell death. Thus, targeting the SYK pathway using SYK inhibitor represents an innovative strategy to sensitize tumors to paclitaxel and inhibit tumor spreading. To test the hypotheses, we proposed the following Aims.
Aim 1 : Elucidate the mechanisms behind how SYK mediates paclitaxel resistance.
Aim 2 : Determine whether inactivating SYK signaling in ovarian cancer cells reduces cell migration and invasion via altering cytoskeletal dynamics.
Aim 3 : Evaluate the efficacy of SYK inhibitor and paclitaxel combination in patient-derived xenograft (PDX) models and identify predictive markers. Our data will provide the critical pre-clinical data to support future clinical trials to determine whether the clinically available SYK inhibitors can improve clinical outcome in ovarian cancer patients either as a drug to sensitize paclitaxel or as a monotherapy to delay disease recurrence. The results of this study will have an impact on the timely translation of our bench discoveries to the clinic, and will renew our hope for better patient outcome by augmenting conventional chemotherapy.
The expected results from this study will provide new insight into the translational application of the SYK inhibitor in treating ovarian cancer patients with recurrent disease and will also help us to understand the roles of SYK signaling in the pathogenesis of paclitaxel resistance. This application should have an impact on the future introduction of the SYK inhibitor as a new drug in the clinical management of ovarian cancer patients.
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