Less than half of newly diagnosed women with HGSOC survive to five years. This poor overall survival results from late stage diagnosis, tumor relapse and ultimate resistance to conventional chemotherapy. Cancer initiating cells (CICs) are known to be major contributors to chemotherapy resistance given that they are not eradicated by cytotoxic therapies; unfortunately existing therapies to treat HGSOC do not eradicate the CICs. We have found that miR-181a is frequently overexpressed in recurrent, platinum-resistant HGSOC tumors and promotes platinum resistance through the maintenance of ovarian CIC through its regulation of the Wnt signaling pathway. Specifically, we have shown that distinct Wnt active cell subsets isolated from HGSOC tumors express high levels of miR-181a and are responsible for the platinum- resistance phenotype and maintenance of CICs. Targeted inhibition of the Wnt pathway through either ?catenin shRNA or small molecule inhibition of the Wnt transcriptional axis resulted in platinum sensitivity and CIC eradication. To date, few pathways have been identified as key mediators of ovarian CIC maintenance and our preliminary studies suggest miR-181a may act as a rheostat balancing the activation of Wnt signaling in a subset of HGSOC tumor cells, thus introducing a novel regulatory mechanism controlling the balance between self-renewal and proliferation or quiescence and differentiation.
We aim to extend on this concept and test the hypothesis that miR-181a activation of the Wnt signaling pathway plays a hitherto unappreciated role in the emergence of HGSOC platinum-resistance through the maintenance of CICs thus introducing a novel targetable pathway for the treatment of chemoresistant HGSOC. In order to substantiate this hypothesis we will establish the mechanism by which miR- 181a regulates the Wnt signaling pathway, functionally assess Wnt-driven tumor cells isolated from primary HGSOC tumors and lastly, investigate the therapeutic benefits of selectively targeting the Wnt signaling pathway. Identifying relevant pathways and biological targets that elicit ovarian CIC phenotype and platinum resistant offers an unprecedented opportunity to target the cell population ultimately responsible for the high mortality of HGSOC. Successful completion of these aims will greatly increase understanding of how miR-181a regulates Wnt activation, contributes to CICs and platinum resistance and introduce a potentially novel mechanism-based therapeutic option for patients afflicted with HGSOC.
Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer deaths in women. Poor overall survival results from resistance to platinum-based chemotherapy and high rate of recurrence, highlighting the urgent need for a greater understanding of the molecular alterations driving these factors in the most common and lethal form of EOC, high-grade serous cancer (HGSOC). Cancer initiating cells (CICs) are known to be major contributors to chemotherapy resistance given that they are not eradicated by cytotoxic therapies; unfortunately existing therapies to treat HGSOC do not eradicate the CICs. We have found that a novel microRNA, miR-181a, can promote the maintenance of platinum resistant CICs through the activation of the Wnt/?catenin pathway and specifically targeting this pathway can sensitize cells to platinum and eradicate CICs.
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