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Subset of Preexisting, Poly-Resistant Cancer Stem Cells in High-Grade Serous Ovarian Cancer

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[Technical Report, Annual Report]

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High-grade ovarian cancer responds very well to primary chemotherapy and yet almost always returns in 6-24 months and often in a form that is resistant to chemotherapy. Using novel technologies for cloning the plurality of cancer stem cells from HGOC tumors, we have identified a minority of cancer stem cells in each tumor that are resistant to a wide range of chemotherapeutic drugs to which they have never been exposed. Based on the hypothesis that these polyresistant cells drive recurrent disease, the present proposal seeks to clone polyresistant cells in an additional 20 cases of ovarian cancer, understand the molecular mechanisms by which these cells evade a broad array of chemotherapeutic drugs, and to identify drugs that circumvent and even leverage this resistance mechanism to selectively eliminate these preexisting cells that likely drive recurrent disease in these patients. Important new data suggest that the resistance driven by these polyresistance cancer stem cell variants may be a tractable problem. The first is that all polyresistant cells share, in common, a broad pattern of gene expression previously implicated in ancient mechanisms that respond to exogenous chemicals, or xenobiotics, in the environment. The second is that the pattern of polyresistance- down to the specific chemotherapeutic drugs, is identical not only in different cancer stem cells within a patient but across patients, suggesting that the polyresistance phenomenon is surprisingly uniform. The last is that our initial attempts to find drugs that circumvent the polyresistance mechanism in one case successfully eliminates polyresistant clones from other tumors. Working with our clinical collaborators we will ask of these data based on five cases can be extending to a cohort of 20 additional cases of high-grade ovarian cancer. We anticipate these studies will lead to new approaches to the prevention of recurrent disease in women with this aggressive cancer.


Subject Categories:

  • Anatomy and Physiology
  • Medicine and Medical Research

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[A, Approved For Public Release]