Each year Ovar’coming Together funds research which advances treatment, cure and early detection for ovarian cancer. All of the research money distributed by Ovar’coming Together stays in the state of Indiana. It is our hope that we can provide the much needed seed money to those researchers dedicated to fighting this disease. In 2008, Ovar’coming Together awarded a $20,000 in research grant.

Targeting of Ovarian Cancer-Initiating Cells by Epigenetic Therapies, Curt Balch, PhD. 

Ovarian cancer is the most lethal gynecologic malignancy. Unfortunately, while over 70% of patients respond to standard therapies, 90% of these will relapse, due to the onset of drug-resistant disease that is almost always fatal. An emerging theory of drug resistance supports the existence of a tumor subpopulation of “cancer stem cells” that are singularly capable of propagating the malignant phenotype. Cancer stem cells are believed to derive from normal tissue stem cells that are long-lived and necessarily resistant to a variety of environmental insults. Consequently, those resistance-conferring properties are highly likely to be present in their malignant stem cell counterparts. The defining characteristic of tumor stem cells is the ability to form neoplasms at very low cell densities upon engraftment into immunodeficient mice.

Our research group has now isolated “ovarian cancer-initiating cells” (OCICs) that organize anchorage-independent spheres in culture, form tumors upon injection of only 100 cells (as compared to a requirement of over 105 cells from the bulk parent tumor), and express the cell surface markers CD44 and CD 117, allowing their reproducible isolation. Those OCICs are also more resistant to the conventional therapies cisplatin and paclitaxel, in agreement with the cancer stem cell theory of drug resistance. A now emerging theory of tumorigenesis posits that cancer-initiating cells gain repressive epigenetic marks (e.g., DNA methylation and histone deacetylation) in full-fledged tumors. As DNMT and HDAC inhibitors are well-documented differentiating agents for a number of malignancies, we hypothesize that these agents could halt or even reverse the process of tumor “differentiation.”

Consequently, in this proposed project, we will examine the feasibility of specifically targeting our candidate ovarian tumor stem cells in whole animals, using DNMT and HDAC inhibitors, in addition to assessing whether those treatments can sensitize resistant tumors to cisplatin. We strongly believe that the disruption of repressive epigenetic programs, necessary for tumor development from the progenitor cells solely responsible for propagation for ovarian malignancies, will greatly benefit patients suffering from this terrible disease.

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