In 2007, Ovar’coming Together awarded $30,000 in research grants. The proposals were reviewed by a national review board with final determination being made by the Ovar’coming Together Executive Committee. In addition, $29,675 was gifted to Indiana University Cancer Center for ovarian cancer research. Proceeds form the Old Bags Luncheon provided the gift award, and was donated in memory of Susie Hazelett.

Research Title	Researcher and Institution	Amount Awarded
In Vivo Targeting of Ovarian Cancer Stem Cells by Epigenetic Therapies	Submitted by Curtis Balch, Ph.D. Medical Sciences Program Indiana University	$10,000
Targeting the TG-2 Fibronection Interaction For Blocking Metastasis in Ovarian Cancer	Submitted by Daniela Matei, M.D and John J. Turchi, Ph.D. Research and Sponsored Programs Indiana University Simon Cancer Center	$20,000
Ovarian Cancer Research Gift in memory of Susie Hazelett	Indiana University Cancer Center	$29,675
Total Funded for 2007 Research		$59,675

In Vivo Targeting of Ovarian Cancer Stem Cells by Epigenetic Therapies -  Dr. Curt Balch, Ph.D.   

Ovarian cancer is the most lethal gynecological 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 small tumor subpopulation of malignant progenitors, known as “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 tumor cells that specifically possess that attribute (enhanced tumorigenicity), forming tumors at a density of only 100 cells, as compared to a requirement of over 106 (unfractionated) cells from the bulk parent tumor.  Those ovarian tumor stem-like cells are also more resistant to the conventional therapies cisplatin and paclitaxel, in agreement with the cancer stem cell theory of drug resistance. 

Another characteristic inherent to all stem cells is a high degree of epigenetic repression, mediated by large, multisubunit complexes, known as Polycomb, that associate with transcriptional silencing enzymes such as DNA methyltransferases (DNMTs) and histone deacetylases (HDACs).  As DNMT and HDAC inhibitors are well-documented differentiating agents for a number of malignancies, we hypothesize that these agents could disrupt the activity of Polycomb complexes that is required for the “undifferentiated” phenotype and self-renewal of ovarian cancer stem cells. 

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, in the progenitor cells solely responsible for propagation for ovarian malignancies, will greatly benefit patients suffering from this terrible disease.

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Targeting the TG-2 Fibronection Interaction For Blocking Metastasis in Ovarian Cancer – Dr. Daniela Matei and John Turchi, Ph.D.

Background: Ovarian cancer is the leading cause of mortality among gynecological malignancies.  With current treatment, the majority of patients succumb to their disease.  We utilized microarray analysis and we found that tissue transglutaminase (TG2) is overexpressed in ovarian cancer cells and tumors.  The functional role of TG2 has not been studied in ovarian cancer.  Our preliminary data suggest that this protein is important for cancer cell adhesion and migration.  We showed that TG2 knockdown decreased cell attachment to the extracellular matrix, cell migration and tumor dissemination in the peritoneal cavity.  Based on these preliminary data, we hypothesize the TG2-fibronectin-integrin complex functions at the interface between ovarian cancer cells and the tumor microenvironment promoting peritoneal metastasis and can be targeted for treatment.  In this project, we propose to target this complex and to find small molecules inhibitors for TG2-Fn, with the goal of limiting IP metastasis in ovarian cancer.  We propose to test this hypothesis experimentally by addressing three research objectives:

Specific Aims:

1. Develop a fluorescence polarization assay (FPA) to measure the TG2-fibronectin interaction.
2. Screen ChemDiv library for small molecule inhibitors of TG2 and its interaction with fibronectin by using the FPA adapted to high throughput screening.
3. Determine activity of hits in cell culture based assays for cell adhesion and spreading/migration.

Cancer Relevance:  The role of TG2 in ovarian cancer has not been studied and the emphasis on mechanisms of metastasis modulated by TG2 is novel.  The experiments proposed will demonstrate the function of TG2 in ovarian cancer metastasis and will lead to possible therapeutic interventions to limit the IP spread of ovarian tumors.  This approach is highly relevant to ovarian cancer research as it would jumpstart the search for a new treatment to block EOC metastasis.  The ultimate goal is to block TG2 function, the spread of tumors in the peritoneal space and its lethal complications. 

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