Epithelial ovarian cancer (EOC) is the most frequent cause of gynecologic malignancy-related mortality in women. Although advances in platinum/taxane-based chemotherapy have resulted in improved survival, patients typically experience disease relapse within 2 years of the initial treatment and develop resistance to therapy. Therefore, development of new therapies is a high priority. Molecular targeted drugs hold promise as independent therapeutic agents or chemotherapy response modifiers and could contribute substantial improvements to the outlook of women with EOC. microRNAs (miRNAs) are -22 nucleotide non-coding RNAs, which negatively regulate gene expression in a sequence-specific manner. We have generated the first evidence that miRNAs exhibit genomic alterations at high frequency and their expression is remarkably deregulated in ovarian cancer. This strongly suggests that miRNAs are involved in the initiation and progression of this disease. Indeed, our preliminary studies demonstrate that miRNA is a new class of novel biomarker with strong potential application to EOC in eariy detection, diagnosis and therapeutic response prediction. We hypothesize that miRNAs might serve two roles in the evolution of predictive and therapeutic strategies in EOC. First, it is possible that miRNAs might accurately predict response and resistance to a given chemotherapy. Second, and potentially more exciting in the long term, is the potential that selected mlRNA's might serve as therapeutic tools and/or chemotherapy response modifiers that will offer novel therapeutic opportunities for EOC. We propose the following specific aims to develop miRNA-based therapeutic tools for EOC.
Specific Aim 1 : Determine the function and therapeutic potential of select miRNAs in vitro.
Specific Aim 2 : Determine the therapeutic potential of select miRNAs in vivo.
Specific Aim 3 : Develop one or more constructs directed to specific mlRNA's in Phase l/ll trials.
Specific Aim 4 : Evaluate the predictive value of miRNAs response and resistance to a given chemotherapy.

Public Health Relevance

(See Instructions): Epithelial ovarian cancer is the most frequent cause of gynecologic cancer-related mortality in women. miRNAs are small non-coding RNAs, which negatively regulate gene expression in a sequence-specific manner. We will conduct a detailed study of miRNA in ovarian cancer, which has not been carried out to date, with the intent to (i) discover new biomarkers for ovarian cancer clinical management or prognosis;(ii) discover novel and important therapeutic targets.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
7P50CA083638-15
Application #
8474623
Study Section
Special Emphasis Panel (ZCA1-RPRB-M)
Project Start
Project End
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
15
Fiscal Year
2013
Total Cost
$499,351
Indirect Cost
$120,006
Name
Research Institute of Fox Chase Cancer Center
Department
Type
DUNS #
064367329
City
Philadelphia
State
PA
Country
United States
Zip Code
19111
Zhong, Qian; Peng, Hong-Ling; Zhao, Xia et al. (2015) Effects of BRCA1- and BRCA2-related mutations on ovarian and breast cancer survival: a meta-analysis. Clin Cancer Res 21:211-20
Duraiswamy, Jaikumar; Freeman, Gordon J; Coukos, George (2014) Dual blockade of PD-1 and CTLA-4 combined with tumor vaccine effectively restores T-cell rejection function in tumors--response. Cancer Res 74:633-4; discussion 635
Li, Chunsheng; Wang, Junying; Hu, Jia et al. (2014) Development, optimization, and validation of novel anti-TEM1/CD248 affinity agent for optical imaging in cancer. Oncotarget 5:6994-7012
Hu, Xiaowen; Feng, Yi; Zhang, Dongmei et al. (2014) A functional genomic approach identifies FAL1 as an oncogenic long noncoding RNA that associates with BMI1 and represses p21 expression in cancer. Cancer Cell 26:344-57
Matthaiou, Efthymia-Iliana; Barar, Jaleh; Sandaltzopoulos, Raphael et al. (2014) Shikonin-loaded antibody-armed nanoparticles for targeted therapy of ovarian cancer. Int J Nanomedicine 9:1855-70
Do, T-V; Xiao, F; Bickel, L E et al. (2014) Aurora kinase A mediates epithelial ovarian cancer cell migration and adhesion. Oncogene 33:539-49
Zhang, S; Mercado-Uribe, I; Xing, Z et al. (2014) Generation of cancer stem-like cells through the formation of polyploid giant cancer cells. Oncogene 33:116-28
Feng, Yi; Hu, Xiaowen; Zhang, Youyou et al. (2014) Methods for the study of long noncoding RNA in cancer cell signaling. Methods Mol Biol 1165:115-43
Liu, Hanqing; Beck, Tim N; Golemis, Erica A et al. (2014) Integrating in silico resources to map a signaling network. Methods Mol Biol 1101:197-245
Ye, Qunrui; Song, De-Gang; Poussin, Mathilde et al. (2014) CD137 accurately identifies and enriches for naturally occurring tumor-reactive T cells in tumor. Clin Cancer Res 20:44-55

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