Assessing a Novel Synthetic Lethal Phenotype Sensitizing Ovarian Cancer to Chemotherapy
Abstract
Ovarian cancer remains a lethal disease because current frontline treatment is unable to completely eradicate disease. This means that most women diagnosed with ovarian cancer will ultimately die from a recurrence of their disease that is resistant to platinum-based chemotherapy. Despite intense investigation, the genetic events responsible for determining the response of ovarian cancer to platinum chemotherapy remains poorly understood. We have recently identified a microRNA, miR-520g/h, that is expressed in a subset of ovarian cancers and is associated with more than a year of extra survival for women recently diagnosed with ovarian cancer. MicroRNAs (miR-520g/h) are an endogenous class of RNA transcripts that play a critical role in regulating diverse patterns of gene expression. These tiny transcripts are attractive candidates because an individual miRNAs can simultaneously target and silence hundreds of protein-encoding gene products. Our preliminary data indicate miR-520g/h not only dramatically sensitizes ovarian cancers to platinum, but also modifies the patterns by which this disease metastasizes within the peritoneal cavity. However, expression of miR-520g/h in healthy cells has no impact on their response to chemotherapy. These observations have led us to hypothesize that miR-520g/h creates a unique phenotype that can be powerfully exploited to improve ovarian cancer outcomes. The goal of this proposal is to determine the mechanism by which miR-520g/h sensitizes ovarian cancers to platinum chemotherapy and determine how this unique phenotype alters the metastasis and tumorigenicity of this disease. Insight generated by the proposed work has enormous potential to generate fundamental new insight into the mechanisms by which ovarian and other cancers respond to chemotherapy and how these responses can be manipulated to optimize patient benefits. The impact of the proposed work in the short term is the identification of a target genes and gene signatures that can be further developed into therapies such as small molecule inhibitors. Over the long term, the impact of this work is the potential to improve survival in women with ovarian cancer for not only military families but all women who develop ovarian cancer during their lifetime.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510064
Entities
People
- Claire Mach
Organizations
- United States Army
- University of Houston