Treating Ovarian Cancer with MicroRNAs
Ovarian cancer is the fifth leading cause of cancer death in women in the United States. Although advances in surgery and chemotherapy have improved five-year survival to nearly 50 percent, most (approximately 80 percent) women with ovarian cancer eventually die from their disease. Platinum-based chemotherapy is the standard of care for all women newly diagnosed with ovarian cancer. However, approximately 20 percent of women with advanced ovarian cancers demonstrate de novo resistance to these agents. Additionally, recurrent ovarian cancer eventually becomes resistant to platinum-based therapy, leading to death. Thus, there is an urgent need for novel therapeutic strategies that can either enhance the efficacy of current chemotherapy or target specific oncogenic pathways.
Dr. Matthew L. Anderson, assistant professor of Obstetrics and Gynecology, and his team at Baylor College of Medicine are making important breakthroughs in advancing ovarian cancer therapy by utilizing microRNAs. MicroRNAs are small, non-coding RNA transcripts that play a critical role in silencing patterns of gene expression. Altered patterns of miRNA expression have been documented in many different human diseases, including epithelial ovarian cancer. However, the mechanisms by which these transcripts impact cancer often remain poorly understood. Furthermore, it is not yet clear which of these transcripts will be most effective for treating different human diseases. Using novel bioinformatic platforms developed here at BCM, Dr. Anderson and his team have identified key gene expression modules regulated by specific microRNAs, pinpointing specific drivers that they believe can be most effectively used for therapeutic purposes. For example, Dr. Anderson’s team has discovered that miR-520h dramatically sensitizes ovarian cancer cell lines to cisplatin, a platinum-based chemotherapy drug and improves survival when used to target cells in in vivo models of this disease. The power of this approach is underscored by the fact that dramatic improvements in outcome are observed with less than 5 percent of the dose of cisplatin typically used in the clinic. A patent application based on Dr. Anderson’s study on miR-520, titled “MicroRNAs Sensitize Cancers to Therapy,” has been filed by Baylor College of Medicine.
More recently, Dr. Anderson’s team has found another miRNA family, miR- 148, may also be a highly effective target for treating ovarian cancer. Their work has shown that different members of the miR-148 family often are lost in ovarian cancer and that replacement of these transcripts inhibits proliferation, migration and invasion while enhancing programmed cell death. Using a novel strategy to parse key drivers for microRNAs, the team has found that loss of miR-148 is mediated by their ability to regulate MTMR9, and regulate aspects of phosphoinositide metabolism not previously implicated in cancer. This link is confirmed by the fact that experimental knockdown of MTMR9 directly reduces proliferation and induces apoptosis in multiple ovarian cancer cell lines. These observations provide novel insight into mechanisms by which fundamental aspects of cell metabolism promote cancer growth and metastasis that can potentially be used not only to treat ovarian cancer but possibly many other human cancers.
Leveraging the well-established bioinformatics and biological platforms, Dr. Anderson’s team continues to explore novel anticancer miRNAs, and they are in the process of combining those miRNAs with next-generation delivery vehicles for pre-clinical animal model studies and future clinical trials.
• miRNAs promote the growth and metastasis of ovarian cancer cells by coordinately regulating the expression of gene expression modules critical for regulating genomic stability, cell proliferation and metabolism, and thereby present attractive targets for novel therapeutic approaches.
• The miR-520h and other key microRNAs can be used to dramatically sensitize ovarian cancer to platinum-based chemotherapy and overcome the polygenic resistance to chemotherapy that almost always leads to the death of patients diagnosed with ovarian cancer.
• Levels of miR-148 may serve as a prognostic marker for ovarian cancer outcome and replacement of miR-148 can be used to treat patients who are deficient in this miRNA.
• Downstream proteins and pathways regulated by the above miRNAs are also promising novel cancer targets, as evidenced by the role of MTMR9 and novel aspects of phosphoinositide metabolism discovered in the miR-148 study.
• Synthetic mimics for miR-520 and other human microRNA transcripts are potentially useful and effective for treating a wide range of other cancers, given the central role that platinum-based agents play in standard of care treatment for other human cancers.
BLG Project Manager
Brian Phillips, Ph.D. (email@example.com)