MicroRNA Signature of Poorly Resectable Ovarian Cancer
Primary cytoreductive surgery is standard front-line treatment for patients with advanced ovarian cancer. The goal of surgery is to reduce the tumor to as small a volume as possible, and surgical efforts that leave residual tumor nodules exceeding 2 cm in size provide no survival benefit. Despite aggressive surgery by an experienced surgeon, roughly one-third of patients do not achieve an adequate surgical resection and therefore suffer the pain, risks and morbidity of surgery without benefit, while at the same time experiencing a delay in initiating needed chemotherapy. Ovarian cancer outcomes could be improved by a test that identifies, prior to surgery, patients who are likely to have poorly resectable disease. Such a test does not currently exist.
MicroRNAs are a novel class of cancer biomarkers that are commonly dysregulated in ovarian and other cancers and that have proven to have diagnostic and prognostic value. Tumor biology plays a critical role in determining ovarian cancer resectability, and we have found that miRNA expression profiles in ovarian cancer tissues correlate with ovarian cancer resectability. Furthermore, we have shown that tumor-derived microRNAs circulate in plasma where they can be quantitatively measured, laying the foundation for miRNA-based blood tests. Collectively, the literature and preliminary data suggest that it will be possible to develop a blood-based miRNA test that can identify patients prior to surgery who have poorly resectable ovarian cancer.
Our translational research goal is to develop and validate a microRNA-based blood test that improves the predictive accuracy of clinical factors for identifying patients with poorly resectable ovarian cancer. Patients identified by the test could forego ineffective surgery and instead receive treatment using neoadjuvant chemotherapy. Specifically we are working to refine and validate a “resection signature” comprised of a panel of roughly 5-10 miRNA markers measurable in plasma that correlate with residual disease status. The output of our work will be a blood test, based on a panel of miRNA markers, that when combined with clinical features, identifies patients with poorly resectable disease with high specificity and clinically useful sensitivity.
Project 3 Publications
1. Bendoraite A, Knouf EC, Garg KS, Parkin RK, Kroh EM, O'Briant KC, Ventura AP, Godwin AK, Karlan BY, Tewari M. Regulation of miR-200 family microRNAs and ZEB transcription factors in ovarian cancer: evidence supporting a mesothelial-to-epithelial transition. Gynecol Oncol. 2010 Jan;116(1):117-25.
2. Sarkar D, Parkin R, Wyman S, Bendoraite A, Sather C, Delrow J, Godwin AK, Drescher C, Huber W, Gentleman R, Tewari M. Quality Assessment and Data Analysis for microRNA Expression Arrays. Nucleic Acids Res. 2009 Feb:37(2):e17. PMCID: PMC2577037
3. Wyman SK, Parkin RK, Mitchell PS, Fritz BR, O’Briant K, Godwin AK, Urban N, Drescher CW, Knudsen BS, Tewari M. Repertoire of microRNAs in epithelial ovarian cancer as determined by next generation sequencing of small RNA cDNA libraries. PLoS ONE. 2009;4(4):e5311. PMCID: PMC2668797
4. Bar M, Wyman SK, Fritz BR, Qi J, Garg KS, Parkin RK, Kroh EM, Bendoraite A, Mitchell PS, Nelson AM, Ruzzo WL, Ware C, Radich JP, Gentleman R, Ruohola-Baker H, Tewari M. MicroRNA discovery and profiling in human embryonic stem cells by deep sequencing of small RNA libraries. Stem Cells. 2008 Oct;26(10):2496-505.
5. Mitchell PS, Parkin RK, Kroh EM, Fritz BR, Wyman SK, Pogosova-Agadjanyan EL, Peterson A, Noteboom J., O'Briant KC, Allen A, Lin DW, Urban N, Drescher CW, Knudsen BS, Stirewalt DL, Gentleman R, Vessella RL, Nelson PS, Martin DB, Tewari M. Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci U S A. 2008 Jul 29;105(30):10513-8. PMCID: PMC2492472.