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Research at Mass General
Michael J. Birrer, MD, PhDDirector of Medical Gynecologic Oncology
Director, Gynecologic Oncology Research ProgramMassachusetts General Hospital Cancer Center
Professor of MedicineHarvard Medical School
The Birrer laboratory has had a long-term interest in characterizing the molecular origins of gynecologic cancers. This interest includes the identiﬁcation and characterization of mutations in oncogenes and tumor suppressor genes within cancers of the ovary, endometrium and cervix. In addition, we have extensively characterized the differential gene expression in these tumors. The role of these genes in the development of these cancers has been tested using in vitro and in vivo model systems. Our laboratory is focused on using the genomic events characterized in these cancers to produce translational science endeavors, which will result in clinically important discoveries. These genomic abnormalities form the basis for early detection assays, prevention strategies, and novel therapeutic approaches. Our laboratory focuses on bench-to-bedside-and-back-again approaches to produce clinically relevant strategies to improve the outcome of women with these types of cancers.
Michael J. Birrer, MD, PhDPrincipal Investigator
Our laboratory focuses on characterizing the function and clinicopathologic impact of key genes and pathways in ovarian cancer. The laboratory was awarded an NCI Director’s Challenge grant for the genomic analysis of ovarian cancer and, in collaboration with Me-morial Sloan Kettering Cancer Center, Univer-sity of Pennsylvania, Fox Chase Cancer Center, and the Australia Ovarian Cancer Study, has conducted a large-scale study of expression proﬁling. These efforts have characterized differential gene expression on the whole-genome level between ovarian tumors of different histology and tumor grade. The study identiﬁed pathways that underlie the clinical pathologic characteristics of these tumors and identiﬁed clear cell and mucinous tumors of the ovaries as unique tumors unrelated to other histologic subgroups. This discovery has established for the ﬁrst time unique trials for patients with these cancers. We have also shown that low malignant potential tumors of the ovary (Grade 0) are a unique form of serous tumors and require speciﬁc therapeutic approaches. As a result, the laboratory has been instrumental in testing the MEK inhibitor AZD6244 for Grade 0 tumors. More recently, the laboratory was awarded an RC4 grant (in collaboration with Giovanni Parmigiani, PhD, of the Dana-Farber Cancer Institute) to validate previously identiﬁed gene expression signatures which classify patients into good versus poor prognosis, utilizing 1600 clinical trial specimens from the recently completed GOG clinical trial 218. The results will be rapidly integrated into prospective clinical trials of patients with advanced-stage ovarian cancer.
To further facilitate biomarker analysis and target identiﬁcation for effective management of ovarian cancer, our laboratory has contributed to the development of a curated Ovarian Data database that provides standardized gene expression and clinical data for 2,970 ovarian cancer patients from 23 studies spanning 11 gene expression measurement platforms (http://bcb.dfci.harvard.edu/ovariancancer). This work facilitates biomarker discovery through a robust meta-analysis framework that limits the impact cohort-speciﬁc biases while combining the statistical powers of numerous studies.
Through collaboration with Steven Skates, PhD, the laboratory received an Early Detection Research Network UO1 grant to identify novel early detection approaches to this disease. We will compare the gene expres-sion proﬁles of ovarian cancer with its normal counterparts found on the surface of the ovary and fallopian tube. Through a collaborative effort with Steven Carr, PhD of the Broad Institute, we will identify the early genomic abnormalities in ovarian cancer and validate these ﬁndings using specimens from Massachusetts General Hospital, Brigham and Women’s Hospital and DFCI to translate our work into serum-based early detection assays.
Presently, we are analyzing the function of newly identiﬁed activated pathways in ovarian cancers and utilizing in vivo models for the discovery of novel therapeutic approaches. An NIH R-01 grant was awarded to investigate the role of FGF18/FGFR4 signaling, previously shown to be associated with poor clinical outcome, in the pathogenesis of serous ovarian cancer. Large-scale prospective validation and pharmaceutical targeting studies are underway.
Last but not least we have established two large multisite research consortia: The Consortium for Long-Term Ovarian Cancer Survival and The Consortium for Prediction of Early Stage Ovarian Cancer Recurrence. These collaborative research structures allow for collection of very rare tumor specimens, such as those of patients who survived more than eight years and those pf patients who had developed recurrency of an early stage tumor. These samples will be analyzed through multiple genomics and proteomics assays to identify predictors of long-term survival and recurrence, respectively.
Research directions for the future include: 1) Characterizing the function of genes associ-ated with clinicopathologic characteristics of ovarian cancer; 2) characterizing new tumor cellular subsets of ovarian cancer for their clinical features and their role in tumor formation; 3) identifying novel early detection, prevention and therapeutic targets; and 4) utilizing the genomic abnormalities found in ovarian cancer as targets for novel imaging techniques. Our laboratory efforts remain highly translational and collaborative in nature, and we are committed to bringing laboratory-based and scientiﬁcally rational concepts into the clinic to improve the lives of women with these cancers.
View all publications from the Birrer Lab
Riester M, Wei W, Waldron L, Culhane AC, Trippa L, Oliva E, Kim S, Michor F, Hutterenhower C, Parmigiani G, Birrer MJ. Risk prediction for Late-Stage Ovarian Cancer by Meta-Analysis of 1525 patient samples. J Natl Cancer Instit. 2014 106(5).
Wei W, Mok SC, Oliva E, Kim SH, Mohapatra G, Birrer MJ. FGF18 as a prognostic and therapeutic biomarker in ovarian cancer. J Clin Invest. 2013 Oct 1;123(10):4435-48.
Zaid TM, Yeung TL, Thompson MS, Leung CS, Harding T, Co NN, Schmandt RS, Kwan SY, Rodriguez- Aguay C, Lopez-Berestein G, Sood AK, Wong KK, Birrer MJ, Mok SC. Identiﬁcation of FGFR4 as a potential therapeutic target for advanced-stage, high-grade serous ovarian cancer. Clin Cancer Res. 2013 Feb 15;19(4):809-20.
Farley J, Brady WE, Vathipadiekal V, Lankes HA, Coleman R, Morgan MA, Mannel R, Yamada SD, Mutch D, Rodgers WH, Birrer M, Gershenson DM. Selumetinib in women with recurrent low-grade serous carcinoma of the ovary or peritoneum: an open-label, single-arm, phase 2 study. Lancet Oncol. 2013 Feb;14(2):134-40.
Burger RA, Brady MF, Bookman MA, Fleming GF, Monk BJ, Huang H, Mannel RS, Homesley HD, Fowler J, Greer BE, Boente M, Birrer MJ, Liang SX; Gynecologic Oncology Group. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med. 365(26):2473-83, 2011 Dec 29.
Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature. 474(7353):609-15, 2011 Jun 29.
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