Michael J. Birrer, MD, PhD
Director of Medical Gynecologic Oncology
Director, Gynecologic Oncology Research Program
Massachusetts General Hospital Cancer Center
Professor of Medicine
Harvard 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, endometrial 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 better manage women with these cancers.
Michael J. Birrer, MD, PhD
Our laboratory focuses on characterizing the function and clinicopathologic impact of key genes and pathways in gynecologic cancers. The majority of our work is focused on ovarian cancer, although we have projects on endometrial and cervical cancer. In 2000, the laboratory was awarded one of the Massachusetts General Hospital Director’s Challenge grants for the genomic analysis of ovarian cancer. The laboratory—in collaboration with Memorial Sloan Kettering Cancer Center, University of Pennsylvania, Fox Chase Cancer Center, and the Australia Ovarian Cancer Study—has conducted a large-scale study of expression profiling. These efforts have systematically characterized differential gene expression on the whole-genome level between ovarian tumors of different histology and tumor grade. The study led to the identification of activated biochemical pathways, which underlie the clinical pathologic characteristics of these tumors. Subsequently, our findings made possible the identification of clear cell and mucinous tumors of the ovaries as unique tumors essentially unrelated to the majority of ovarian cancers. This discovery has directly led to a change in clinical trial structure in the gynecologic cancer group, establishing for the first time unique trials for patients with these cancers.
We are presently testing activated pathways within these tumors, utilizing in vivo models for the discovery of novel therapeutic approaches. Employing the same approach, the laboratory has shown that low malignant potential tumors of the ovary (Grade 0) are a unique form of serous tumors and therefore require specific therapeutic approaches. Based upon our observations, the development of low malignant potential tumors and low-grade invasive cancers is clearly a unique process associated with unique malignant pathways. As a result of this work, the laboratory has been instrumental in testing the MEK inhibitor AZ6244 in clinical trials with women diagnosed with low-grade cancers. More recently, the laboratory completed two large profiling studies (greater than 300 specimens) on advanced-stage papillary serous tumors of the ovary. These studies have generated differential gene expression signatures which classify patients into good prognosis versus poor prognosis groups and identified new and novel targets for the therapy and prevention of the disease.
The laboratory has recently been awarded an RC4 grant (in collaboration with Giovanni Parmigiani, PhD, of the Dana Farber Cancer Institute) to extend these studies into a validation study, utilizing 1600 clinical trial specimens from the recently completed GOG clinical trial 218. The genomic analysis will characterize both expression level and DNA copy number on paraffin-embedded material from the trial and correlate the results with clinical outcome. The results of this study will be rapidly integrated into prospective clinical trials of patients with advanced-stage ovarian cancer.
This genomic database will be extended into efforts to identify early detection biomarkers for ovarian cancer. Through collaboration with Steven Skates, PhD, the laboratory has successfully received an Early Detection Research Network UO1 grant to identify new and novel early detection approaches to this disease. We will systematically compare the gene expression profiles of ovarian cancer with its normal counterparts found on the surface of the ovary and fallopian tube. Through a collaborative effort with Ronny Drapkin, MD, PhD, of Dana Farber Cancer Institute (DFCI) and Steven Carr, PhD of the Broad Institute, we will identify the early genomic abnormalities in ovarian cancer. We will validate these findings using specimens from Massachusetts General Hospital, Brigham and Women’s Hospital and DFCI and ultimately translate our work into serum-based early detection assays.
Research direction for the future will focus on four major directions: 1) Characterizing the function of clinical pathologic impact of key genes whose dysregulation is associated with clinicopathologic characteristics of ovarian cancer; 2) characterizing new tumor cellular subsets of ovarian cancer for their role in tumor formation and for the clinical features of the disease; 3) utilizing the genomic characteristics of ovarian cancer to identify new and 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. We are committed to bring laboratory-based and scientifically rational concepts into the clinic to improve the lives of women with these cancers.
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