The Laboratory of Gynecologic Cancer Research focuses upon the characterization of the molecular biology of gynecologic cancers. The laboratory has identified the genetic alterations of specific oncogenes and tumor suppressor genes in cervical, endometrial and ovarian cancers and correlated these results the clinical behavior of these cancers. In 2000, the laboratory was awarded one of the Director’s Challenge Grants for the genomic analysis of ovarian cancer. The laboratory had conducted a large-scale study of expression profiling of ovarian cancer in collaboration with MDACC, MSKCC, and University of Penn. These efforts have resulted in the characterized the whole genome gene expression profile of ovarian tumors of different histology and grade. This effort identified activated pathways, which are critical for the clinicopathologic characteristics of these tumors. These results have led to the identification of clear cell and mucinous tumor as unique tumors which in turn have fundamentally changed the clinical trails structure at the Gynecologic Oncology Group. This group has now established separate clinical trials for these tumors. Further, utilizing this same approach, the laboratory has shown that low malignant potential tumors of the ovarian (grade 0) to be unique form of serous tumors and therefore requiring a specific therapeutic approach. Based upon this work, the laboratory is beginning a clinical trial using a MEK inhibitor in patients with advanced stage recurrent LMP tumors. More recently, the laboratory completed two larger profiling studies (>300 specimens) on advanced stage papillary serous tumors of the ovary. These studies have generated differential expression gene lists, which can classify these patients into good versus poor prognostic group and identify many potential targets or the therapy and prevention of the disease.
The research direction for the future will focus on three major directions: 1.) characterizing the function and clinicopathologic impact of key genes whose dysregulation is associated with clinical characteristics of ovarian cancer, 2.) characterizing new tumor cellular subsets for their role in tumor formation and the clinical features of the cancer, and 3.) extending these discoveries into the clinic. For the first direction, the laboratory has begun to characterize several genes whose expression predict for the drug resistant phenotype of recurrence ovarian cancer. These genes are unique and involve different aspects of cellular physiology and are both intra and extra cellular. The approach is an in vitro assessment of expression modulation on sensitivity to chemotherapy and then extension into an othortopic model for in vivo validation. In addition, the laboratory is characterizing genes, which are prognostic for the survival of patients with advanced stage papillary serous tumors of the ovary. Finally, other future projects include further characterization of genes, which identify prominent pathways in clear cell and mucinous tumors with the goal being providing mechanistic underpinning of these genes for the unique clinical characteristics of these tumors.
The second direction extends from preliminary work performed on the gene expression patterns of cellular subsets of ovarian tumors. Through collaboration with investigators at MDACC the laboratory has profiled isolated endothelial cells from ovarian tumors and compared them to those of normal ovaries. This has provided a rich list of potential novel targets, which is now under exploration. In a second project, the laboratory is determining the expression of stromal fibroblasts within ovarian tumors compared to those of the normal ovary. This project has the potential to uncover important mechanisms underlying these tumors and potential therapeutic targets. Both of these projects focus on diploid cell populations, which due to their genomic stability may be more optimal therapeutic targets.
The third direction will obviously depend upon the results of the first two, but is ultimately the most important effort. This effort will require a seamless integration of gynecologic oncology research with the clinical management of patients. One of the attractive aspects of the gynecologic oncology efforts at MGH is the high patient volume and expert clinical care. The Gynecologic Cancer Research Program will address important clinical questions within this field. The major clinical questions in ovarian cancer span from the identification of patients at risk for developing ovarian cancer, to the better therapy of patients with advance stage cancer. At present, there are no mechanisms to identify women at risk for the development of sporadic ovarian cancer and this makes early detection or prevention studies essentially impossible. For early stage ovarian cancer, accurate identification of high-risk patients is critical to effectively treat those patients who will recur and minimize toxic effects of therapy on those patients who will not recur. The major clinical questions involving advanced stage disease are identifying risk of recurrence, determining the mechanisms of resistance to chemotherapy and identifying new therapeutic targets. In order to address these questions, a robust clinical trial structure will be implemented. All trials will involve translational research. This would require an effective interaction with biotech companies, large pharmaceutical firms and academic sources of interesting small molecule inhibitors. Finally, a robust genomics facility available and integrated into the programs will assist in making the “bench to bedside” transition of these cutting edge efforts more efficient. This work would require further validation in patient specimens and the monitoring of targets during therapy. While focusing essentially on expression profiling, cgh and other platforms will certainly be very important and applied to clinical samples. It is not difficult to imagine clinical trials, in which the patient’s tumor is analyzed for important known genomic abnormalities will be designed and the patient treated specifically based upon those molecular features.