Ronny Drapkin

Department of Pathology
Dana-Farber Cancer Institute
Jimmy Fund Building, Room 215D

44 Binney Street
Boston. MA 02115
Tel: (617) 632-4380
Fax: (617) 582-8761
Email: ronny_drapkin@dfci.harvard.edu
Web Page: The Drapkin Lab Page

Research in the Drapkin laboratory focuses on understanding the pathogenesis and genetic alterations involved in women’s cancers with a specific interest in ovarian cancer. A major goal is to translate these important biological principles into clinically useful diagnostic and therapeutic tools.

To accomplish these goals, the laboratory integrates genomic studies of human ovarian cancer, new culture model systems, and rigorous protein biochemistry and molecular biology to explore three complementary approaches:

Ovarian cancer genetics
Mutations in BRCA1 account for 5-10 percent of all ovarian and breast cancers. We recently identified and characterized a BRCA1-interacting protein called BRIP1. We showed that BRIP1 is a DNA helicase that functions together with BRCA1 to mediate efficient repair of DNA double strand breaks. Moreover, we found that in a small number of early-onset breast and ovarian cancers, in which the BRCA1 and BRCA2 genes are normal, the BRIP1 gene carries alterations that encode defective helicase proteins. These observations provide a biochemical link between disease development and BRIP1 activity and suggest that BRIP1 may be the product of a cancer gene. We are actively pursuing studies to define the biological function of BRIP1.

Pathogenesis
Ovarian cancer is heterogeneous disease thought to arise from the ovarian surface epithelium (OSE) but a clear understanding of the processes underlying neoplastic transformation of this epithelium is lacking. Recent studies show that the fallopian tubal fimbria, rather than the OSE, is a common site for early serous carcinomas, the most lethal form of the disease. In collaboration with the laboratory of Dr. Crum, we found that the tubal fimbria is the preferred site for the development of in situ carcinomas. In addition, we found normal-appearing precursor lesions, called ‘p53 signatures’ that harbor p53 mutations and evidence of DNA damage. We recently developed a novel ex-vivo culture model system that enables us to study the biological properties of the fallopian tube fimbria and define genotoxic stressors that predispose the serous cells to neoplastic transformation.

Biomarkers
Using genome-scale approaches, we are searching for biomarkers of ovarian cancer that, once characterized, can be developed into clinical tools for early detection. We identified human epididymis protein 4 (HE4) as a glycoprotein that is overexpressed and secreted by ovarian cancers. Serum studies indicate that HE4 circulates in the bloodstream of women with ovarian cancer. Interestingly, the HE4 gene resides on chromosome 20q13, a region that is commonly amplified in ovarian cancers. Our analysis shows that a trio of proteins that are encoded on 20q13 is overexpressed in ovarian cancer, including HE4. Current studies indicate that these candidate biomarkers also confer a proliferative advantage to tumor cells. Work in progress is aimed at defining the underlying mechanism of these effects

References:

• Levanon K, Crum CP, Drapkin R. New insights into the pathogenesis of serous ovarian cancer and its clinical impact. J Clin Oncol, in press.
• De Nicolo A, Tancredi M, Lombardi G, Flemma C, Barbuti S, Di Cristofano C, Sobhian B, Bevilacqua G, Drapkin R*, Caligo MA. A novel breast cancer-associated BRIP1 (FANCJ/BACH1) germline mutation impairs protein stability and function. Clinical Can Res 2008; 14: 4672-4680. *corresponding author.
• Crum CP, Drapkin R, Miron A, Ince TA, Muto M, Kindelberger DW, Lee Y. The distal fallopian tube: a new model for pelvic serous carcinogenesis. Curr Opin in Obstet and Gynecol 2007; 19: 3-9.
• Drapkin R*, Horsten HV, Lin Y, Mok SC, Crum CP, Welch WR, Hecht J. Human epididymis protein 4 (HE4) is a secreted glycoprotein that is overexpressed by serous and endometrioid ovarian carcinomas. Cancer Res 2005, 65: 2162-2169. *corresponding author.