Research Department

Medical Oncology/Molecular and Cellular

Area of Research

Biography

Dr. Drapkin received his PhD in 1996 and his MD in 1998 from the University of Medicine and Dentistry of New Jersey, followed by postgraduate training in anatomic pathology at Brigham and Womens Hospital. He completed a research fellowship with Dr. David Livingston at Dana-Farber, where he developed a keen interest in the pathogenesis and genetics of womens cancers. He joined the Dana-Farber faculty in 2005.

Recent Awards

• Distinguished Alumnus Award - UMDNJ Graduate School of Biomedical Sciences, 2008
• Best Research Award from the Lynne Cohen Foundation for Ovarian Cancer Research, 2006
• Dunkin Donuts Rising Stars Award, 2005
• The Ovarian Cancer Research Fund Investigator Award, 2004

Research

Our laboratory seeks to understand the pathogenesis and genetic alterations involved in womens cancers, with a specific interest in ovarian cancer.

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.

Select Publications

• Lee Y, Miron A, Drapkin R, Nucci MR, Medeiros F, Saleemuddin A, Garber J, Birch C, Mou H, Gordon RW, Cramer DW, McKeon FD, Crum CP. 2007. A candidate precursor to serous carcinoma that originates in the distal fallopian tube. J Pathol 211:26-35.
• Erkko H, Xia B, Nikkila J, Schleutker J, Syrhakoski K, Mannermaa A, Kallioniemi A, Pylkas K, Karppinen SM, Rapakko K, Miron A, Sheng Q, Li G, Mattila H, Bell DW, Haber DA, Grip M, Reiman M, Jukkola-Vuorinen A, Mustonen A, Kere J, Aaltonen LA, Kosma VM, Kataja V, Soini Y, Drapkin RI, Livingston DM, Winqvist R. 2007. A recurrent mutation in PALB2 in Finnish cancer families. Nature 446: 316-9.
• Drapkin R, Lin Y, Horsten HH, Welch WR, Crum CP, Mok SC, Hecht JH. 2005. Human Epididymis protein 4 (HE4) is a secreted glycoprotein that is overexpressed by serous and endometrioid ovarian carcinomas. Cancer Research 65: 2162-2169.
• Drapkin R, Crum CP, Hecht JH. 2004. Expression of candidate tumor markers in ovarian carcinoma and benign ovary: evidence for a link between epithelial phenotype and neoplasia. Human Pathology 35: 1014-1021.
• Cantor S*, Drapkin R*, Zhang F, Lin Y, Han J, Pamidi S, Livingston D. 2004. The BRCA1-associated protein BACH1 is a DNA helicase targeted by clinically relevant inactivating mutations. Proc. Natl. Acad. Sci USA 101: 2357-2362.
  (* denotes equal contribution)
  
• Levanon K, Ng V, Piao HY, Zhang Y, Chang MC, Roh MH, Kindelberger DW, Hirsch MS, Crum CP, Marto JA, Drapkin R. Primary ex vivo cultures of human fallopian tube epithelium as a model for serous ovarian carcinogenesis. Oncogene 2010; 29: 1103-1113.
• Clauss A, Ng V, Liu J, Piao HY, Russo M, Vena N, Sheng Q, Hirsch MS, Bonome T, Matulonis U, Ligon AH, Birrer MJ, Drapkin R. Overexpression of Elafin in ovarian carcinoma is driven by genomic gains and activation of the nuclear factor kB pathway and is associated with poor overall survival. Neoplasia 2010; 12: 161-172.
• Karst AM, Drapkin R. Ovarian cancer pathogenesis: a model in evolution. J Oncol 2010; 2010:932371
• Levanon K, Crum C, Drapkin R. New insights into the pathogenesis of serous ovarian cancer and its clinical impact. J Clin Oncol 2008; 26: 5284-5293
• De Nicolo A, Tancredi M, Lombardi G, Flemma CC, Barbuti S, Di Cristofano C, Sobhian B, Bevilacqua G, Drapkin R, Caligo MA. A novel breast cancer-associated BRIP1 (FANCJ/BACH1) germline mutations impairs protein stability and function. Clin Cancer Res 2008; 14: 4672-4680.

Trainees

• Clauss, Adam, PhD
• Duraisamy, Sekhar, PhD
• Piao, Huiying, MD
• Fotheringham, Susan, PhD
• Karst, Alison, PhD
• Perets, Ruth, MD, PhD