Associated Partners

Massachusetts General Hospital is the third oldest general hospital in the United States and the oldest and largest hospital in New England. Mass General brings a tradition of excellence today, as it has consistently placed among the top hospitals on the U.S. News & World Report Best Hospitals Honor Roll since the survey began in 1990. In 2014, Mass General was named #2 in the nation and #1 in New England based on our quality of care, patient safety and reputation in 16 clinical specialties.

Mass General offers sophisticated diagnostic and therapeutic care and it has long been a leader in successfully bridging innovative science with state-of-the-art clinical medicine with the largest hospital-based research program in the United States.

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 improve the outcome of women with these types of cancers.

1982-1985 - Instructor in Medicine, Harvard Medical School, Boston, MA

1988-2008 - Attending Physician, National Naval Medical Center, Bethesda, MD

1988-2008 - Attending Physician, Clinical Center, NCI, Bethesda, MD

1988-2008 - Assistant Professor, Uniformed Services University of Health Sciences, Department of Medicine, Naval Hospital Bethesda, Bethesda, MD

1991-2008 - Chief, Molecular Mechanisms Section, Cell and Cancer Biology Department, CCR, NCI, NIH, Bethesda, MD

1997-2008 - Deputy Branch Chief, Cell and Cancer Biology Branch CCR, NIH Bethesda, MD

2008-present - Professor of Medicine, Harvard Medical School

2001-2002 - Co Chair-Committee for Experimental Medicine GOG

2002-present - Chair- Committee for Experimental Medicine GOG

2003-present - Member-Chairman’s Advisory Committee GOG

2002-2004 - Member-Gynecologic Oncology Program Committee ASCO

2004-2005 - Member-SGO Program Committee

2005-present - Member-Gynecologic Cancer Steering Committee

2009-present - Co-Chair of the Gynecologic Cancer Steering Committee of the National Institute of Health

2009-present - Chair of the Translational Science Working Group of the Gynecologic Cancer intergroup

1976 Phi Lambada Epsilon

1976 Sigma Xi Award

1977-1982 Medical Scientist Training Program (5T32 GM7288)

1980 Alpha Omega Alpha National Medical Honorary Society

1988 Outstanding Performance Uniformed Services University of Health Sciences

1992 DCPC Employee of the Month

1992 PHS Achievement Award

1993 PHS Citation

1994 EEO Officer's Achievement Award

2010 Best Doctors in America

2010 Top Doctors in Boston

• Mok SC, Bonome T, Vathipadiekal V, Bell A, Johnson ME, Wong KK, Park DC, Hao K, Yip DK, Donninger H, Ozbun L, Samimi G, Brady J, Randonovich M, Pise-Masison CA, Barrett JC, Wong WH, Welch WR, Berkowitz RS, Birrer MJ. A gene signature predictive for outcome in advanced ovarian cancer identifies a survival factor: microfibril-associated glycoprotein 2. Cancer Cell. 2009 Dec 8;16(6):521-32. PMID: 19962670

• 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. 2011 Dec 29;365(26):2473-83.

• Stany MP, Vathipadiekal V, Ozbun L, Stone RL, Mok SC, Xue H, Kagami T, Wang Y, McAlpine JN, Bowtell D, Gout PW, Miller DM, Gilks CB, Huntsman DG, Ellard SL, Wang YZ, Vivas-Mejia P, Lopez-Berestein G, Sood AK, Birrer MJ. Identification of novel therapeutic targets in microdissected clear cell ovarian cancers. PLoS One. 2011;6(7):e21121

• Vathipadiekal V, Saxena D, Mok SC, Hauschka PV, Ozbun L, Birrer MJ. Identification of a potential ovarian cancer stem cell gene expression profile from advanced stage papillary serous ovarian cancer. PLoS One. 2012;7(1):e29079

• 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. doi: 10.1172/JCI70625. Epub 2013 Sep 9. PubMed PMID: 24018557; PubMed Central PMCID: PMC3784549.

• Cancer Genome Atlas Research Network, Kandoth C, Schultz N, Cherniack AD, Akbani R, Liu Y, Shen H, Robertson AG, Pashtan I, Shen R, Benz CC, Yau C, Laird PW, Ding L, Zhang W, Mills GB, Kucherlapati R, Mardis ER, Levine DA. Integrated genomic characterization of endometrial carcinoma. Nature. 2013 May 2;497(7447):67-73. doi: 10.1038/nature12113. PubMed PMID: 23636398.

• Ganzfried BF, Riester M, Haibe-Kains B, Risch T, Tyekucheva S, Jazic I, Wang XV, Ahmadifar M, Birrer MJ, Parmigiani G, Huttenhower C, Waldron L. CuratedOvarianData: Clinically annotated data for the ovarian cancer transcriptome. Database (Oxford). 2013 Apr 2;2013

• 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):134-140.

• Liu JF, Tolaney SM, Birrer M, Fleming GF, Buss MK, Dahlberg SE, Lee H, Whalen C, Tyburski K, Winer E, Ivy P, Matulonis UA. A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer. Eur J Cancer. 2013 Sep; 49(14):2972-8. PMID: 23810467.

• Zaid T, Yeung TL, Thompson MS, Leung C, Harding T, Co N, Schmandt RE, Kwan SY, Rodriguez-Aguayo C, Lopez-Berestein G, Sood AK, Wong KK, Birrer MJ, Mok SCIdentification of FGFR4 as a Potential Therapeutic Target for Advanced-Stage High-grade Serous Ovarian Cancer. Clin Cancer Res. 2013 Jan 29.

• Verhaak RG, Tamayo P, Yang JY, Hubbard D, Zhang H, Creighton CJ, Fereday S, Lawrence M, Carter SL, Mermel CH, Kostic AD, Etemadmoghadam D, Saksena G, Cibulskis K, Duraisamy S, Levanon K, Sougnez C, Tsherniak A, Gomez S, Onofrio R, Gabriel S, Chin L, Zhang N, Spellman PT, Zhang Y, Akbani R, Hoadley KA, Kahn A, Köbel M, Huntsman D, Soslow RA, Defazio A, Birrer MJ, Gray JW, Weinstein JN, Bowtell DD, Drapkin R, Mesirov JP, Getz G, Levine DA, Meyerson M. Prognostically relevant gene signatures of high-grade serous ovarian carcinoma.J Clin Invest. 2013 Jan 2;123(1):517-25.

• Rister M, Wei W, Waldron L, Culhane AC, Trippa L, Oliva E, Kim SH, Michor F, Huttenhower C, Parmigiani G, Birrer MJ. Risk Prediction for Late-Stage Ovarian Cancer by Meta-analysis of 1525 Patient Samples. J Natl Cancer Inst. 2014 Apr 3;106(5). PMID: 24700803

• Peterson VM, Castro CM, Chung J, Miller NC, Ullal AV, Castano MD, Penson RT, Lee H, Birrer MJ, Weissleder R. Ascites analysis by a microfluidic chip allows tumor-cell profiling. Proc Natl Acad Sci U S A. 2013 Dec 17;110(51):E4978-86. PMID: 24297935.

• Ghosh D, Bagley AF, Na YJ, Birrer MJ, Bhatia SN, Angela M. Belcher. Deep, noninvasive imaging and surgical guidance of submillimeter tumors using targeted M13-stabilized single- walled carbon nanotubes. Proc Natl Acad Sci U S A. 2014 Sep 11; 111(38):13948-13953.

• Leung CS, Yeung TL, Yip KP, Pradeep S, Balasubramanian L, Liu J, Wong KK, Mangala LS, Armaiz-Pena GN, Lopez-Berestein G, Sood AK, Birrer MJ, Mok SC. Calcium-dependent FAK/CREB/TNNC1 signaling mediates the effect of stromal MFAP5 on ovarian cancer metastatic potential. Nat. Commun. 2014 Oct 3;5:5092. PMCID: PMC4185407

The five-year survival of patients with high grade epithelial ovarian cancer is directly related to tumor stage. Women with early stage disease (stage I and II) have a 5-year survival rate ranging from 65 – 90% compared with 19 - 47% for advanced stage disease (stage III and IV). The standard of care for patients with high-grade early stage ovarian cancer is surgery followed by 6 cycles of adjuvant chemotherapy. However, it is commonly accepted that patients with early-stage ovarian cancer are over treated and many are exposed to the short and long term toxicities of chemotherapy with minimal benefit. Thus, the identification of accurate prognostic markers to stratify patients with early-stage disease into those who will benefit from chemotherapy and spare patients from unecessary treatment has become an important translational science effort with cost-effectiveness ramifications. In addition, the specific genomic abnormalities which distinguish recurrent from non-recurrent early stage ovarian cancer may provide a better understanding of their biology and identify potential novel therapeutic targets.

In this study, we propose to utilize DNA CNV technology, RNA sequencing technology, Non- coding RNA expression analysis to accurately characterize the genomic profiles of FFPE specimens from recurrent and non-recurrent early stage ovarian cancers. However, for this project to be successful it will require large numbers of fully clinically annotated specimens making it necessary to form an international consortium to link multiple bio-repositories to provide sufficient numbers of specimens. This proposal will leverage the resources of a consortium collaboration that involves a number of European and North-American centers. Since these specimens were derived from gynecologic oncology centers, they have extensive clinical data. Further, it is important to note that none of these existing resources are sufficient to address this important question individually but combined will provide adequate numbers of specimens.

This project reflects an approach that will provide the needed data to develop clinically relevant biomarkers in the early stage ovarian cancer space that can predict for tumor recurrence, prognosticate patient survival, and perhaps identify early detection markers and targetable biomarkers. The PI that coordinates the multi-site research is located at MGH.

Comparative Proteomic Analysis Reveals Sex and Estrogen Receptor β Effects in the Pressure Overloaded Heart Kararigas G, Fliegner D, Forler S, Klein O, Schubert C, Gustafsson JA, Klose J, Regitz- Zagrosek V.. J Proteome Res. 2014 Nov 19 PMID: 25406860

MALDI imaging mass spectrometry: Discrimination of pathophysiological regions in traumatized skeletal muscle by characteristic peptide signatures. Klein O, Strohschein K, Nebrich G, Oetjen J, Trede D, Thiele H, Alexandrov T, Giavalisco P, Duda GN, von Roth P, Geissler S, Klose J, Winkler T.Proteomics. 2014 Oct;14(20):2249-60. doi: 10.1002/pmic.201400088. Epub 2014 Aug PMID: 25056804

Individualized proteomics.Forler S, Klein O, Klose J.J Proteomics. 2014 Jul 31;107:56-61. doi: 10.1016/j.jprot.2014.04.003. Epub 2014 Apr 13. PMID: 24732725

Application of two-dimensional gel-based mass spectrometry to functionally dissect resistance to targeted cancer therapy.Klein O, Rohwer N, de Molina KF, Mergler S, Wessendorf P, Herrmann M, Klose J, Cramer T. Proteomics Clin Appl. 2013 Dec;7(11-12):813-24. doi: 10.1002/prca.201300056.PMID: 24307263

Identification of fibronectin as a major factor in human serum to recruit subchondral mesenchymal progenitor cells.Kulawig R, Krüger JP, Klein O, Konthur Z, Schütte H, Klose J, Kaps C, Endres M.Int J Biochem Cell Biol. 2013 Jul;45(7):1410-8. doi: 10.1016/j.biocel.2013.04.016. Epub 2013 Apr 21. PMID: 23612019

Proteomic profiling of secreted proteins for the hematopoietic support of interleukin-stimulated human umbilical vein endothelial cells.Bal G, Kamhieh-Milz J, Sterzer V, Al-Samman M, Debski J, Klein O, Kamhieh-Milz S, Bhakdi S, Salama A. Cell Transplant. 2013;22(7):1185-99. doi: 10.3727/096368912×657288. Epub 2012 Oct 1.

Proteomic analysis of midtrimester amniotic fluid to identify novel biomarkers for preterm delivery.Fotopoulou C, Kyeyamwa S, Linder M, Thieme D, Hartenstein S, Klein O, Dudenhausen JW, Henrich W, Kalache KD, Bamberg C. J Matern Fetal Neonatal Med. 2012 Dec;25(12):2488-93. doi: 10.3109/14767058.2012.712565. Epub 2012 Aug 24.

Mesenchymal stromal cells rescue cortical neurons from apoptotic cell death in an in vitro model of cerebral ischemia.Scheibe F, Klein O, Klose J, Priller J. Cell Mol Neurobiol. 2012 May;32(4):567-76. doi: 10.1007/s10571-012-9798-2.PMID: 22290155

Functional comparison of chronological and in vitro aging: differential role of the cytoskeleton and mitochondria in mesenchymal stromal cells.Geißler S, Textor M, Kühnisch J, Könnig D, Klein O, Ode A, Pfitzner T, Adjaye J, Kasper G, Duda GN. PLoS One. 2012;7(12):e52700. doi: 10.1371/journal.pone.0052700. Epub 2012 Dec 28. PMID: 23285157

Kainate promotes alterations in neuronal RNA splicing machinery. Rohe M, Nebrich G, Klein O, Mao L, Zabel C, Klose J, Hartl D. J Proteome Res. 2011 Apr 1;10(4):1459-67. doi: 10.1021/pr101008p. Epub 2011 Feb 24. PMID: 21265575

Aging in mouse brain is a cell/tissue-level phenomenon exacerbated by proteasome loss. Mao L, Römer I, Nebrich G, Klein O, Koppelstätter A, Hin SC, Hartl D, Zabel C. J Proteome Res. 2010 Jul 2;9(7):3551-60. doi: 10.1021/pr100059j.PMID: 20469937

A large number of protein expression changes occur early in life and precede phenotype onset in a mouse model for huntington disease. Zabel C, Mao L, Woodman B, Rohe M, Wacker MA, Kläre Y, Koppelstätter A, Nebrich G, Klein O, Grams S, Strand A, Luthi-Carter R, Hartl D, Klose J, Bates GP.Mol Cell Proteomics. 2009 Apr;8(4):720-34. doi: 10.1074/mcp.M800277-MCP200. Epub 2008 Nov 30. PMID: 19043139

Biosketch Mirjana Kessler, Ph.D.

Institute: Max Planck Institute for Infection Biology, Department of Molecular Biology

Mirjana Kessler is a postdoctoral researcher at the Department of Molecular Biology of the Max Planck Institute for Infection Biology, Berlin. Together with her colleagues she has established long-term 3-D organoid cultures generated from patient tissue, which faithfully recreates the tissue architecture of the epithelial layer found in vivo. This model has enabled analysis of the cellular processes that regulate tissue maintenance in healthy fallopian tubes. She is now investigating the molecular mechanisms of host-pathogen interactions between the tubal epithelium and the human genital pathogen Chlamydia trachomatis and their potential involvement in the development of ovarian cancer.

Mirjana Kessler completed her basic studies at Belgrade University, at the Division of Molecular Biology and Physiology. She carried out her PhD work at the Institute for Genetics at Heinrich Heine University in Düsseldorf, where she investigated developmental biology and apoptosis. In 2006 she moved to the Max Planck Institute in Berlin, where she developed expertise in complex 3D human epithelial cell culture models based on the maintenance of adult stem cells obtained from patient material.