DF/HCC Program Affiliation

Gynecologic Cancer, Leader

DF/HCC Associations

Member, Center Scientific Council
MGH, GYN, Clinical Trial Chairs

Research Abstract

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.

Publications

• Nosov V,Su F,Amneus M,Birrer M,Robins T,Kotlerman J,Reddy S,Farias-Eisner R.Validation of serum biomarkers for detection of early-stage ovarian cancer.Am J Obstet Gynecol 2009 Mar 12.
  19285648
• Farley J,Fuchiuji S,Darcy KM,Tian C,Hoskins WJ,McGuire WP,Hanjani P,Warshal D,Greer BE,Belinson J,Birrer MJ.Associations between ERBB2 amplification and progression-free survival and overall survival in advanced stage, suboptimally-resected epithelial ova
  19272639
• Singh S,Manda SM,Sikder D,Birrer MJ,Rothermel BA,Garry DJ,Mammen PP.Calcineurin activates cytoglobin transcription in hypoxic myocytes.J Biol Chem 2009 Feb 9.
  19203999
• Merritt WM,Lin YG,Han LY,Kamat AA,Spannuth WA,Schmandt R,Urbauer D,Pennacchio LA,Cheng JF,Nick AM,Deavers MT,Mourad-Zeidan A,Wang H,Mueller P,Lenburg ME,Gray JW,Mok S,Birrer MJ,Lopez-Berestein G,Coleman RL,Bar-Eli M,Sood AK.Dicer, Drosha, and outcomes in
  19092150
• Leaner VD,Chick JF,Donninger H,Linniola I,Mendoza A,Khanna C,Birrer MJ.Inhibition of AP-1 transcriptional activity blocks the migration, invasion, and experimental metastasis of murine osteosarcoma.Am J Pathol 2009 Jan;174(1):265-75.
  19074613
• Chung TK,Cheung TH,Huen NY,Wong KW,Lo KW,Yim SF,Siu NS,Wong YM,Tsang PT,Pang MW,Yu MY,To KF,Mok SC,Wang VW,Li C,Cheung AY,Doran G,Birrer MJ,Smith DI,Wong YF.Dysregulated microRNAs and their predicted targets associated with endometrioid endometrial adenoc
  19065659
• Callahan MJ,Nagymanyoki Z,Bonome T,Johnson ME,Litkouhi B,Sullivan EH,Hirsch MS,Matulonis UA,Liu J,Birrer MJ,Berkowitz RS,Mok SC.Increased HLA-DMB expression in the tumor epithelium is associated with increased CTL infiltration and improved prognosis in ad
  19047092
• Arora S,Wang Y,Jia Z,Vardar-Sengul S,Munawar A,Doctor KS,Birrer M,McClelland M,Adamson E,Mercola D.Egr1 regulates the coordinated expression of numerous EGF receptor target genes as identified by ChIP-on-chip.Genome Biol 2008;9(11):R166.
  19032775
• Anglesio MS,Arnold JM,George J,Tinker AV,Tothill R,Waddell N,Simms L,Locandro B,Fereday S,Traficante N,Russell P,Sharma R,Birrer MJ,deFazio A,Chenevix-Trench G,Bowtell DD.Mutation of ERBB2 provides a novel alternative mechanism for the ubiquitous activati
  19010816
• Lorenzi PL,Llamas J,Gunsior M,Ozbun L,Reinhold WC,Varma S,Ji H,Kim H,Hutchinson AA,Kohn EC,Goldsmith PK,Birrer MJ,Weinstein JN.Asparagine synthetase is a predictive biomarker of L-asparaginase activity in ovarian cancer cell lines.Mol Cancer Ther 2008 Oct
  18852115
• Park DC,Yeo SG,Wilson MR,Yerbury JJ,Kwong J,Welch WR,Choi YK,Birrer MJ,Mok SC,Wong KK.Clusterin interacts with Paclitaxel and confer Paclitaxel resistance in ovarian cancer.Neoplasia 2008 Sep;10(9):964-72.
  18714397
• Sood AK,Birrer MJ.Highlights from the 2008 Annual Meeting of the American Association for Cancer Research.Gynecol Oncol 2008 Jul;110(1):5-6.
  18595162
• Bonome T,Levine DA,Shih J,Randonovich M,Pise-Masison CA,Bogomolniy F,Ozbun L,Brady J,Barrett JC,Boyd J,Birrer MJ.A gene signature predicting for survival in suboptimally debulked patients with ovarian cancer.Cancer Res 2008 Jul 1;68(13):5478-86.
  18593951
• Stany MP,Bonome T,Wamunyokoli F,Zorn K,Ozbun L,Park DC,Hao K,Boyd J,Sood AK,Gershenson DM,Berkowitz RS,Mok SC,Birrer MJ.Classification of ovarian cancer: a genomic analysis.Adv Exp Med Biol 2008;622:23-33.
  18546616
• Zhang L,Volinia S,Bonome T,Calin GA,Greshock J,Yang N,Liu CG,Giannakakis A,Alexiou P,Hasegawa K,Johnstone CN,Megraw MS,Adams S,Lassus H,Huang J,Kaur S,Liang S,Sethupathy P,Leminen A,Simossis VA,Sandaltzopoulos R,Naomoto Y,Katsaros D,Gimotty PA,DeMichele A
  18458333
• Farley J,Ozbun LL,Birrer MJ.Genomic analysis of epithelial ovarian cancer.Cell Res 2008 May;18(5):538-48.
  18427574
• Litkouhi B, Litkouhi B, Fleming E, Welch WR, Berkowitz RS, Birrer MJ, Mok SC.Overexpression of CEACAM6 in borderline and invasive mucinous ovarian neoplasms.Gynecol Oncol 2008 May;109(2):234-9.
  18331757
• Landen CN Jr,Birrer MJ,Sood AK.Early events in the pathogenesis of epithelial ovarian cancer.J Clin Oncol 2008 Feb 20;26(6):995-1005.
  18195328
• Mok SC,Kwong J,Welch WR,Samimi G,Ozbun L,Bonome T,Birrer MJ,Berkowitz RS,Wong KK.Etiology and pathogenesis of epithelial ovarian cancer.Dis Markers 2007;23(5-6):367-76.
  18057520
• Samimi G,Ozbun L,Johnson ME,Mok SC,Birrer MJ.Biomarkers of mucinous tumors of the ovary.Dis Markers 2007;23(5-6):389-96.
  18057522
• Farley J,Ozbun L,Samimi G,Birrer MJ.Cell cycle and related protein.Dis Markers 2007;23(5-6):433-43.
  18057526
• Kelloff GJ,Sullivan DC,Baker H,Clarke LP,Nordstrom R,Tatum JL,Dorfman GS,Jacobs P,Berg CD,Pomper MG,Birrer MJ,Tempero M,Higley HR,Petty BG,Sigman CC,Maley C,Sharma P,Wax A,Ginsberg GG,Dannenberg AJ,Hawk ET,Messing EM,Grossman HB,Harisinghani M,Bigio IJ,Gr
  17655039
• Gershenson DM,Birrer M.Time for action: a "sea change" in treatment strategies for rare types of epithelial ovarian cancer.Gynecol Oncol 2007 Jul;106(1):1-3.
  17574071
• Birrer MJ, Johnson ME, Hao K, Wong KK, Park DC, Bell A, Welch WR, Berkowitz RS, Mok SC.Whole genome oligonucleotide-based array comparative genomic hybridization analysis identified fibroblast growth factor 1 as a prognostic marker for advanced-stage sero
  17538174
• Lu C,Bonome T,Li Y,Kamat AA,Han LY,Schmandt R,Coleman RL,Gershenson DM,Jaffe RB,Birrer MJ,Sood AK.Gene alterations identified by expression profiling in tumor-associated endothelial cells from invasive ovarian carcinoma.Cancer Res 2007 Feb 15;67(4):1757-6
  17308118
• Mok SC, Elias KM, Wong KK, Ho K, Bonome T, Birrer MJ.Biomarker discovery in epithelial ovarian cancer by genomic approaches.Adv Cancer Res 2007;96:1-22.
  17161674
• Fountain J,Trimble E,Birrer MJ.Summary and discussion of session recommendations.Gynecol Oncol 2006 Nov;103(2 Suppl 1):S23-5.
  17027068
• Farley J,Bast RC Jr,Birrer MJ.Biomarkers and clinical trial design.Gynecol Oncol 2006 Nov;103(2 Suppl 1):S3-5.
  17027069
• Farley J,Birrer MJ,Christian MC.The future of phase II trials.Gynecol Oncol 2006 Nov;103(2 Suppl 1):S20-2.
  17027074
• Sunde JS, Donninger H, Wu K, Johnson ME, Pestell RG, Rose GS, Mok SC, Brady J, Bonome T, Birrer MJ.Expression Profiling Identifies Altered Expression of Genes That Contribute to the Inhibition of Transforming Growth Factor-{beta} Signaling in Ovarian Canc
  16951150
• Birrer MJ.Ovarian cancer: not a borderline issue!.Cancer Biol Ther 2006 Jul;5(7):786-7.
  16921259
• DiFeo A,Narla G,Hirshfeld J,Camacho-Vanegas O,Narla J,Rose SL,Kalir T,Yao S,Levine A,Birrer MJ,Bonome T,Friedman SL,Buller RE,Martignetti JA.Roles of KLF6 and KLF6-SV1 in ovarian cancer progression and intraperitoneal dissemination.Clin Cancer Res 2006 Ju
  16778100
• Wamunyokoli FW, Bonome T, Lee JY, Feltmate CM, Welch WR, Radonovich M, Pise-Masison C, Brady J, Hao K, Berkowitz RS, Mok S, Birrer MJ.Expression profiling of mucinous tumors of the ovary identifies genes of clinicopathologic importance.Clin Cancer Res 200
  16467078
• Nummela P,Yin M,Kielosto M,Leaner V,Birrer MJ,Holtta E.Thymosin beta4 is a determinant of the transformed phenotype and invasiveness of S-adenosylmethionine decarboxylase-transfected fibroblasts.Cancer Res 2006 Jan 15;66(2):701-12.
  16423999
• Tsuda H, Ito YM, Ohashi Y, Wong KK, Hashiguchi Y, Welch WR, Berkowitz RS, Birrer MJ, Mok SC.Identification of overexpression and amplification of ABCF2 in clear cell ovarian adenocarcinomas by cDNA microarray analyses.Clin Cancer Res 2005 Oct 1;11(19 Pt 1
  16203778
• Zorn KK,Bonome T,Gangi L,Chandramouli GV,Awtrey CS,Gardner GJ,Barrett JC,Boyd J,Birrer MJ.Gene expression profiles of serous, endometrioid, and clear cell subtypes of ovarian and endometrial cancer.Clin Cancer Res 2005 Sep 15;11(18):6422-30.
  16166416
• Jazaeri AA,Awtrey CS,Chandramouli GV,Chuang YE,Khan J,Sotiriou C,Aprelikova O,Yee CJ,Zorn KK,Birrer MJ,Barrett JC,Boyd J.Gene expression profiles associated with response to chemotherapy in epithelial ovarian cancers.Clin Cancer Res 2005 Sep 1;11(17):6300
  16144934
• Tsuda H, Birrer MJ, Ito YM, Ohashi Y, Lin M, Lee C, Wong WH, Rao PH, Lau CC, Berkowitz RS, Wong KK, Mok SC.Identification of DNA copy number changes in microdissected serous ovarian cancer tissue using a cDNA microarray platform.Cancer Genet Cytogenet 200
  15571795
• Tsuda H,Bandera CA,Birrer MJ,Hashiguchi Y,Berkowitz RS,Mok SC.Cyclin E amplification and overexpression in clear cell adenocarcinoma of the ovary.Oncology 2004;67(3-4):291-9.
  15557791
• Donninger H,Bonome T,Radonovich M,Pise-Masison CA,Brady J,Shih JH,Barrett JC,Birrer MJ.Whole genome expression profiling of advance stage papillary serous ovarian cancer reveals activated pathways.Oncogene 2004 Oct 21;23(49):8065-77.
  15361855
• Sherman ME,Berman J,Birrer MJ,Cho KR,Ellenson LH,Gorstein F,Seidman JD.Current challenges and opportunities for research on borderline ovarian tumors.Hum Pathol 2004 Aug;35(8):961-70.
  15297963
• Farley J,Uyehara C,Hashiro G,Belnap C,Birrer M,Salminen E.Cyclooxygenase-2 expression predicts recurrence of cervical dysplasia following loop electrosurgical excision procedure.Gynecol Oncol 2004 Feb;92(2):596-602.
  14766253
• Zorn KK, Jazaeri AA, Awtrey CS, Gardner GJ, Mok SC, Boyd J, Birrer MJ.Choice of normal ovarian control influences determination of differentially expressed genes in ovarian cancer expression profiling studies.Clin Cancer Res 2003 Oct 15;9(13):4811-8.
  14581352
• Winter WE 3rd,Seidman JD,Krivak TC,Chauhan S,Carlson JW,Rose GS,Birrer MJ.Clinicopathological analysis of c-kit expression in carcinosarcomas and leiomyosarcomas of the uterine corpus.Gynecol Oncol 2003 Oct;91(1):3-8.
  14529656
• Farley JH,Birrer MJ.Biologic directed therapies in gynecologic oncology.Curr Oncol Rep 2003 Nov;5(6):459-67.
  14521804
• Farley J,Smith LM,Darcy KM,Sobel E,O'Connor D,Henderson B,Morrison LE,Birrer MJ.Cyclin E expression is a significant predictor of survival in advanced, suboptimally debulked ovarian epithelial cancers: a Gynecologic Oncology Group study.Cancer Res 2003 Ma
  12649182
• Manzano RG,Montuenga LM,Dayton M,Dent P,Kinoshita I,Vicent S,Gardner GJ,Nguyen P,Choi YH,Trepel J,Auersperg N,Birrer MJ.CL100 expression is down-regulated in advanced epithelial ovarian cancer and its re-expression decreases its malignant potential.Oncoge
  12080474