MGH Center For Cancer Research ANNUAL REPORT 2015-201610

. . .Birrer Laboratory

Michael J. Birrer, MD, PhD

Lorenzo Ceppi, MD

Giulia Fulci, PhD

Shasha He, MD

Joanna Krzystyniak, PhD

Sam Lauffer

Ting Li, MD

Young Jeong Na, MD, PhD

Tsun Yee Tsang, PhD

Wei Wei, PhD

Our laboratory focuses on characterizing the

function and clinicopathologic impact of key

genes and pathways in ovarian cancer. The

laboratory was awarded an NCI Director’s

Challenge grant for the genomic analysis of

ovarian cancer and, in collaboration with Me-

morial Sloan Kettering Cancer Center, Univer-

sity of Pennsylvania, Fox Chase Cancer Center,

and the Australia Ovarian Cancer Study, has

conducted a large-scale study of expression

profiling. These efforts have characterized

differential gene expression on the whole-

genome level between ovarian tumors of

different histology and tumor grade. The study

identified pathways that underlie the clinical

pathologic characteristics of these tumors

and identified clear cell and mucinous tumors

of the ovaries as unique tumors unrelated to

other histologic subgroups. This discovery

has established for the first time unique trials

for patients with these cancers. We have also

shown that low malignant potential tumors

of the ovary (Grade 0) are a unique form of

serous tumors and require specific therapeutic

approaches. As a result, the laboratory has

been instrumental in testing the MEK inhibitor

AZD6244 for Grade 0 tumors. More recently,

the laboratory was awarded an RC4 grant

(in collaboration with Giovanni Parmigiani,

PhD, of the Dana-Farber Cancer Institute) to

validate previously identified gene expression

signatures which classify patients into good

versus poor prognosis, utilizing 1600 clinical

trial specimens from the recently completed

GOG clinical trial 218. The results will be rap-

idly integrated into prospective clinical trials of

patients with advanced-stage ovarian cancer.

To further facilitate biomarker analysis

and target identification for effective

management of ovarian cancer, our laboratory

has contributed to the development of a

curatedOvarianData database that provides

standardized gene expression and clinical

data for 2,970 ovarian cancer patients from

23 studies spanning 11 gene expression

measurement platforms (http://bcb.dfci.

harvard.edu/ovariancancer). This work facilitates

biomarker discovery through a robust meta-

analysis framework that limits the impact

cohort-specific biases while combining the

statistical powers of numerous studies.

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, endometrium 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.

Michael J. Birrer, MD, PhD

Principal Investigators

11

Co-amplification and overexpression of FGF18 and its receptor FGFR4 (on chromosome 5q31.3-qTER)

have been validated as predictive of poor clinical outcome in this patient with advanced stage, high-

grade serous ovarian cancer. Using cell culture and xenograft models, we show that FGF18/FGFR4

signaling activated NF-kB signaling and promoted tumor progression by modulating the ovarian tumor

aggressiveness and microenvironment.

Selected Publications:

Riester M, Wei W, Waldron L,

Culhane AC, Trippa L, Oliva E,

Kim S, Michor F, Hutterenhower

C, Parmigiani G, Birrer MJ. Risk

prediction for Late-Stage Ovarian

Cancer by Meta-Analysis of 1525

patient samples. J Natl Cancer Instit.

2014 106(5).

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.

Zaid TM, Yeung TL, Thompson

MS, Leung CS, Harding T, Co NN,

Schmandt RS, Kwan SY, Rodriguez-

Aguay C, Lopez-Berestein G, Sood

AK, Wong KK, Birrer MJ, Mok SC.

Identification of FGFR4 as a potential

therapeutic target for advanced-

stage, high-grade serous ovarian

cancer. Clin Cancer Res. 2013 Feb

15;19(4):809-20.

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):134-40.

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. 365(26):2473-83, 2011

Dec 29.

Cancer Genome Atlas Research

Network. Integrated genomic

analyses of ovarian carcinoma. Nature.

474(7353):609-15, 2011 Jun 29.

Through collaboration with Steven Skates,

PhD, the laboratory received an Early Detec-

tion Research Network UO1 grant to identify

novel early detection approaches to this

disease. We will compare the gene expres-

sion profiles of ovarian cancer with its normal

counterparts found on the surface of the ovary

and fallopian tube. Through a collaborative

effort with Steven Carr, PhD of the Broad

Institute, we will identify the early genomic

abnormalities in ovarian cancer and validate

these findings using specimens from Mas-

sachusetts General Hospital, Brigham and

Women’s Hospital and DFCI to translate our

work into serum-based early detection assays.

Presently, we are analyzing the function of

newly identified activated pathways in ovarian

cancers and utilizing in vivo models for the

discovery of novel therapeutic approaches. An

NIH R-01 grant was awarded to investigate

the role of FGF18/FGFR4 signaling, previously

shown to be associated with poor clinical

outcome, in the pathogenesis of serous ovar-

ian cancer. Large-scale prospective validation

and pharmaceutical targeting studies are

underway.

Research directions for the future include: 1)

Characterizing the function of genes associ-

ated with clinicopathologic characteristics

of ovarian cancer; 2) characterizing new

tumor cellular subsets of ovarian cancer for

their clinical features and their role in tumor

formation; 3) identifying novel early detec-

tion, prevention and therapeutic targets; and

4) utilizing the genomic abnormalities found

in ovarian cancer as targets for novel imag-

ing techniques. Our laboratory efforts remain

highly translational and collaborative in nature,

and we are committed to bringing laboratory-

based and scientifically rational concepts into

the clinic to improve the lives of women with

these cancers.