CURRICULUM VITAE

Part I General Information

DATE PREPARED 09/23/11

Name: Sabina Signoretti, M.D.

Office Address: Department of Pathology,

Brigham and Women’s Hospital, Thorn 504A

75 Francis Street

Boston MA 02115

Ph : 617-525-7437

e-mail:

Home Address: 77 Wenham Street Apt.2, Jamaica Plain, MA 02130

Work E:Mail: Work FAX: 617-264-5169

Place of birth: Rome, Italy

Education:

1982-1988 M.D. University of Rome “La Sapienza”, Rome, Italy

Postdoctoral Training:

Residencies:

1989-1993 Resident in Pathology, University of Rome “La Sapienza”

Fellowships:

1995-1996 Research Fellow in Hematopathology, Beth Israel Hospital, Boston, MA

1996-1997 Research Fellow in Molecular Pathology, Beth Israel Deaconess Medical Center, Boston MA.

Licensure and Certification:

1988 State licensure examination, Italy

Academic Appointments:

1996-1997 Research Fellow, Harvard Medical School, Boston, MA

1999-2003 Instructor in Pathology, Harvard Medical School

2003-2008 Assistant Professor of Pathology, Harvard Medical School

2009- Associate Professor of Pathology, Harvard Medical School

Hospital Appointments:

1993-1995; 1998 Attending Pathologist, Istituto Dermopatico dell'Immacolata (IDI), Rome, Italy

1999-2003 Research Associate, Brigham and Women’s Hospital

1999- Associate Pathologist, Dana-Farber Cancer Institute

2003- Associate Pathologist, Brigham and Women’s Hospital

2006- Affiliate Faculty, Harvard Stem Cell Institute

2006- Member, DFCI/BWH Center for Molecular Oncologic Pathology

2011- Visiting Postdoctoral Scholar, Broad Institute of Harvard and MIT

Hospital and Health Care Organization Responsabilities:

1993-1995; 1998 Diagnostic Dermatopathology, Istituto Dermopatico

dell'Immacolata (IDI), Rome, Italy

1996-1997 Supervisor of the Core Molecular Pathology Laboratory at

Beth Israel Deaconess Medical Center

1999-2004 Associate Pathologist, Prostate Cancer Pathology Core Facility and In situ Hybridization Core Facility, Dana-Farber Harvard Cancer Center (DF/HCC)

2005- Associate Pathologist, Specialized Histopathology Core Facility, Dana-Farber Harvard Cancer Center (DF/HCC)

Major Administrative Responsibilities:

Local

2004- Director, Tissue Acquisition Pathology and Clinical Data Core of DF/HCC Kidney Cancer SPORE and Program

2008- Director, DF/HCC Tissue Microarray and Imaging (TMI) Core

2010- Co-Leader, DF/HCC Kidney Cancer Program

Major Committee Assignments:

Local

2004- Member, DF/HCC Kidney Cancer SPORE Governance Committee

2004- Co-chair, DF/HCC Kidney Cancer SPORE Specimens & Data Utilization Committee

2005- Member, DF/HCC Specialized Histopathology Core Facility User Committee

2005- Member, DF/HCC Tissue Microarray Core Facility User Committee

2008- Member, DFCI/BWH Center for Molecular Oncologic Pathology Advisory Committee

2008- Member, DF/HCC Scientific Council

2009- Member, Urologic Disease Working Group of The Cancer Genome Atlas (TCGA) Program (NCI/ NHGRI)

2010- Member, NCI Renal Cancer Task Force (RCTF)

2011- Kidney Cancer Analysis Working Group of The Cancer Genome Atlas (TCGA) Program (NCI/ NHGRI)

Professional Societies (Member):

1999- American association for Cancer Research

New England Society of Pathologists

US and Canadian Academy of Pathology

Grant review activities:

2003 Scientific Reviewer, Cell Biology Review Panel #1, Department of Defense Prostate Cancer Research Program

2004- 2005 Scientific Reviewer, Pathobiology Review Panel #3, Department of Defense Prostate Cancer Research Program

2006- Scientific Reviewer, Pathobiology Review Panel #2, Department of Defense Prostate Cancer Research Program

Community Service Related to Professional Work:

2006; 2010 Mentor, DF/HCC Continuing Umbrella of Research Experiences (CURE) Program

2007- 2009 Mentor, Partners Student Success Jobs Program, Brigham and Women’s Hospital

Editorial activities:

2004- Ad hoc reviewer:

American Journal of Pathology, American Journal of Physiology, Breast Cancer Research, British Journal of Cancer, BJU International, Cancer, Cancer Research, Clinical Cancer Research, Development, Developmental Biology, Diagnostic Molecular Pathology, Human Pathology, International Journal of Cancer, Journal of Urology, Laboratory Investigation, Lancet Oncology, Nature Medicine, PLoS ONE

2008- Member, Editorial Board:

Clinical Cancer Research

Diagnostic Molecular Pathology

Awards and Honors:

1988 M.D, summa cum laude, University of Rome

1998 The Daland Award, The New England Cancer Society, Worcester, MA

2001 Hershey Young Investigator Award, Boston MA

2002 CaP CURE Award

2007 Partners in Excellence Award, Student Success Jobs Program Mentor

Part II Research, Teaching, and Clinical Contribution

A. Narrative Report:

Research contributions: My research is focused on genitourinary malignancies, including prostate, bladder and renal cancer.

Defining the cell(s) of origin of tumors is fundamental to elucidate the molecular mechanisms involved in their pathogenesis. A major limitation for the identification of the cell type(s) involved in the initiation and propagation of prostate and bladder cancers is that the identity of stem cells and differentiation programs in these epithelia remains unclear. My research aims to identify cell lineages in the prostate and bladder urothelium. I have previously demonstrated that p63 is selectively expressed in basal cells of the prostate and urothelium and that p63-deficient mice present defects in the development of these tissues. My subsequent studies have shown that the early developing prostate (prostate buds) consists exclusively of p63-positive basal cells, which then give rise to secretory cells and thus represent progenitor/stem cells. In contrast, my analysis of the urothelium shows that umbrella (superficial) cells can develop and be maintained independently from p63-positive cells. I am currently utilizing animal models to further characterize the role of p63 in the development and renewal of the prostate and bladder epithelium. This approach is likely to offer new insights in the biology of prostate and bladder development and open new perspectives in the identification of the cell of origin of prostate and bladder carcinoma.

An important focus of my research in kidney cancer is the identification of novel oncogenes and tumor suppressor genes. In collaboration with Drs. Kaelin and Beroukhim at DFCI and the Broad Institute, we are currently using an integrated analysis of single-nucleotide polymorphism (SNP) arrays data with matched gene expression data to identify genes targeted by non-random genetic aberrations in RCC. Results from these studies have the potential to identify new drug targets and may eventually lead to new therapeutic approaches for patients with kidney cancer.

My laboratory is also very involved in translational research activities. I currently serve as the Director of the Tissue Acquisition, Pathology, and Clinical Data (TAPCD) Core of the DF/HCC Kidney Cancer SPORE and Program. I am also the Director of the DF/HCC Tissue Microaaray and Imaging Core.

Teaching contributions: I have been actively involved in teaching since the beginning of my career. I daily teach and tutor post-doctoral fellows and research assistant working in my research laboratory. Moreover, I serve as a Tutor in the Pathology course at Harvard Medical School.

Clinical contributions: Throughout my career I have been involved in both patient care and in the development of new tools that could be helpful in the diagnosis and treatment of diseases. As a Research Fellow, I developed a novel PCR-based T-cell clonality assay, which is currently being utilized for the diagnosis of T-cell lymphomas (Signoretti et al., Am J Pathol, 1999 and accompanying editorial). More recently, I demonstrated that p63 is a reliable marker of prostate basal cells that is not expressed in prostate carcinoma. After extensive validation by other groups, p63 immunohistochemistry is currently used in routine clinical practice for the evaluation of challenging prostate biopsies.

B. Funded Research Support:

Past

1996-1997 Oncor, Inc. Evaluation of the Oncor HER-2/neu (ERBB2) gene amplification detection kit for the interpahse detection of HER-2/neu (ERBB2) genomic sequences in human breast tissue for node-negative primary breast cancer. Multi-institutional study for FDA approval of the HER-2/neu (ERBB2) gene amplification detection kit. (Kit FDA approved Jan 1998). Co-investigator.

1997-1998 Ministero della Pubblica Istruzione, Rome, Italy. Detection of B-cell clonality in cutaneous B-cell infiltrates. Co-investigator.

2001 Hershey Foundation Award (Signoretti, DFCI). A mouse model for prostate stem cells. Principal Investigator.

2001-2004 DOD U.S. Army, CDMRP - New Investigator Award (Signoretti, DFCI). The basal cell marker p63 and prostate stem cells. Principal Investigator.

2002 CaP CURE Foundation Award (Signoretti, DFCI). An animal model for the identification of prostate stem cells. Principal Investigator.

2002-2007 NIH/NCI. Prostate Cancer SPORE / Pathology Core (Kantoff, DFCI). Co-investigator.

2004-2006 NIH/NCI. Kidney Cancer SPORE Developmental Project (Signoretti, BWH). Molecular analysis of renal cell carcinoma using Single Nucleotide Polymorphisms (SNP) arrays. Principal Investigator.

2005-2007 NIH/NIDDK-R21. Defining cell lineages in the bladder urothelium (Signoretti, BWH). Principal Investigator.

2006-2008 NIH/NCI. Kidney Cancer SPORE Developmental Project. Development of mouse orthotopic xenografts of human renal cell carcinoma (Signoretti, BWH). Principal Investigator.

02/08/06-02/07/10 DOD. U.S. Army. CDMRP - Idea Development Award. p63 in development and maintenance of the prostate epithelium (Signoretti, BWH). Principal Investigator.

2007 NIH/NCI. ICBP Pilot Project supported by 5U54 CA112962-03 (Golub, DFCI). Integrating gene expression with high-resolution genetic analysis to identify oncogenic kinases in kidney cancer. Principal Investigator.

01/01/07-12/31/08 Doris Duke Charitable Foundation. Distinguished Clinical Scientist Award (Kaelin, DFCI). Co-investigator.

06/01/07-06/30/09 Harvard Stem Cell Institute. Seed Grant. Identification of Stem Cells In Prostate and Bladder Epithelia (Signoretti, BWH). Principal Investigator.

09/01/09 – 08/31/10 NIH/NCI. of the Kidney Cancer SPORE P50 CA101942 - Developmental Project. Clinical, histological and molecular determinants of bilateral renal cell cancer. Principal Investigator.

Current

Active

04/01/01-03/31/11 NIH/NCI. PO1 CA089021. The Role of PTEN and PI3K Pathway in Prostate Cancer (Cantley, BIDMC). Co-investigator.

05/19/06-11/30/11 NIH/NCI. DF/HCC P30 CA06516. Specialized Histopathology Core (Aster, BWH). Co-investigator.

05/19/06-11/30/11 NIH/NCI. DF/HCC P30 CA06516. Tissue Microarray and Imaging (TMI) Core (Signoretti, BWH). Principal Investigator.

06/01/09-05/31/14 NIH/NCI. Kidney Cancer SPORE P50 CA101942. Tissue Acquisition Pathology and Clinical Data Core (CORE# 3) (Signoretti, BWH). Principal Investigator.

06/01/09-05/31/14 NIH/NCI. Kidney Cancer SPORE P50 CA101942. Treatment of VHL-/- clear cell renal carcinoma with HIF2a siRNA (Kaelin DFCI, Choueiri DFCI, Signoretti BWH). Co-Principal Investigator of Project 2.

09/01/10 – 07/31/15 NIH/NIDDK. 1R01DK089975 (Signoretti, BWH). Mechanisms Regulating Prostate Epithelium Maintenance and Regeneration. Principal Investigator.

04/01/11-03/31/15 NIH/NCI. 1R01 CA152330-01 (Seth, BIDMC). Pathway Specific Imaging in VHL Deficient Renal Cancer. Co-investigator.

11/01/11-10/30/15 NIH/NCI. 1R01CA154475-01 (Pedrosa, BIDMC). Non-invasive Physiologic Predictors of Aggressiveness in Renal Cell Carcinoma. Co-investigator.

11/01/11-10/30/12 NIH/NCI. Kidney Cancer SPORE P50 CA101942. Director’s choice Award. Characterization of molecular alterations in metanephric adenoma of the kidney. Principal Investigator.

C. Current Research Activities

#1: Role of p63 in development and renewal of the prostate and bladder epithelium

Unraveling the mechanisms regulating the development and renewal of normal tissues is not only one of the main goals of developmental biology but also an essential step for the elucidation of the mechanisms underlying the development of pathological processes, namely cancer. Although epithelial stem cells have been identified in the skin and intestine, the way the prostate and bladder epithelium are formed and maintained remains unclear.

The basal cell marker p63 is selectively expressed in the basal cells of several epithelia, including the prostate and the bladder. My research group has previously demonstrated that p63-deficient (p63-/-) mice present defects in prostate buds and urothelial development (Signoretti et al., Am J Pathol 2000). We have more recently performed in vivo studies utilizing the p63-/- mouse as a tool to define cell lineages in the prostate epithelium and urothelium. Results from these studies show that when developmental defects of p63-/- embryos are abolished by injecting p63+/+ ES cells into 3.5dpc p63-/- blastocysts, only p63+/+ cells compose the normal prostate epithelium of 7-weeks old chimeric mice. These findings indicate that prostate secretory cells of young adult mice derive from p63-positive progenitor cells that constitute the prostate buds. Surprisingly, in contrast with the prostate findings, analysis of the urothelium of the rescued p63-/- chimeras demonstrates that urothelial umbrella cells can develop independently from p63-positive basal and intermediate cells (Signoretti et al, Proc Natl Acad Sci U S A 2005).

My current research aims at further defining stem cells and differentiation programs in the adult prostate and bladder epithelia. Specifically, we are performing genetic lineage tracing experiments to directly follow the fate of p63-positive cells in the prostate and bladder epithelia in vivo.

The secondary goal of this endeavor is to identify molecular mechanisms mediating p63 function during both development and tumorogenesis. We have shown that prostate basal cells predominantly express the DNp63a isosform and that DNp63a is required for cell survival. Importantly, we have also demonstrated that Fatty Acid Synthase (FASN) is a functionally relevant target of p63 and is required for mediating its pro-survival effects (Sabbisetti, PLoS ONE, 2009). Our results establish a novel functional link between this p53 family member and lipid metabolism and suggest that maintenance of fatty acid synthesis is a key mechanism through which p63 acts as a pro-survival molecule in both development and cancer.

Research #2: Molecular Analysis Of Renal Cell Carcinoma Using Single Nucleotide Polymorphisms (SNP) Arrays

Clear cell renal cell carcinoma (cRCC) represents the most common and fatal form of renal cancer and accounts for 70-80% of cases. In patients with advanced disease, response rates to traditional chemotherapy and radiotherapy are, unfortunately, very low. The introduction of cytokine-based immunotherapy with interferon-a or interleukin-2 for patients with metastatic disease has shown survival improvements, but the treatment is often not well tolerated and only a limited subset of patients experience clinically meaningful benefit. Recently, tyrosine kinase inhibitors (TKIs) that target the VHL pathway, including sorafenib and sunitinib, have shown clear activity in metastatic cRCC and have received approval by the FDA. However, not all the patients treated with these targeted therapies experience a substantial clinical benefit and almost all of them eventually progress. Therefore, more effective treatments for cRCC are warranted.

Kinases are tractable therapeutic targets with multiple small molecule inhibitors in development. Identification of new kinases that play an important role in the development and progression of cRCC would enable rapid development of more effective therapeutic approaches. High-throughput genetic studies represent a unique opportunity to identify the tumor suppressor genes (TSGs) and oncogenes, including kinases, upon which genetic subtypes of cRCC depend. High-resolution single nucleotide polymorphism (SNP) arrays are able simultaneously to delineate regions of copy-number gain and loss and loss-of-heterozygosity (LOH) at high resolution throughout the genome. In collaboration with Drs. Kaelin and Beroukhim at DFCI and the Broad Institute, we are currently performing integrated analysis of SNP array data describing chromosomal aberrations with matched gene expression data to identify candidate kinases targeted by these aberrations in cRCC (Beroukhim et al, Cancer Res, 2009). Results from these studies will shed light on the molecular mechanisms underlying kidney cancer development and might eventually lead to more effective targeted therapies for this disease.

D. Report of Teaching:

1. Local contributions

Medical School Teaching

1995; 1998 Resident teaching: daily training of pathology Residents from University of Rome “la Sapienza”, rotating through the Pathology Service of Istituto Dermopatico dell’Immacolata. 4 Residents per year. Preparation and contact time: 1-3 hours/day.

1997 Resident teaching: Clinical Pathology rotation (of one month duration) in the Molecular Pathology Laboratory at Beth Israel Deaconess Medical Center. 6 Residents per year. Preparation and contact time: 5-10 hours/week.