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Sabina Signoretti, MD
Scientist, Brigham and Women's Hospital
Associate Professor of Pathology, Harvard Medical School

Brigham and Women's Hospital
Department of Pathology
75 Francis Street
Boston, MA 02115


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Research Narrative:

     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 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 (Signoretti et al., Am J Pathol 2000). 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 (Signoretti et al, Proc Natl Acad Sci U S A 2005). 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 in renal cancer. 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.
 


Education:
MD

Publications (Pulled from Harvard Catalyst Profiles):

1. Flaifel A, Xie W, Braun DA, Ficial M, Bakouny Z, Nassar AH, Jennings RB, Escudier B, George DJ, Motzer RJ, Morris MJ, Powles T, Wang E, Huang Y, Freeman GJ, Choueiri TK, Signoretti S. PD-L1 expression and clinical outcomes to cabozantinib, everolimus and sunitinib in patients with metastatic renal cell carcinoma: analysis of the randomized clinical trials METEOR and CABOSUN. Clin Cancer Res. 2019 Aug 01.

2. Cho DC, Cohen MB, Panka DJ, Collins M, Ghebremichael M, Atkins MB, Signoretti S, Mier JW. Editor's Note: The Efficacy of the Novel Dual PI3-Kinase/mTOR Inhibitor NVP-BEZ235 Compared with Rapamycin in Renal Cell Carcinoma. Clin Cancer Res. 2019 07 01; 25(13):4194.

3. Currall BB, Chen M, Sallari RC, Cotter M, Wong KE, Robertson NG, Penney KL, Lunardi A, Reschke M, Hickox AE, Yin Y, Wong GT, Fung J, Brown KK, Williamson RE, Sinnott-Armstrong NA, Kammin T, Ivanov A, Zepeda-Mendoza CJ, Shen J, Quade BJ, Signoretti S, Arnos KS, Banks AS, Patsopoulos N, Liberman MC, Kellis M, Pandolfi PP, Morton CC. Corrigendum: Loss of LDAH associated with prostate cancer and hearing loss. Hum Mol Genet. 2019 05 15; 28(10):1753-1754.

4. Patel HD, Puligandla M, Shuch BM, Leibovich BC, Kapoor A, Master VA, Drake CG, Heng DY, Lara PN, Choueiri TK, Maskens D, Singer EA, Eggener SE, Svatek RS, Stadler WM, Cole S, Signoretti S, Gupta RT, Michaelson MD, McDermott DF, Cella D, Wagner LI, Haas NB, Carducci MA, Harshman LC, Allaf ME. The future of perioperative therapy in advanced renal cell carcinoma: how can we PROSPER? Future Oncol. 2019 May; 15(15):1683-1695.

5. Zou Y, Palte MJ, Deik AA, Li H, Eaton JK, Wang W, Tseng YY, Deasy R, Kost-Alimova M, Dancík V, Leshchiner ES, Viswanathan VS, Signoretti S, Choueiri TK, Boehm JS, Wagner BK, Doench JG, Clish CB, Clemons PA, Schreiber SL. A GPX4-dependent cancer cell state underlies the clear-cell morphology and confers sensitivity to ferroptosis. Nat Commun. 2019 04 08; 10(1):1617.

6. Chakraborty AA, Laukka T, Myllykoski M, Ringel AE, Booker MA, Tolstorukov MY, Meng YJ, Meier SR, Jennings RB, Creech AL, Herbert ZT, McBrayer SK, Olenchock BA, Jaffe JD, Haigis MC, Beroukhim R, Signoretti S, Koivunen P, Kaelin WG. Histone demethylase KDM6A directly senses oxygen to control chromatin and cell fate. Science. 2019 03 15; 363(6432):1217-1222.

7. Pignon JC, Jegede O, Shukla SA, Braun DA, Horak CE, Wind-Rotolo M, Ishii Y, Catalano PJ, Grosha J, Flaifel A, Novak JS, Mahoney KM, Freeman GJ, Sharpe AH, Hodi FS, Motzer RJ, Choueiri TK, Wu CJ, Atkins MB, McDermott DF, Signoretti S. irRECIST for the Evaluation of Candidate Biomarkers of Response to Nivolumab in Metastatic Clear Cell Renal Cell Carcinoma: Analysis of a Phase II Prospective Clinical Trial. Clin Cancer Res. 2019 Apr 01; 25(7):2174-2184.

8. Currall BB, Chen M, Sallari RC, Cotter M, Wong KE, Robertson NG, Penney KL, Lunardi A, Reschke M, Hickox AE, Yin Y, Wong GT, Fung J, Brown KK, Williamson RE, Sinnott-Armstrong NA, Kammin T, Ivanov A, Zepeda-Mendoza CJ, Shen J, Quade BJ, Signoretti S, Arnos KS, Banks AS, Patsopoulos N, Liberman MC, Kellis M, Pandolfi PP, Morton CC. Loss of LDAH associated with prostate cancer and hearing loss. Hum Mol Genet. 2018 12 15; 27(24):4194-4203.

9. Oser MG, Fonseca R, Chakraborty AA, Brough R, Spektor A, Jennings RB, Flaifel A, Novak JS, Gulati A, Buss E, Younger ST, McBrayer SK, Cowley GS, Bonal DM, Nguyen QD, Brulle-Soumare L, Taylor P, Cairo S, Ryan CJ, Pease EJ, Maratea K, Travers J, Root DE, Signoretti S, Pellman D, Ashton S, Lord CJ, Barry ST, Kaelin WG. Cells Lacking the RB1 Tumor Suppressor Gene Are Hyperdependent on Aurora B Kinase for Survival. Cancer Discov. 2019 02; 9(2):230-247.

10. Signoretti S, Flaifel A, Chen YB, Reuter VE. Renal Cell Carcinoma in the Era of Precision Medicine: From Molecular Pathology to Tissue-Based Biomarkers. J Clin Oncol. 2018 Oct 29; JCO2018792259.