Skip to contents

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


Edit Profile


Research Narrative:

My laboratory is involved in translational research activities in genitourinary malignancies, especially renal cell carcinoma (RCC), which is the most common form of kidney cancer. Our research efforts in this area have focused on the identification of novel oncogenes and tumor suppressor genes that could function as new drug targets and thus might lead to new therapeutic approaches for patients with RCC. We conducted the first genome-wide analysis of copy-number changes and gene expression profiles in both sporadic and Von-Hippel Lindau (VHL) disease-associated clear cell renal cell carcinomas (ccRCC) (Beroukhim et al, Cancer Res 2009). Results showed that sporadic tumors without biallelic VHL inactivation are heterogeneous and include tumors with genomic profiles highly dissimilar to the majority of ccRCC, suggesting that they represent a separate group of cancers that do not respond to treatments that target the VHL pathway. We subsequently continued to work on the molecular characterization ccRCC as part of the NCI-sponsored The Cancer Genome Atlas (TCGA) effort(Creighton et al, Nature 2013).

In the past decade, the availability of approved agents with distinct mechanisms of action (immunotherapy, vascular endothelial growth factor [VEGF] pathway, and mammalian target of rapamycin [mTOR] inhibitors) has complicated treatment decisions for patients with advanced RCC. For this reason, my group has been very interested in building predictive models (for either FDA-approved or investigational drugs) that can help medical oncologists select the most appropriate therapy for a given patient. Over the past years, we have extensively analyzed the role of the enzyme carbonic anhydrase IX (CAIX) and other elements of the VHL-HIF pathway both as diagnostic and predictive biomarkers for VEGF-targeted therapy in ccRCC. More recently, we performed a multi-institutional study, which demonstrated that mutations in MTOR pathway genes are associated with response to mTOR inhibitors in patients with metastatic RCC, providing a potential predictive biomarker for rapalogs in this tumor type (Kwiatkowski et al, Clin Cancer Res 2016). In the past few years, my laboratory has also been deeply involved in the characterization of the expression of immunomodulatory molecules, including PD-L1, in tumors form patients with RCC and bladder cancer. This work has provided important insights into the role of PD-L1 as a potential predictive biomarker and a target of immunotherapy in genitourinary cancers. For instance, our analysis of PD-L1 expression in non-clear-cell Renal Cell Carcinoma (non-ccRCC) tissue samples provided a rationale for conducting clinical trial testing the efficacy of PD-1 inhibitors in patients with metastatic non-ccRCC (Choueiri et al, Ann Oncol 2014). Moreover, our detailed comparison of PD-L1 expression in primary ccRCCs and corresponding metastases highlighted the heterogeneity of PD-L1 expression in this tumor type, implying that accurate assessment of PD-L1 as a predictive biomarker for PD-1 blockade in ccRCC may require analysis of metastatic lesions (Callea et al, Cancer Immunol Res 2015). Our current efforts in this field of research are directed at identifying biomarkers of response to PD-1/PD-L1 immune checkpoints blockade through the analysis of clinical trial patient cohorts.


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.