James Brugarolas

Realizing the few options available for kidney cancer patients, Dr. Brugarolas decided to dedicate his life to finding a cure. Following completion of medical school in his home country of Spain in 1993, he came to the U.S. seeking to better understand the biological underpinnings of cancer. As a graduate student at MIT, his research in the laboratory of Tyler Jacks, Ph.D. provided fundamental understanding on how cell proliferation is regulated by both external and internal cues. In a series of highly-cited manuscripts in Nature, Proceedings of the National Academy of Sciences, and The Journal of Cell Biology, he reported that growth signals control the cell cycle by modulating the activity of CDK4 and CDK2, and that constitutive activation of these kinases was sufficient to confer cell proliferation autonomy. His studies revealed that the so-called guardian of the genome, the p53 protein, imposed a cell cycle arrest through p21, but that p21 was dispensable for p53-mediated cell death, and provided insight into the mechanism of p21 action.

Following his Ph.D. at MIT (1998), Dr. Brugarolas pursued training in internal medicine at Duke University Medical Center. Afterwards, in 2001, he enrolled in a combined oncology fellowship program at the Dana-Farber Cancer Institute, Brigham and Women’s Hospital, and Massachusetts General Hospital. As an instructor at Harvard Medical School, his research in the laboratory of William G. Kaelin, M.D., led to novel insights into mTOR, a master regulator of cell growth. In highly-cited manuscripts, he reported that mTOR was regulated in response to oxygen levels providing mechanistic insight, and that mTOR regulated HIF. This work earned him a Claudia Adams Barr Award for Innovative Basic Cancer Research from the Dana-Farber Cancer Institute, and a Young Investigator Award from the Brigham and Women’s Hospital.

In 2006, Dr. Brugarolas was recruited to UT Southwestern, where he sought to build a state-of-the-art program in kidney cancer. His research program was built around 6 pillars: molecular genetics, signaling, drug screening, animal modeling, biomarkers, and clinical trials. After a few years, his lab reported important discoveries in each area. (i) Their research established the foundation for the first molecular genetic classification of sporadic clear cell renal cell carcinoma (ccRCC, the most common type), reported the first comprehensive genomic analysis of non-clear cell tumors, identified the first somatically-mutated gene that may predict for drug responsiveness, and defined a novel familial renal cancer syndrome. (ii) They characterized a feedback loop linking the two dominant signaling pathways in kidney cancer (the VHL/HIF and mTOR pathways), identified a novel mTOR effector, established that HIF regulates mitochondrial respiration in vivo, and validated HIF-2 as a target for ccRCC. (iii) They developed a broadly applicable chemical genetic screening platform to identify compounds synthetic lethal with genes mutated in RCC and completed a 200,000 small molecule screen identifying several promising leads. (iv) They generated the first genetically-engineered mouse models that reproduce the mutations of human ccRCC and showed for the first time that RCC tumorgrafts (PDX models) reproduce the genetics, biology, and drug responsiveness of RCC in patients. (v) Finally, they explored the therapeutic potential of glycolysis inhibition in a patient with an unusual form of RCC resulting from a germline mutation in the two-hit tumor suppressor gene, fumarate hydratase, and opened several investigator-initiated clinical trials to probe into mechanisms of resistance to mTOR and HIF inhibitors. He was recognized for these discoveries with awards from the V Foundation for Cancer Research, Doris Duke, March of Dimes and the American Cancer Society.

In 2013, Dr. Brugarolas became the founding Director of the Kidney Cancer Program (KCP), at UT Southwestern. The KCP, which involves over 20 physicians and more than 60 affiliated laboratories, is possibly the largest and most innovative such program in the country. With survival rates for stage IV patients which are more than double national benchmarks and improved across stages, the program provides superb care and an exceptional patient experience that is magnified by a passionate patient council. Radiation expertise is unmatched, with the development of novel approaches and likely the broadest panel of clinical trials.

Dr. Brugarolas was inducted to the American Society for Clinical Investigation, and is the Principal Investigator of one of two National Cancer Institute-designated Specialized Programs of Research Excellence (SPORE) in kidney cancer in the U.S. This program builds on state-of-the-art platforms in pathology, imaging, and data analytics. Research projects are supported by the largest live kidney cancer biobank, and the most comprehensive animal models of kidney cancer, both patient-derived xenografts, where more than 1,000 tumors have been implanted in mice, as well as genetically engineered mice. Imaging advances have led to improved predictive algorithms and sensitive MRI protocols for the detection of bone metastases. Team scientists are building a web-based self-updating registry drawing information directly from the medical record with automatic queries linked to genomics (available for more than 500 samples), research samples, and research data. The SPORE projects build on the development of a first-in-class drug targeting the most important driver of kidney cancer, the HIF-2 protein, and the development of the first modern, genetically-based, classification of adult and childhood kidney cancers. In addition, by deploying a long-standing tradition of excellence in the study of metabolism and the study of how nutrients are processed, investigators seek to determine the malignant potential of small renal masses. The SPORE and the KCP provide financial support to over 50 investigators at UTSW.

Dr. Brugarolas, a professor of Internal Medicine (Hematology/Oncology), Cancer Biology, Genetics, Development and Disease, is the Sherry Wigley Crow Endowed Chair in Cancer Research. He is a member of the Renal Task Force of the Genitourinary Steering Committee of the National Cancer Institute. He has served on advisory boards, panels and committees at NCI-designated cancer centers, the American Cancer Society, and the National Cancer Institute.

Education:

1987-1993 M.D. Medicine, University of Navarra Medical School, Spain
1993-1998 Ph.D. Biology, Mentor: Tyler Jacks, Ph.D., Massachusetts Institute of Technology, USA
1998-1999 Intern, Internal Medicine, Duke University Medical Center
1999-2001 Resident, Internal Medicine, Duke University Medical Center
2001-2003 Fellow, Medical Oncology, Dana-Farber Cancer Institute, Brigham and Women’s Hospital, Massachusetts General Hospital
2002-2003 Postdoctoral, Fellow, Mentor: William G. Kaelin, Jr., M.D., Dana-Farber Cancer Institute

Honors and Awards:

Books:

mTORC1 Signaling and Hypoxia. In mTOR Pathway and mTOR Inhibitors in Cancer Therapy

Brugarolas, J (2010). Humana Press

Research Translation and Personalized Medicine. In Renal Cell Carcinoma

Brugarolas, J. (2012). Springer US

Featured Publications:

An Empirical Approach Leveraging Tumorgrafts to Dissect the Tumor Microenvironment in Renal Cell Carcinoma Identifies Missing Link to Prognostic Inflammatory Factors.Wang T, Lu R, Kapur P, Jaiswal BS, Hannan R, Zhang Z, Pedrosa I, Luke JJ, Zhang H, Goldstein LD, Yousuf Q, Gu YF, McKenzie T, Joyce A, Kim MS, Wang X, Luo D, Onabolu O, Stevens C, Xie Z, Chen M, Filatenkov A, Torrealba J, Luo X, Guo W, He J, Stawiski E, Modrusan Z, Durinck S, Seshagiri S, Brugarolas J Cancer Discov 2018 JunSafety and Efficacy of Stereotactic Ablative Radiation Therapy for Renal Cell Carcinoma Extracranial Metastases.Wang CJ, Christie A, Lin MH, Jung M, Weix D, Huelsmann L, Kuhn K, Meyer J, Desai N, Kim DWN, Pedrosa I, Margulis V, Cadeddu J, Sagalowsky A, Gahan J, Laine A, Xie XJ, Choy H, Brugarolas J, Timmerman R, Hannan R Int. J. Radiat. Oncol. Biol. Phys. 2017 May 98 1 91-100Modeling Renal Cell Carcinoma in Mice: Bap1 and Pbrm1 Inactivation Drive Tumor Grade.Gu YF, Cohn S, Christie A, McKenzie T, Wolff NC, Do QN, Madhuranthakam A, Pedrosa I, Wang T, Dey A, Busslinger M, Xie XJ, Hammer RE, McKay RM, Kapur P, Brugarolas J Cancer Discov 2017 MayTargeting Renal Cell Carcinoma with a HIF-2 antagonist.Chen W, Hill H, Christie A, Kim MS, Holloman E, Pavia-Jimenez A, Homayoun F, Ma Y, Patel N, Yell P, Hao G, Yousuf Q, Joyce A, Pedrosa I, Geiger H, Zhang H, Chang J, Gardner KH, Bruick RK, Reeves C, Hwang TH, Courtney K, Frenkel E, Sun X, Zojwalla N, Wong T, Rizzi JP, Wallace EM, Josey JA, Xie Y, Xie XJ, Kapur P, McKay RM, Brugarolas J Nature 2016 SepMulticenter Validation of Enhancer of Zeste Homolog 2 Expression as an Independent Prognostic Marker in Localized Clear Cell Renal Cell Carcinoma.Ho TH, Kapur P, Eckel-Passow JE, Christie A, Joseph RW, Serie DJ, Cheville JC, Thompson RH, Homayoun F, Panwar V, Brugarolas J, Parker AS J. Clin. Oncol. 2017 Oct JCO2017733238Addressing metabolic heterogeneity in clear cell renal cell carcinoma with quantitative Dixon MRI.Zhang Y, Udayakumar D, Cai L, Hu Z, Kapur P, Kho EY, Pavía-Jiménez A, Fulkerson M, de Leon AD, Yuan Q, Dimitrov IE, Yokoo T, Ye J, Mitsche MA, Kim H, McDonald JG, Xi Y, Madhuranthakam AJ, Dwivedi DK, Lenkinski RE, Cadeddu JA, Margulis V, Brugarolas J, DeBerardinis RJ, Pedrosa I JCI Insight 2017 Aug 2 15Discontinuing VEGF-targeted Therapy for Progression Versus Toxicity Affects Outcomes of Second-line Therapies in Metastatic Renal Cell Carcinoma.De Velasco G, Xie W, Donskov F, Albiges L, Beuselinck B, Srinivas S, Agarwal N, Lee JL, Brugarolas J, Wood LA, Rha SY, Kollmannsberger C, North S, Kanesvaran R, Rini BI, Broom R, Yamamoto H, Kaymakcalan MD, Heng DYC, Choueiri TK Clin Genitourin Cancer 2017 Jun 15 3 403-410.e2Hypoxia-inducible factor-1a activates insig-2 transcription for degradation of HMG CoA reductase in the liver.Hwang S, Nguyen AD, Jo Y, Engelking LJ, Brugarolas J, DeBose-Boyd RA J. Biol. Chem. 2017 AprBAP1 and PBRM1 in metastatic clear cell renal cell carcinoma: tumor heterogeneity and concordance with paired primary tumor.Eckel-Passow JE, Serie DJ, Cheville JC, Ho TH, Kapur P, Brugarolas J, Thompson RH, Leibovich BC, Kwon ED, Joseph RW, Parker AS BMC Urol 2017 Mar 17 1 19Renal Cell Carcinoma With Pulmonary Metastasis and Metachronous Non-Small Cell Lung Cancer.Bowman IA, Pedrosa I, Kapur P, Brugarolas J Clin Genitourin Cancer 2017 Feb