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 the Chair of the Programmatic Panel of the Congressionally Directed Medical Research Program in Kidney Cancer, and a member of the Renal Task Force of the Genitourinary Steering Committee of the National Cancer Institute. He has served in advisory boards, panels and committees at NCI-designated cancer centers, the American Cancer Society, and the National Cancer Institute.
- Medical School
- Universidad de Navarra (1993)
- Graduate School
- Massachusetts Institute of Technology (1998)
- Duke University - Medicine Internship (1999), Internal Medicine
- Duke University - Medicine Residency (2001), Internal Medicine
- Massachusetts General Hospital, Brigham & Women's Hospital and Dana-Farber Cancer Institute, Harvard Medical School (2003), Medical Oncology
- Kidney cancer, renal cell carcinoma (RCC)
- Molecular genetics and genomics of cancer
- Molecularly targeted therapies
- Research translation
- Signaling mechanisms and mechanisms of resistance to targeted agents
- Predictive Biomarkers for Molecularly Targeted Therapies in Renal Cell Carcinoma.
- Brugarolas J J Natl Compr Canc Netw 2016 Jul 14 7 925-7
- Hepatic mTORC1 Opposes Impaired Insulin Action to Control Mitochondrial Metabolism in Obesity.
- Kucejova B, Duarte J, Satapati S, Fu X, Ilkayeva O, Newgard CB, Brugarolas J, Burgess SC Cell Rep 2016 Jun
- Clear cell renal cell carcinoma subtypes identified by BAP1 and PBRM1 expression.
- Joseph RW, Kapur P, Serie DJ, Parasramka M, Ho TH, Cheville JC, Frenkel E, Parker AS, Brugarolas J J. Urol. 2015 Aug
- High-throughput simultaneous screen and counterscreen identifies homoharringtonine as synthetic lethal with von Hippel-Lindau loss in renal cell carcinoma.
- Wolff NC, Pavía-Jiménez A, Tcheuyap VT, Alexander S, Vishwanath M, Christie A, Xie XJ, Williams NS, Kapur P, Posner B, McKay RM, Brugarolas J Oncotarget 2015 Jul 6 19 16951-62
- Stereotactic Radiation Therapy of Renal Cancer Inferior Vena Cava Tumor Thrombus.
- Hannan R, Margulis V, Chun SG, Cannon N, Kim DW, Abdulrahman RE, Sagalowsky A, Pedrosa I, Choy H, Brugarolas JB, Timmerman RD Cancer Biol. Ther. 2015 Mar 0
- Spectrum of diverse genomic alterations define non-clear cell renal carcinoma subtypes.
- Durinck S, Stawiski EW, Pavía-Jiménez A, Modrusan Z, Kapur P, Jaiswal BS, Zhang N, Toffessi-Tcheuyap V, Nguyen TT, Pahuja KB, Chen YJ, Saleem S, Chaudhuri S, Heldens S, Jackson M, Peña-Llopis S, Guillory J, Toy K, Ha C, Harris CJ, Holloman E, Hill HM, Stinson J, Rivers CS, Janakiraman V, Wang W, Kinch LN, Grishin NV, Haverty PM, Chow B, Gehring JS, Reeder J, Pau G, Wu TD, Margulis V, Lotan Y, Sagalowsky A, Pedrosa I, de Sauvage FJ, Brugarolas J, Seshagiri S Nat. Genet. 2014 Nov
- Bap1 is essential for kidney function and cooperates with Vhl in renal tumorigenesis.
- Wang SS, Gu YF, Wolff N, Stefanius K, Christie A, Dey A, Hammer RE, Xie XJ, Rakheja D, Pedrosa I, Carroll T, McKay RM, Kapur P, Brugarolas J Proc. Natl. Acad. Sci. U.S.A. 2014 Nov 111 46 16538-43
- Molecular genetics of clear-cell renal cell carcinoma.
- Brugarolas J J. Clin. Oncol. 2014 Jun 32 18 1968-76
- PDGF/VEGF Receptor Inactivation by Sunitinib Results in Tsc1/Tsc2-Dependent Inhibition of TORC1.
- Tran TA, Kinch L, Peña-Llopis S, Kockel L, Grishin N, Jiang H, Brugarolas J Mol. Cell. Biol. 2013 Jul
- Cooperation and Antagonism among Cancer Genes: The Renal Cancer Paradigm.
- Peña-Llopis S, Christie A, Xie XJ, Brugarolas J Cancer Res. 2013 Jul 73 14 4173-9
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
Honors & Awards
- Elected Member
American Society for Clinical Investigation (2013)
- Individual Investigator Research Award
Cancer Prevention and Research Institute of Texas (2010)
- Research Scholar
American Cancer Society (2008)
- Basil O'Connor Research Award
March of Dimes (2007)
- Clinical Scientist Development Award
Doris Duke Charitable Foundation (2007)
- V Scholar Award
The V Foundation for Cancer Research (2007)
- Virginia Murchison Linthicum Endowed Scholar in Medical Research
UT Southwestern Medical School (2006)
- Young Investigator Award
Department of Medicine, Brigham and Womens Hospital, Harvard Medical School (2004)
- Claudia Adams Barr Award for Innovative Basic Cancer Research
Dana-Farber Cancer Institute (2003)
- American Society for Clinical Investigation (2013)
- American Association for Cancer Research (2006)
- American Society for Advancement of Science (2006)
- American Society of Clinical Oncology (2006)
- MIT chapter of Sigma Xi Scientific Research Society of North America (1998)