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
- Germline BAP1 mutation predisposes to familial clear-cell renal cell carcinoma.
- Farley MN, Schmidt LS, Mester JL, Pena-Llopis S, Pavia-Jimenez A, Christie A, Vocke CD, Ricketts CJ, Peterson J, Middelton L, Kinch L, Grishin N, Merino MJ, Metwalli AR, Xing C, Xie XJ, Dahia PL, Eng C, Linehan WM, Brugarolas J Mol. Cancer Res. 2013 May
- Effects on survival of BAP1 and PBRM1 mutations in sporadic clear-cell renal-cell carcinoma: a retrospective analysis with independent validation.
- Kapur P, Peña-Llopis S, Christie A, Zhrebker L, Pavía-Jiménez A, Rathmell WK, Xie XJ, Brugarolas J Lancet Oncol. 2013 Feb 14 2 159-67
- BAP1 loss defines a new class of renal cell carcinoma.
- Peña-Llopis S, Vega-Rubín-de-Celis S, Liao A, Leng N, Pavía-Jiménez A, Wang S, Yamasaki T, Zhrebker L, Sivanand S, Spence P, Kinch L, Hambuch T, Jain S, Lotan Y, Margulis V, Sagalowsky AI, Summerour PB, Kabbani W, Wong SW, Grishin N, Laurent M, Xie XJ, Haudenschild CD, Ross MT, Bentley DR, Kapur P, Brugarolas J Nat. Genet. 2012 Jul 44 7 751-9
- A validated tumorgraft model reveals activity of dovitinib against renal cell carcinoma.
- Sivanand S, Peña-Llopis S, Zhao H, Kucejova B, Spence P, Pavia-Jimenez A, Yamasaki T, McBride DJ, Gillen J, Wolff NC, Morlock L, Lotan Y, Raj GV, Sagalowsky A, Margulis V, Cadeddu JA, Ross MT, Bentley DR, Kabbani W, Xie XJ, Kapur P, Williams NS, Brugarolas J Sci Transl Med 2012 Jun 4 137 137ra75
- Succination of Keap1 and activation of Nrf2-dependent antioxidant pathways in FH-deficient papillary renal cell carcinoma type 2.
- Kinch L, Grishin NV, Brugarolas J Cancer Cell 2011 Oct 20 4 418-20
- Interplay between pVHL and mTORC1 pathways in clear-cell renal cell carcinoma.
- Kucejova B, Peña-Llopis S, Yamasaki T, Sivanand S, Tran TA, Alexander S, Wolff NC, Lotan Y, Xie XJ, Kabbani W, Kapur P, Brugarolas J Mol. Cancer Res. 2011 Sep 9 9 1255-65
- Regulation of TFEB and V-ATPases by mTORC1.
- Peña-Llopis S, Vega-Rubin-de-Celis S, Schwartz JC, Wolff NC, Tran TA, Zou L, Xie XJ, Corey DR, Brugarolas J EMBO J. 2011 Aug 30 16 3242-58
- Exploring a glycolytic inhibitor for the treatment of an FH-deficient type-2 papillary RCC.
- Yamasaki T, Tran TA, Oz OK, Raj GV, Schwarz RE, Deberardinis RJ, Zhang X, Brugarolas J Nat Rev Urol 2011 Mar 8 3 165-71
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)