Select Recent Publications
Tran TA, Leong HS, Pavia-Jimenez A, Fedyshyn S, Yang J, Kucejova B, Sivanand S, Spence P, Xie X-J, Peña-Llopis S, Power N, Brugarolas J. FGFR-Dependent and –Independent Paracrine Signaling by Sunitinib-Resistant RCC Mol Cell Biol 6(13):1836-55 (2016)
This study reports the development of an innovative system to dissect determinants of sensitivity and resistance to inhibitors of angiogenesis. We show that primary cell cultures from patient tumors can activate mitogenic signaling in endothelial cells and that this process can be interrupted by sunitinib. Interestingly, tumor cells derived from sunitinib-resistant tumors activated endothelial cells despite sunitinib. This study provides an experimental system to dissect resistance to angiogenesis inhibitors and begins to unravel the complexity.
Joseph RW, Kapur P, Serie DJ, Parasramka M, Ho TH, Cheville JC, Frenkel E, Parker AS, Brugarolas J. Clear cell renal cell carcinoma subtypes identified by BAP1 and PBRM1 expression J Urol 195(1):180-7 (2016)
A study in collaboration with investigators from Mayo clinic that shows that the 4 molecular subtypes of ccRCC we defined are associated with different outcomes in patients.
Wolff NC, Pavia-Jimenez A, Tcheuyap VT, Alexander S, Vishwanath M, Christie A, Xie XJ, Williams NS, Kapur P, Posner B, McKay RM, Brugarolas J. High-throughput simultaneous screen and counterscreen identifies homoharringtonine as synthetic lethal with von Hippel-Lindau loss in renal cell carcinoma Oncotarget 6(19):16951-62 (2015)
A unique synthetic lethal screening strategy identified a drug with activity against VHL-deficient ccRCC that could be repurposed for renal cell carcinoma.
Hannan R, Margulis V, Chun SG, Cannon N, Kim DW, Abdulrahman RE, Sagalowsky A, Pedrosa I, Choy H, Brugarolas J, Timmerman RD Stereotactic radiation therapy of renal cancer inferior vena cava tumor thrombus Cancer Biol Ther 16(5):657-61 (2015)
First report of successful deployment of stereotactic radiation therapy for the management of renal cancer invasion into the vena cava.
Durinck S, Stawiski EW, Pavia-Jimenez 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, Pena-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* Spectrum of diverse genomic alterations define non-clear cell renal carcinoma subtypes Nat Genet 47(1):13-21 (2015) *, shared correspondence
First integrated genomic analysis of non clear-cell renal cell cancers.
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 Bap1 is essential for kidney function and cooperates with Vhl in renal tumorigenesis Proc Natl Acad Sci U S A 111(46):16538-43 (2014)
This manuscript reports the first mouse model of clear-cell renal cell carcinoma reproducing the mutations of human tumors.
Joseph RW, Kapur P, Serie DJ, Eckel-Passow JE, Parasramka M, Ho T, Cheville JC, Frenkel E, Rakheja D, Brugarolas J, Parker A Loss of BAP1 protein expression is an independent marker of poor prognosis in patients with low-risk clear cell renal cell carcinoma Cancer 120(7):1059-67 (2014)
By studying a cohort of 1,400 patients in collaboration with investigators at Mayo clinic, we established that BAP1 is an independent prognostic factor in clear-cell renal cell carcinoma.
Brugarolas J Molecular genetics of clear-cell renal cell carcinoma J Clin Oncol 32(18):1968-76 (2014)
Review summarizing recent discoveries about the molecular genetics of clear-cell renal cell carinoma.
Tran TA, Kinch L, Pena-Llopis S, Kockel L, Grishin N, Jiang H, Brugarolas J Platelet-Derived Growth Factor/Vascular Endothelial Growth Factor Receptor Inactivation by Sunitinib Results in Tsc1/Tsc2-Dependent Inhibition of TORC1 Mol Cell Biol 33:3762-79 (2013)
By using insect cells in which a single ancestral VEGF and PDGF receptor exists, this study identifies a novel adaptor protein, provides insight into core signal transduction pathways, and sheds light into the mechanism of tumor suppression by sunitinib.
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. Novel Germline BAP1 Variant Cosegregates with Familial Clear Cell Renal Cell Carcinoma Mol Cancer Res 11:1061-71 (2013)
This study reports the discovery of a novel familial kidney cancer syndrome resulting from mutations in the BAP1 gene.
Pena-Llopis S, Christie A, Xie XJ, Brugarolas J. Cooperation and Antagonism among Cancer Genes: The Renal Cancer Paradigm Cancer Res 73:4173-9 (2013)
A meta-analysis revealing positive and negative interactions among tumor suppressor genes on chromosome 3p.
Brugarolas J. PBRM1 and BAP1 as Novel Targets for Renal Cell Carcinoma Cancer J 19:324-32 (2013)
Discoveries about the BAP1 and PBRM1 genes will pave the way for the next generation of therapies.
Straka C, Kim DW, Timmerman RD, Pedrosa I, Jacobs C, Brugarolas J. Ablation of a Site of Progression With Stereotactic Body Radiation Therapy Extends Sunitinib Treatment From 14 to 22 Months J Clin Oncol 31(23):e401-3 (2013)
By subduing oligometastatic resistance, stereotactic radiation may prolong responsiveness to systemic therapies in patients.
Kapur P, Pena-Llopis S, Christie A, Zhrebker L, Pavia-Jimenez A, Rathmell WK, Xie XJ, Brugarolas J. Effects on survival of BAP1 and PBRM1 mutations in sporadic clear-cell renal-cell carcinoma: a retrospective analysis with independent validation Lancet Oncol 14:159-167 (2013)
By showing that BAP1- and PBRM1-mutated tumors are associated with markedly different outcomes in patients, this study sets the foundation for the first molecular genetic classification of sporadic ccRCC.
Jacobs C, Kim DW, Straka C, Timmerman RD, Brugarolas J. Prolonged survival of a patient with papillary renal cell carcinoma and brain metastases using pazopanib J Clin Oncol 31(7):e114-7 (2013)
The administration of pazopanib at unconventionally high doses forestalled metastatic growth in the brain and extended life expectancy.
Hasan M, Koch J, Rakheja D, Pattnaik AK, Brugarolas J, Dozmorov I, Levine B, Wakeland EK, Lee-Kirsch MA, Yan N. Trex1 regulates lysosomal biogenesis and interferon-independent activation of antiviral genes Nat Immunol 14:61-71 (2013)
A report showing that the master lysosomal regulator TFEB is also regulated by the Trex1 endonuclease.
Sudarshan S, Karam JA, Brugarolas J, Thompson RH, Uzzo R, Rini B, Margulis V, Patard JJ, Escudier B, Linehan WM. Metabolism of kidney cancer: from the lab to clinical practice Eur Urol 63:244-51 (2013)
Pena-Llopis S, Vega-Rubin-de-Celis S, Liao A, Leng N, Pavia-Jimenez 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 SWW, Grishin N, Laurent M, Xie X-J, Haudenschild CD, Ross MT, Bentley DR, Kapur P, Brugarolas J. BAP1 loss defines a new class of renal cell carcinoma Nat Genet 44(7):751-759 (2012)
A study reporting that BAP1 is inactivated in 15% of renal cancers and that BAP1 and PBRM1 mutations in tumors tend to be mutually exclusive.
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 X-J, Kapur P, Williams NS, Brugarolas J. A Validated Tumorgraft Model Reveals Activity of Dovitinib Against Renal Cell Carcinoma Sci Transl Med 4, 137ra75 (2012)
Animal models of kidney cancer are lacking. This report shows that human tumors implanted in mice (tumorgrafts) behave like the tumors in patients. Tumorgrafts reproduce the histology, gene expression, and mutations of renal cancer in patients. Furthermore, the treatment responsiveness of renal cancer in patients is preserved in mice. Using tumorgrafts as a model we show that an investigational agent, dovitinib, is superior to two drugs in use in the clinic.
Jonasch E, Futreal PA, Davis IJ, Bailey ST, Kim WY, Brugarolas J, Giaccia AJ, Kurban G, Pause A, Frydman J, Zurita AJ, Rini BI, Sharma P, Atkins MB, Walker CL, Rathmell WK. State of the Science: An Update on Renal Cell Carcinoma Mol Can Res 10:859-880 (2012)
Brugarolas J: Research Translation and Personalized Medicine, in Figlin RA, Rathmell WK, Rini BI (eds): Renal Cell Carcinoma: Translational Biology, Personalized Medicine, and Novel Therapeutic Targets, Springer US, 2012, pp 161-191
Pena-Llopis S, Brugarolas J. TFEB, a novel mTORC1 effector implicated in lysosome biogenesis, endocytosis and autophagy Cell Cycle 10:3987-8 (2011)
Kinch L, Grishin NV, Brugarolas J. Succination of Keap1 and Activation of Nrf2-Dependent Antioxidant Pathways in FH-Deficient Papillary Renal Cell Carcinoma Type 2 Cancer Cell 20:418-420 (2011)
A preview with a model for how succination of Keap1 in FH-deficient tumors may affect its function.
Mata MA, Satterly N, Versteeg GA, Frantz D, Wei S, Williams N, Schmolke M, Peña-Llopis S, Brugarolas J, Forst CV, White MA, Garcia-Sastre A, Roth MG, Fontoura BM. Chemical inhibition of RNA viruses reveals REDD1 as a host defense factor Nat Chem Biol 7: 712-719 (2011)
A chemical-genetic screen involving a library of 200,000 compounds identifies REDD1, a protein we previously showed is a critical regulator of mTORC1, as a host defense factor.
Peña-Llopis S, Vega-Rubin-de-Celis S, Schwartz JC, Wolff NC, Tran TAT, Zou L, Xie X-J, Corey DR, Brugarolas J. Regulation of TFEB and V-ATPases by mTORC1 EMBO J 30(16): 3242-3258 (2011)
A compelling experimental paradigm coupled with sophisticated bioinformatic and statistical analyses led us to discover that the transcription factor EB (TFEB), a master regulator of lysosomal biogenesis which is translocated in renal tumors, is regulated by mTORC1. The data provide a rationale for evaluating mTORC1 inhibitors in patients with translocation RCC.
Kucejova B, Peña-Llopis S, Yamasaki T, Sivanand S, Tran TAT, Alexander S, Wolff NC, Lotan Y, Xie X-J, Kabbani W, Kapur P, Brugarolas J. Interplay between pVHL and mTORC1 pathways in clear-cell renal cell carcinoma Mol Can Res 9: 1255-1265 (2011)
The two most important pathways in ccRCC are those governed by pVHL and mTORC1. This paper describes a negative feedback loop linking these two pathways that involves REDD1. In addition, the report implicates REDD1 and TSC1 as tumor suppressor genes in sporadic ccRCC.
Yamasaki T, Tran TA, Oz OK, Raj GV, Schwarz RE, Deberardinis RJ, Zhang X, Brugarolas J. Exploring a glycolytic inhibitor for the treatment of an FH-deficient type-2 papillary RCC Nat Rev Urol 8: 165-171 (2011)
A tour de force to identify and exploit vulnerabilities in a tumor of a 24-year-old woman presenting with an unusual form of renal cancer. The first account of the use of a glycolytic inhibitor against a tumor deficient for a Krebs cycle enzyme and a report that is used by medical school instructors to teach students about bench-to-bedside research translation.
Wolff NC, Vega-Rubin-de-Celis S, Xie XJ, Castrillon DH, Kabbani W, Brugarolas J. Cell-Type-Dependent Regulation of mTORC1 by REDD1 and the Tumor Suppressors TSC1/TSC2 and LKB1 in Response to Hypoxia Mol Cell Biol 31: 1870-1884 (2011)
Using a variety of genetically engineered mouse strains including a novel Redd1-deficient mouse strain, the study reports the discovery that hypoxia signals are transduced to mTORC1 through different pathways in a tissue specific manner. The manuscript is also a cautionary tale about the undiscerning use of reporter mice.
Kucejova B, Sunny NE, Nguyen AD, Hallac R, Fu X, Peña-Llopis S, Mason RP, Deberardinis RJ, Xie XJ, Debose-Boyd R, Kodibagkar VD, Burgess SC, Brugarolas J. Uncoupling hypoxia signaling from oxygen sensing in the liver results in hypoketotic hypoglycemic death Oncogene 30: 2147-2160 (2011)
Following evidence that HIF regulates mitochondrial respiration in vitro, this report shows for the first time in vivo, that constitutive HIF activation in hepatocytes in mice is sufficient to suppress mitochondrial respiration resulting in a block in glucose and ketone production and causing the death of mice within days.
Wolff N, Kabbani W, Bradley T, Raj G, Watumull L, Brugarolas J. Sirolimus and temsirolimus for epithelioid angiomyolipoma J Clin Oncol 28: e65-68 (2010)
An account of how an understanding of tumor genetics and the availability of molecularly targeted drugs saved the life of a 24-year-old man presenting with an unusual kidney tumor and unstoppable bleeding.
Vega-Rubin-de-Celis S, Abdallah Z, Kinch L, Grishin NV, Brugarolas J*, Zhang X*. Structural analysis and functional implications of the negative mTORC1 regulator REDD1 Biochemistry 49: 2491-2501 (2010) *Shared correspondence
A report of the crystal structure of REDD1 that challenges the conventional view of REDD1 action.
Zhou J, Brugarolas J, Parada LF. Loss of Tsc1, but not Pten, in renal tubular cells causes polycystic kidney disease by activating mTORC1 Hum Mol Genet 18: 4428-4441 (2009)
An evaluation of the role of PTEN and Tsc1 in renal cyst development.
Brugarolas J, Lotan Y, Watumull L, Kabbani W. Sirolimus in metatastic renal cell carcinoma J Clin Oncol 26: 3457-3460 (2008)
The first account on the use of sirolimus (rapamycin) for the treatment of renal cancer. A report of far-reaching consequences for individuals and societies that cannot afford temsirolimus (and everolimus).
Brugarolas J. Renal-cell carcinoma - molecular pathways and therapies N Engl J Med 356: 185-187 (2007)
An editorial accompanying two phase III clinical trials marking the advent of molecularly targeted approaches to renal cancer treatment.
Brugarolas J, Lei K, Hurley RL, Manning BD, Reiling JH, Hafen E, Witters LA, Ellisen LW, Kaelin WG, Jr. Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex Genes Dev 18: 2893-2904 (2004)
This manuscript reports the discovery that hypoxia signals are transduced to mTORC1 through the TSC1/TSC2 complex and REDD1, a protein of previously unknown function.
Majumder PK, Febbo PG, Bikoff R, Berger R, Xue Q, McMahon LM, Manola J, Brugarolas J, McDonnell TJ, Golub TR, Loda M, Lane HA, Sellers WR. mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways Nat Med 10: 594-601 (2004)
Brugarolas J, Kaelin WG, Jr. Dysregulation of HIF and VEGF is a unifying feature of the familial hamartoma syndromes Cancer Cell 6: 7-10 (2004)
Brugarolas JB, Vazquez F, Reddy A, Sellers WR, Kaelin WG, Jr. TSC2 regulates VEGF through mTOR-dependent and -independent pathways Cancer Cell 4: 147-158 (2003)
The exploration of similarities between two otherwise divergent syndromes, VHL and TSC, led to the discovery that a functional link existed between HIF and mTORC1 and established a rationale for the evaluation of mTORC1 inhibitors against RCC.
Brugarolas J, Moberg K, Boyd SD, Taya Y, Jacks T, Lees JA. Inhibition of cyclin-dependent kinase 2 by p21 is necessary for retinoblastoma protein-mediated G1 arrest after gamma-irradiation Proc Natl Acad Sci U S A 96: 1002-1007 (1999)
Brugarolas J, Bronson RT, Jacks T. p21 is a critical CDK2 regulator essential for proliferation control in Rb-deficient cells J Cell Biol 141: 503-514 (1998)
Brugarolas J, Jacks T. Double indemnity: p53, BRCA and cancer Nat Med 3: 721-722 (1997)
Brugarolas J, Chandrasekaran C, Gordon JI, Beach D, Jacks T, Hannon GJ. Radiation-induced cell cycle arrest compromised by p21 deficiency Nature 377: 552-557 (1995)
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