Select Recent Publications
Ma Y, Joyce A, Brandenburg O, Saatchi F, Stevens C, Toffessi Tcheuyap V, Christie A, Do QN, Fatunde O, Macchiaroli A, Wong SC, Woolford L, Yousuf Q, Miyata J, Carrillo D, Onabolu O, McKenzie T, Mishra A, Hardy T, He W, Li D, Ivanishev A, Zhang Q, Pedrosa I, Kapur P, Schluep T, Kanner SB, Hamilton J, Brugarolas J. HIF2 Inactivation and Tumor Suppression with a Tumor-Directed RNA-Silencing Drug in Mice and Humans. Clin Can Res. (2022)
The first of its kind, a proof-of-principle study showing that a systemically administered tumor-directed HIF2α small-interfering RNA can downregulate HIF2α protein in human clear cell renal cell carcinoma leading to anti-tumor activity.
Mulgaonkar A, Elias R, Woolford L, Guan B, Nham K, Kapur P, Christie A, Tcheuyap VT, Singla N, Bowman IA, Stevens C, Hao G, Brugarolas J, Sun X. ImmunoPET Imaging with 89Zr-Labeled Atezolizumab Enables In Vivo Evaluation of PD-L1 in Tumorgraft Models of Renal Cell Carcinoma. Clin Can Res. (2022)
Supporting a clinical trial (NCT04006522), a double-blind analysis of ImmunoPET using a Zr-labeled anti-PD-L1 antibody detects PD-L1 expressing human RCC in mice.
Hannan R, Christensen M, Christie A, Garant A, Pedrosa I, Robles L, Mannala S, Wang C, Hammers H, Arafat W, Courtney K, Bowman IA, Sher D, Ahn C, Cole S, Choy H, Timmerman R, Brugarolas J. Stereotactic Ablative Radiation for Systemic Therapy-naïve Oligometastatic Kidney Cancer. Euro Urol Onc. (2022)
This prospective phase II clinical trial found that focused SAbR to oligometastases effectively controls tumor progression while preserving patients’ quality of life.
Acosta PH, Panwar V, Jarmale V, Christie A, Jasti J, Margulis V, Rakheja D, Cheville J, Leibovich BC, Parker A, Brugarolas J, Kapur P, Rajaram S. Intratumoral Resolution of Driver Gene Mutation Heterogeneity in Renal Cancer Using Deep Learning. Eur Uro Onc. (2022)
Best-in-class results support deep learning analysis of histopathologic images of renal cell carcinomas. As it evolves, machine learning may serve as a low-cost method to characterize mutations and intratumoral heterogeneity in kidney tumors.
Kapur P, Zhong H, Araj E, Christie A, Cai Q, Kim D, Miyata J, Tcheuyap VT, Brandenburg O, Carrillo D, Pedrosa I, Brugarolas J, Cadeddu JA. Predicting Oncologic Outcomes in Small Renal Tumors. Eur Uro Onc. (2022)
Analysis of clinicopathologic factors of surgically resected small renal masses found that mutations in BAP1 may be a useful prognostic feature to predict aggressiveness and potential of metastasis.
Reig Torras O, Mishra A, Christie A, McKenzie T, Onabolu O, Singla N, Plimack ER, Suárez C, Ornstein MC, Alpaugh RK, Elias R, Bowman IA, McKay RM, Przybycin C, Kapur P, Brugarolas J, Rini B. Molecular Genetic Determinants of Shorter Time on Active Surveillance in a Prospective Phase 2 Clinical Trial in Metastatic Renal Cell Carcinoma. Eur Uro. (2022)
A prospective phase II trial that found mutations in TP53 or SMARCA4 may be predictive indicators for patients with faster disease progression and for whom active surveillance might be a poor treatment option in metastatic renal cell carcinoma.
Hannan R, Christensen M, Hammers H, Christie A, Paulman B, Lin D, Garant A, Arafat W, Courtney K, Bowman I, Cole S, Sher D, Ahn C, Choy H, Timmerman R, Brugarolas J. Phase II Trial of Stereotactic Ablative Radiation for Oligoprogressive Metastatic Kidney Cancer. Eur Uro Onc. (2021)
One of two clinical trials globally to show the potential of SBRT for oligoprogressive kidney cancer.
Elias R, Tcheuyap VT, Kaushik AK, Singla N, Gao M, Reig Torras O, Christie A, Mulgaonkar A, Woolford L, Stevens C, Kettimuthu KP, Pavia-Jimenez A, Boroughs LK, Joyce A, Dakanali M, Notgrass H, Margulis V, Cadeddu JA, Pedrosa I, Williams NS, Sun X, DeBerardinis RJ, Öz OK, Zhong H, Seshagiri S, Modrusan Z, Cantarel BL, Kapur P, Brugarolas J. A renal cell carcinoma tumorgraft platform to advance precision medicine. Cell Rep. (2021)
One of the largest PDX platforms with the most sophisticated applications in precision diagnostics and therapeutics.
Kim K, Zhou Q, Christie A, Stevens C, Ma Y, Onabolu O, Chintalapati S, Mckenzie T, Tcheuyap VT, Woolford L, Zhang H, Singla N, Parida PK, Marquez-Palencia M, Pedrosa I, Margulis V, Sagalowsky A, Xie Z, Wang T, Durinck S, Modrusan Z, Seshagiri S, Kapur P, Brugarolas J, Malladi S. Determinants of renal cell carcinoma invasion and metastatic competence. Nat Comm. (2021)
Utilizing unique aspect of kidney cancer where the tumor grossly invades into the vasculature, study shows that invasion is not always driven by the most aggressive clone and involves transient activation of an abnormal cell fate program.
Kapur P, Gao M, Zhong H, Chintalapati S, Mitui M, Barnes SD, Zhou Q, Miyata J, Carrillo D, Malladi VS, Rakheja D, Pedrosa I, Xu L, Kinch L, Brugarolas J. Germline and sporadic mTOR pathway mutations in low-grade oncocytic tumor of the kidney. Mod Pathol. (2021)
Study identifies signature pathway that characterizes an emerging entity.
Brugarolas J, Rajaram S, Christie A, Kapur P. The Evolution of Angiogenic and Inflamed Tumors: The Renal Cancer Paradigm. Cancer Cell. (2020)
Editorial providing an evolutionary framework for understanding ccRCC progression.
Singla N, Xie Z, Zhang Z, Gao M, Yousuf Q, Onabolu O, McKenzie T, Tcheuyap VT, Ma Y, Choi J, McKay R, Christie A, Torras OR, Bowman IA, Margulis V, Pedrosa I, Przybycin C, Wang T, Kapur P, Rini B, Brugarolas J. Pancreatic tropism of metastatic renal cell carcinoma. JCI Insight (2020)
This manuscript shows for the first time in any type of cancer that the destination of metastasis can inform on the biology of the tumor and predict patient responsiveness to therapy.
Lu T, Wang S, Xu L, Zhou Q, Singla N, Gao J, Manna S, Pop L, Xie Z, Chen M, Luke JJ, Brugarolas J, Hannan R, Wang T. Tumor neoantigenicity assessment with CSiN score incorporates clonality and immunogenicity to predict immunotherapy outcomes. Sci Immunol. (2020)
By utilizing predictive algorithms and a Cauchy-Schwarz index of Neoantigens (CSiN) that incorporates both neoantigen clonality and immunogenicity, clinicians and researchers may improve immune checkpoint therapy responses and outcomes.
Cai Q, Christie A, Rajaram S, Zhou Q, Araj E, Chintalapati S, Singla N, Cadeddu J, Margulis V, Pedrosa I, Rakheja D, McKay RM, Brugarolas J, Kapur P. Ontological analyses reveal clinically-significant clear cell renal cell carcinoma subtypes with convergent evolutionary trajectories into an aggressive type. EBioMedicine. (2020)
This study reports that ccRCC, the most common type of kidney cancer, can be classified into 9 subtypes based on its architecture, and that these subtypes are associated with differential aggressiveness and response to therapy. By deploying novel methodologies, the manuscript also provides the first morphological evolutionary model of ccRCC.
Courtney KD, Ma Y, Diaz de Leon A, Christie A, Xie Z, Woolford L, Singla N, Joyce A, Hill H, Madhuranthakam AJ, Yuan Q, Xi Y, Zhang Y, Chang J, Fatunde O, Arriaga Y, Frankel AE, Kalva S, Zhang S, McKenzie T, Reig Torras O, Figlin RA, Rini BI, McKay RM, Kapur P, Wang T, Pedrosa I, Brugarolas J. HIF-2 Complex Dissociation, Target Inhibition, and Acquired Resistance with PT2385, a First-in-Class HIF-2 Inhibitor, in Patients with Clear Cell Renal Cell Carcinoma. Clin Can Res. (2020)
This publication identifies HIF-2 as the first dependency of ccRCC.
Zhang Y, Schoenhals J, Christie A, Mohamad O, Wang C, Bowman I, Singla N, Hammers H, Courtney K, Bagrodia A, Margulis V, Desai N, Garant A, Choy H, Timmerman R, Brugarolas J, Hannan R. Stereotactic Ablative Radiation Therapy (SAbR) Used to Defer Systemic Therapy in Oligometastatic Renal Cell Cancer. Int J Radiat Oncol Biol Phys. (2019)
This study shows that SAbR is an effective treatment modality for patients with oligometastatic RCC.
Vento J, Mulgaonkar A, Woolford L, Nham K, Christie A, Bagrodia A, de Leon AD, Hannan R, Bowman I, McKay RM, Kapur P, Hao G, Sun X, Brugarolas J. PD-L1 detection using 89Zr-atezolizumab immuno-PET in renal cell carcinoma tumorgrafts from a patient with favorable nivolumab response. J Immunother Cancer. (2019)
By labeling atezolizumab, a therapeutic anti-PD-L1 antibody, with a radiotracer, we developed an imaging biomarker to monitor PD-L1 expression in tumors.
Wardak Z, Christie A, Bowman A, Stojadinovic S, Nedzi L, Barnett S, Patel T, Mickey B, Whitworth T, Hannan R, Brugarolas J, Timmerman R. Stereotactic radiosurgery for multiple brain metastases from renal-cell carcinoma. Clin Genitourin Cancer. (2019)
Bowman IA, Bent A, Le T, Christie A, Wardak Z, Arriaga Y, Courtney K, Hammers H, Barnett S, Mickey B, Patel T, Whitworth T, Stojadinovic S, Hannan R, Nedzi L, Timmerman R, Brugarolas J. Improved survival outcomes for kidney cancer patients with brain metastases. Clin Genitourin Cancer. (2019)
The two companion papers above show that a multidisciplinary approach that includes stereotactic radiosurgery improves prognosis for RCC patients with brain metastases, increasing survival time from months to years.
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. An empirical approach leveraging tumorgrafts to dissect the tumor microenvironment in renal cell carcinoma identifies missing link to prognostic inflammatory factors. Cancer Discov. (2018)
This study dissects the renal cell carcinoma tumor microenvironment by leveraging tumorgrafts. The dissection and downstream analyses uncovered missing links between tumor cells, the tumor microenvironment, systemic manifestations of inflammation, and poor prognosis.
Gu YF, Cohn S, Christie A, McKenzie T, Wolff N, Do QN, Madhuranthakam AJ, Pedrosa I, Wang T, Dey A, Busslinger M, Xie XJ, Hammer RE, McKay RM, Kapur P, Brugarolas J. Modeling renal cell carcinoma in mice: Bap1 and Pbrm1 inactivation drive tumor grade. Cancer Discov. (2017)
This study reports the development of mouse models of the two most common types of kidney cancer, and show that the BAP1 and PBRM1 genes control kidney cancer aggressiveness.
Bowman IA, Pedrosa I, Kapur P, Brugarolas J. Renal cell carcinoma with pulmonary metastasis and metachronous non-small cell lung cancer. Clin Genitourin Cancer. (2017)
This study reports that primary lung cancer may be under-diagnosed in patients with metastatic kidney cancer.
Vega-Rubin-de-Celis S, Peña-Llopis S, Konda M, Brugarolas J. Multistep regulation of TFEB by MTORC1. Autophagy. (2017)
This study reports a novel mechanism of TFEB regulation by MTORC1 that is essential for lysosomal biogenesis.
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. Targeting Renal Cell Carcinoma with a HIF-2 antagonist. Nature. (2016)
This tour de force study validates HIF-2 as a target in ccRCC. It shows that ccRCC can be subdivided according to HIF-2, into HIF-2-dependent and -independent tumors. It identifies biomarkers of HIF-2 dependency and anticipates mechanisms of resistance.
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. (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. (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. (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. (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. (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. (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. (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. (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. (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. (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. (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. (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. (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. (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. (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. (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. (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. (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. (2012)
Study validating that mouse tumorgrafts behave like tumors in patients. Tumorgrafts reproduce the histology, gene expression, and mutations of renal cancer in patients, and the treatment responsiveness is preserved in mice. Using these validated tumorgrafts as a model, 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. (2012)
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. (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. (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. (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. (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. (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. (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. (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. (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. (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. (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. (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. (2007)
An editorial accompanying two phase III clinical trials marking the advent of molecularly targeted approaches to renal cancer treatment.
Other Publications
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. (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. (2004)
Brugarolas J, Kaelin WG, Jr. Dysregulation of HIF and VEGF is a unifying feature of the familial hamartoma syndromes. Cancer Cell. (2004)
Brugarolas JB, Vazquez F, Reddy A, Sellers WR, Kaelin WG, Jr. TSC2 regulates VEGF through mTOR-dependent and -independent pathways. Cancer Cell. (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. (1999)
Brugarolas J, Bronson RT, Jacks T. p21 is a critical CDK2 regulator essential for proliferation control in Rb-deficient cells. J Cell Biol. (1998)
Brugarolas J, Jacks T. Double indemnity: p53, BRCA and cancer. Nat Med. (1997)
Brugarolas J, Chandrasekaran C, Gordon JI, Beach D, Jacks T, Hannon GJ. Radiation-induced cell cycle arrest compromised by p21 deficiency. Nature. (1995)
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