Implicated TSC1 as a tumor suppressor in sporadic renal cancer and as potential predictor of tumor responsiveness to mTORC1 inhibitors (Kucejova et al., Mol Can Res, 2011).
Identified a novel tumor suppressor gene (BAP1) that is mutated in 15% of sporadic clear cell renal cancers (Pena-Llopis et al., Nat Genet, 2012).
Determined that mutations in BAP1 and PBRM1 are mutually exclusive and associated with different prognosis establishing thereby the foundation for the first molecular genetic classification of sporadic renal cancer (Pena-Llopis et al., Nat Genet, 2012 & Kapur et al., Lancet Oncology, 2013).
Discovered a new familial kidney cancer syndrome resulting from germline mutations in the BAP1 gene (Farley et al., Mol Can Res, 2013).
Unraveled positive and negative interactions among tumor suppressor genes on 3p (Pena-Llopis et al., Can Res, 2013).
Completed the first integrated genomic study of non-clear-cell tumors (Durinck et al., Nat Genet, 2015). provided insight into the determinants of sensitivity to sunitinib (Tran et al., Mol Cell Biol, 2013).
Established that REDD1 functions in a negative feedback loop linking the two dominant pathways in renal cancer (VHL/HIF and mTORC1) (Kucejova et al., Mol Can Res, 2011).
Provided atomic level insight on the REDD1 protein and its mechanism of action (Vega-Rubin de Celis et al., Biochem, 2010).
Determined that mTORC1 regulation by hypoxia is tissue-specific and operates through REDD1-dependent and -independent pathways (Wolff et al., Mol Cell Biol, 2011).
Established for the first time that Hif activation is sufficient to block mitochondrial respiration in vivo (Kucejova et al., Oncogene, 2011).
Discovered that the master regulator of the lysosome, the TFEB transcription factor, is regulated by mTORC1 (Pena-Llopis et al., EMBO J, 2011).
Identified a novel adaptor protein of the PDGF/VEGF receptor orthologue in flies and provided insight into the determinants of sensitivity to sunitinib (Tran et al., Mol Cell Biol, 2013).
Validated HIF-2 as a target in ccRCC and demonstrated that ccRCC can be subclassified based on their dependency on HIF-2 into HIF-2-dependent and -independent tumors (Chen et al., Nature, 2016).
Novel high-content screening strategy identifies homoharringtonine, a small molecule FDA-approved for CML, as a drug synthetic lethal with VHL loss in ccRCC (Wolff et al., Oncotarget, 2015).
Completed a screen of a chemical library containing 200,000 compounds and identified several lead compounds with selectivity against VHL-deficient kidney cancer cells.
Created the first animal model of renal cancer (Sivanand et al., Science Translational Medicine, 2012) recapitulating:
Developed a protocol for the utilization of renal cancer tumorgraft models for preclinical drug testing (Pavia-Jimenez et al., Nat Protoc, 2014).
Created the first genetically-engineered mouse model of ccRCC reproducing the genetics of the disease (Wang and Gu et al., PNAS, 2014).
Determined that BAP1 is an independent predictor of ccRCC progression (Joseph et al., Cancer, 2014).
Determined that ccRCC can be divided into 4 molecular subtypes with different outcomes in patients and developed tests that can be applied to the clinic. (Joseph et al., J Urol, 2016).
Developed an experimental system to dissect determinants of sensitivity and resistance to inhibitors of angiogenesis using patient tumors co-cultured with endothelial or other cells (Tran et al., MCB 2016).
Submitted patent application (U.S. Provisional Patent Application No. 62/221,527) for a biomarker of HIF-2 dependency in ccRCC.
Investigator-initiated clinical trial (NCT00831480) to determine the feasibility of everolimus preop in patients with metastatic RCC that can serve to identify determinants of acquired resistance to mTORC1 inhibitors clinically.
Investigator-initiated clinical trial (NCT01896271) to explore whether stereotactic ablative body radiation therapy synergizes with high-dose IL2 and increases the rates of complete durable responses..
First-in-class, first-in-human, phase 1 trial of PT2385, a potent and specific HIF-2 inhibitor (NCT02293980).
Investigator-initiated clinical trial to assess the role of SBRT in oligometastatic RCC (NCT02956798).
First evaluation of a glycolysis inhibitor against a tumor with a mutation rendering it deficient in a TCA cycle enzyme (Yamasaki et al., Nat Rev Urol, 2011).
Genetically-driven life-saving treatment of a patient with a rare cancer type, an epithelioid angiomyolipoma, for which there were no proven treatments (Wolff et al., J Clin Oncol, 2010).
Reported the first patient with RCC treated with the mTORC1 inhibitor sirolimus (Brugarolas et al., J Clin Oncol, 2008).
Effective treatment of progressing brain metastases from papillary renal cancer with supratherapeutic doses of pazopanib (Jacobs et al., J Clin Oncol, 2013).
Incorporation of stereotactic radiation in the management of oligometastatic disease extends the duration of sunitinib systemic therapy (Straka et al., J Clin Oncol, 2013).
Successful therapy of bone metastases from chromophobe renal cancer using temsirolimus (Huelsmann et al., Clin Genitourin Cancer, 2014).
Developed novel treatment strategy involving stereotactic radiation for the control of renal cell carcinoma invasion into the vena cava (Hannan et al., Cancer Biol Ther, 2015).