The identification of molecular pathways deregulated in renal cancer has opened up new therapeutic opportunities. Renal cancers are resistant to conventional chemotherapy and up until 2005, only one drug – IL2 (interleukin-2) – was approved by the FDA. Between 2005 and 2013, seven new treatments were shown to be effective and received FDA approval. These advances were possible because of discoveries about the biology of kidney cancer, and UT Southwestern investigators played and continue to play important roles. Five of the drugs target a pathway regulated by the protein VHL (von Hippel-Lindau). The most important target of VHL is believed to be HIF-2a (hypoxia-inducible factor 2a), which was discovered by UT Southwestern scientists. HIF-2a regulates VEGF (vascular endothelial growth factor), which is the target of bevacizumab, and VEGF activates its receptor (VEGF receptor-2) which is targeted by four other drugs: sorafenib, sunitinib, pazopanib and axitinib.
The second pathway that has led to new treatments for kidney cancer patients is the mTOR (mammalian target of rapamycin) pathway. Research by UT Southwestern scientists led to the finding that the TSC1/TSC2 (tuberous sclerosis complex 1/2) complex is a critical regulator of TOR. This opened up opportunities to treat patients with germline mutations in TSC1 or TSC2 with TOR inhibitors such as temsirolimus and everolimus, and ultimately provided a rationale for treating kidney cancer with this class of drugs.
Back to Top1990–1999
Drs. Hui Tian, Steven McKnight, and David Russell discover HIF-2a (hypoxia-inducible factor 2a, which they name EPAS1), a critical effector downstream of pVHL (von Hippel-Lindau protein). They show that HIF-2a is induced in response to hypoxia, heterodimerizes with HIF-1β, and regulates hypoxia-responsive genes (Tian et al., Genes Dev 1997).
- Tian, H. et al. Endothelial PAS domain protein 1 (EPAS1), a transcription factor selectively expressed in endothelial cells. Genes Dev 11, 72-82, (1997).
Back to Top2000–2009
Using homology searches, Drs. Richard Bruick and McKnight identify a family of prolyl hydroxylases responsible for targeting hypoxia-inducible factor α subunits for pVHL-mediated degradation (Bruick and McKnight, Science 2001).
Bruick, now in his own lab, determines that FIH (factor-inhibiting HIF) is an asparaginyl hydroxylase that modifies and regulates HIF (Lando et al., Genes Dev 2002). Dr. Johann Deisenhofer's lab crystalizes FIH (Dann et al., Proc Natl Acad Sci U S A 2002). Further studies from Dr. Joseph Garcia's lab show that HIF-2a is also regulated by acetylation (Dioum et al., Science 2009).
The Garcia lab shows that HIF-2a is required for hematopoietic development in mice (Scortegagna et al., Nat Genet 2003; Scortegagna et al., Blood 2003), and that HIF-2a is necessary for erythropoietin production (Scortegagna et al., Blood 2005).
Together, the labs of Drs. Bruick and Kevin Gardner provide structural insight into the obligatory dimerization of HIF-2a and HIF-1β and show that mutations disrupting binding abrogate HIF-2 activity (Erbel et al., Proc Natl Acad Sci U S A 2003; Yang et al., J Biol Chem 2005). They discover a large cavity in the PAS-B domain of HIF-2a that they speculate could be bound by artificial ligands that may inhibit dimerization and antagonize HIF-2 activity (Scheuermann et al., Proc Natl Acad Sci U S A 2009).
Using Drosophila as an experimental system, Drs. Xinsheng Gao and Duojia Pan report the discovery that the elusive TSC1/TSC2 (tuberous sclerosis complex 1/2) functions in insulin signaling (Gao and Pan, Genes Dev 2001) and that it regulates TOR (target of rapamycin) (Gao et al., Nat Cell Biol 2002). They show that TSC1/TSC2 is a GAP (GTPase activating protein) towards Rheb (Ras homologue enriched in brain), an essential activator of TOR (Zhang et al., Nat Cell Biol 2003).
- Bruick, R. K. et al. A conserved family of prolyl-4-hydroxylases that modify HIF. Science 294, 1337-1340, (2001).
- Dann, C. E., 3rd et al. Structure of factor-inhibiting hypoxia-inducible factor 1: An asparaginyl hydroxylase involved in the hypoxic response pathway. Proc Natl Acad Sci U S A 99, 15351-15356, (2002).
- Dioum, E. M. et al. Regulation of hypoxia-inducible factor 2alpha signaling by the stress-responsive deacetylase sirtuin 1. Science 324, 1289-1293, (2009).
- Erbel, P. J. et al. Structural basis for PAS domain heterodimerization in the basic helix--loop--helix-PAS transcription factor hypoxia-inducible factor. Proc Natl Acad Sci U S A 100, 15504-15509, (2003).
- Gao, X. et al. Tsc tumour suppressor proteins antagonize amino-acid-TOR signalling. Nat Cell Biol 4, 699-704, (2002).
- Gao, X. et al. TSC1 and TSC2 tumor suppressors antagonize insulin signaling in cell growth. Genes Dev 15, 1383-1392, (2001).
- Lando, D. et al. FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor. Genes Dev 16, 1466-1471, (2002).
- Scheuermann, T. H. et al. Artificial ligand binding within the HIF2alpha PAS-B domain of the HIF2 transcription factor. Proc Natl Acad Sci U S A 106, 450-455, (2009).
- Scortegagna, M. et al. HIF-2alpha; regulates murine hematopoietic development in an erythropoietin-dependent manner. Blood 105, 3133-3140, (2005).
- Scortegagna, M. et al. Multiple organ pathology, metabolic abnormalities and impaired homeostasis of reactive oxygen species in Epas1-/- mice. Nat Genet 35, 331-340, (2003).
- Scortegagna, M. et al. The HIF family member EPAS1/HIF-2alpha; is required for normal hematopoiesis in mice. Blood 102, 1634-1640, (2003).
- Yang, J. et al. Functions of the Per/ARNT/Sim domains of the hypoxia-inducible factor. J Biol Chem 280, 36047-36054, (2005).
- Zhang, Y. et al. Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins. Nat Cell Biol 5, 578-581, (2003).
Back to Top2010–Present
Drs. Uttam Tambar, John MacMillan, Gardner, and Bruick report the identification of chemicals that bind the PAS-B domain cavity and disrupt HIF-2 heterodimerization (Rogers et al., Journal of Medicinal Chemistry 2013; Scheuermann et al., Nat Chem Biol 2013). Lead compounds are licensed to Peloton Therapeutics, a company founded by Dr. McKnight.
Drs. Ralph Mason, Shawn Burgess, and James Brugarolas show that constitutive HIF activation in mice is sufficient to block mitochondrial respiration providing the first evidence in animals of this effect (Kucejova et al., Oncogene 2011).
Dr. Brugarolas discovers that the TSC1 gene is somatically mutated in renal cancer (Kucejova et al., Mol Cancer Res 2011) and proposes that TSC1 mutations predict for responsiveness to mTORC1 inhibitors in patients (Brugarolas, Renal Cell Carcinoma: Translational Biology, Personalized Medicine, and Novel Therapeutic Targets 2012), a paradigm later ratified in other tumor types.
Dr. Brugarolas shows that TFEB (transcription factor EB), a master regulator of lysosome biogenesis which is translocated and overexpressed in translocation carcinomas, is regulated by TORC1 (TOR complex 1) (Pena-Llopis et al., EMBO J 2011).
Drs. Brugarolas and Thomas Bradley report the potential of TORC1 inhibitors in the treatment of epithelioid angiomyolipoma, a tumor type without effective therapies (Wolff et al., J Clin Oncol 2010). A year later, Drs. Ralph DeBerardinis and Brugarolas report the first attempt to inhibit glycolysis for the treatment of a tumor with a genetic defect in the TCA cycle (Yamasaki et al., Nat Rev Urol 2011).
Dr. Brugarolas reports that the gene encoding BAP1 (BRCA1 associated protein-1) is mutated in 15 percent of renal cancers of clear cell type (Pena-Llopis et al., Nat Genet 2012). BAP1 mutations tend to anti-correlate with mutations in PBRM1 (polybromo 1) and tumors with BAP1 and PBRM1 mutations are associated with different biology and outcomes (Pena-Llopis et al., Nat Genet 2012; Kapur et al., The Lancet Oncology 2013). This work establishes the foundation for the first molecular classification of sporadic clear cell renal cell carcinoma.
Dr. Payal Kapur, a urological pathologist, develops a clinical immunohistochemistry test to determine the status of BAP1 and PBRM1 in tumors. In collaboration with researchers at Mayo clinic, Drs. Kapur and Brugarolas show that BAP1 loss predicts the outcome of patients independently of known prognostic variables (Joseph et al., Cancer 2014).
A consortium spearheaded by UT Southwestern Medical Center involving UT Health Science Center at San Antonio, Cleveland Clinic, Case Western, and the National Cancer Institute identifies a novel familial kidney cancer syndrome resulting from germline mutations in the BAP1 gene (Farley et al., Mol Cancer Res 2013).
Dr. Brugarolas generates the first animal model of kidney cancer shown to reproduce: (i) the histology, (ii) gene expression, (iii) DNA copy number alterations, (iv) mutations and, most importantly, (v) drug responsiveness of human tumors (Sivanand et al., Sci Transl Med 2012). In addition, by leveraging their discoveries about the molecular genetics of ccRCC, and in particular their discovery of BAP1 mutations, they are able to generate the first genetically-engineered mouse model reproducing the mutations of human tumors (Wang et al., PNAS 2014).
Drs. Kapur and Brugarolas, in collaboration with scientists at Genentech, report the first integrated genomic analysis of non-clear cell renal tumors (Durinck et al., Nat Genet 2015).
- Brugarolas, J. in Renal Cell Carcinoma: Translational Biology, Personalized Medicine, and Novel Therapeutic Targets (eds R. A. Figlin, W. K. Rathmell, & B. I. Rini) Ch. 8, 161-191 (Springer US, 2012).
- Durinck, S. et al. Spectrum of diverse genomic alterations define non-clear cell renal carcinoma subtypes. Nat Genet 47, 13-21, (2015).
- Farley, M. N. et al. A novel germline mutation in BAP1 predisposes to familial clear-cell renal cell carcinoma. Mol Cancer Res 11, 1061-1071, (2013).
- Joseph, R. W. et al. Loss of BAP1 protein expression is an independent marker of poor prognosis in patients with low risk clear cell renal cell carcinoma. Cancer 120, 1059-1067, (2014).
- Kapur, P. et al. Effects on survival of BAP1 and PBRM1 mutations in sporadic clear-cell renal-cell carcinoma: a retrospective analysis with independent validation. The Lancet Oncology 14, 159-167, (2013).
- Kucejova, B. et al. Interplay between pVHL and mTORC1 pathways in clear-cell renal cell carcinoma. Mol Cancer Res 9, 1255-1265, (2011).
- Kucejova, B. et al. Uncoupling hypoxia signaling from oxygen sensing in the liver results in hypoketotic hypoglycemic death. Oncogene 30, 2147-2160, (2011).
- Pena-Llopis, S. et al. BAP1 loss defines a new class of renal cell carcinoma. Nat Genet 44, 751-759, (2012).
- Pena-Llopis, S. et al. Regulation of TFEB and V-ATPases by mTORC1. EMBO J 30, 3242-3258, (2011).
- Rogers, J. L. et al. Development of inhibitors of the PAS-B domain of the HIF-2alpha; transcription factor. Journal of Medicinal Chemistry 56, 1739-1747, (2013).
- Scheuermann, T. H. et al. Allosteric inhibition of hypoxia inducible factor-2 with small molecules. Nat Chem Biol 9, 271-276, (2013).
- Sivanand, S. et al. A validated tumorgraft model reveals activity of dovitinib against renal cell carcinoma. Sci Transl Med 4, 137ra175, (2012).
- Wang, S.S. et al. Bap1 is essential for kidney function and cooperates with Vhl in renal tumorigenesis. PNAS 111, 16538-16543, (2014).
- Wolff, N. et al. Sirolimus and temsirolimus for epithelioid angiomyolipoma. J Clin Oncol 28, e65-68, (2010).
- Yamasaki, T. et al. Exploring a glycolytic inhibitor for the treatment of an FH-deficient type-2 papillary RCC. Nat Rev Urol 8, 165-171, (2011).
Figure 1 from Tian et al., Genes Dev 1997 illustrating the sequence and domain architecture of HIF-2a.