Landmark Discoveries

Jump to: 1990–1999 | 2000–2009 | 2010–Present

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-2α (hypoxia-inducible factor 2α), which was discovered by UT Southwestern scientists. HIF-2α 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.

Pathways Illustration from NEJM
Illustration of pathways leading to therapeutic developments in renal cancer. Adapted from Brugarolas J. N Engl J Med 2007.

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

Figure 1: Sequence and domain architecture of HIF-2α.
Sequence and domain architecture of HIF-2α. Adapted from Tian et al., Genes Dev 1997.

Drs. Hui Tian, Steven McKnight, and David Russell discover HIF-2α (hypoxia-inducible factor 2a, which they name EPAS1), a critical effector downstream of pVHL (von Hippel-Lindau protein). They show that HIF-2α is induced in response to hypoxia, heterodimerizes with HIF-1β, and regulates hypoxia-responsive genes (Tian et al., Genes Dev 1997).

Bibliography

Back to Top2000–2009

Figure 2
Prolyl-hydroxylase enzymes hydroxylate wild-type HIF-1α in vitro. Adapted from Bruick and McKnight, Science 2001.
TSC1
TSC1 autonomously controls cell and organ size. A, Scanning electron micrograph of a Drosophila compound eye carrying a clone of homozygous TSC1-deficient cells (upper half) made up of larger cells. See also panel B (lower half). C, TSC1 loss increases Drosophila wing-margin bristles (deficient clone shown by the double headed arrow). Adapted from Gao and Pan, Genes Dev 2001.
Tsc1/Tsc2 complex
Determination that the TSC1/TSC2 complex functions as a Rheb GAP. Adapted from Zhang et al., Nat Cell Biol 2003.

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-2α is also regulated by acetylation (Dioum et al., Science 2009).

The Garcia lab shows that HIF-2α is required for hematopoietic development in mice (Scortegagna et al., Nat Genet 2003; Scortegagna et al., Blood 2003), and that HIF-2α 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-2α 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-2α 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).

Bibliography

Back to Top2010–Present

TSC1
Crystal structure showing artificial ligand bound to the cavity in the PAS-B domain of HIF-2α. Adapted from Scheuermann et al., Nat Chem Biol 2013.
Acute Vhl
Acute Vhl inactivation in the mouse results in a Hif-dependent inhibition of mitochondrial respiration with consequent increase in pO2 as determined by oximetry using 19F MRI of oxypherol. Adapted from Kucejova et al., Oncogene 2011.
TSC1 is mutated in ccRCC.
TSC1 is mutated in ccRCC. Sequence chromatogram of a clear cell renal cell carcinoma showing somatically acquired TSC1 mutation. For more information, please see Kucejova et al., Mol Cancer Res 2011.
Renal cell carcinoma
A molecular genetic classification of sporadic renal cell carcinoma. Renal cell carcinoma of clear cell type can be classified according to the status of BAP1 and PBRM1 into 4 different subtypes. Adapted from Pena-Llopis et al., Nat Genet 2012.
BAP1 protein status
Status of BAP1 protein in tumors determines patients’ outcome in a large series from Mayo clinic. Kaplan-Meier estimates of renal cancer-specific survival in patients according to BAP1 protein status in clear cell renal cell carcinoma. Adapted from Joseph et al., Cancer In press.
Germline mutation of BAP1
Germline mutation of BAP1 causes familial renal cancer. Pedigree of family with renal cancer predisposition and germline BAP1 mutation. Adapted from Farley et al., Mol Cancer Res 2013.

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 in press).

A consortium spearheaded by UT Southwestern Medical Center involving UT Health Science Center, Cleveland Clinic, 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).

Bibliography