Renal cell carcinoma: a review of biology and pathophysiology

Over the past decade, our understanding of the biology and pathophysiology of renal cell carcinoma (RCC) has improved significantly. Insight into the disease process has helped us in developing newer therapeutic approaches toward RCC. In this article, we review the various genetic and immune-related mechanisms involved in the pathogenesis and development of this cancer and how that knowledge is being used to develop therapeutic targeted drugs for the treatment of RCC. The main emphasis of this review article is on the most common genetic alterations found in clear cell RCC and how various drugs are currently targeting such pathways. This article also looks at the role of the immune system in allowing the growth of RCC and how the immune system can be manipulated to reactivate cytotoxic immunity against RCC.

[1]  T. Flaig.  Faculty of 1000 evaluation for Safety and efficacy of nivolumab in combination with ipilimumab in metastatic renal cell carcinoma: the checkmate 016 study. , 2018 .

[2]  R. Figlin,et al.  Phase I Dose-Escalation Trial of PT2385, a First-in-Class Hypoxia-Inducible Factor-2α Antagonist in Patients With Previously Treated Advanced Clear Cell Renal Cell Carcinoma. , 2017, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[3]  A. Chaudhari,et al.  Glutamine Addiction in Kidney Cancer Suppresses Oxidative Stress and Can Be Exploited for Real-Time Imaging. , 2017, Cancer research.

[4]  E. Plimack,et al.  Safety and Efficacy of Nivolumab in Combination With Ipilimumab in Metastatic Renal Cell Carcinoma: The CheckMate 016 Study. , 2017, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[5]  Chad A. LaGrange,et al.  Kidney Cancer, Version 2.2017, NCCN Clinical Practice Guidelines in Oncology. , 2017, Journal of the National Comprehensive Cancer Network : JNCCN.

[6]  G. Stephanopoulos,et al.  Glutaminase and poly(ADP-ribose) polymerase inhibitors suppress pyrimidine synthesis and VHL-deficient renal cancers , 2017, The Journal of clinical investigation.

[7]  A. Jemal,et al.  Cancer statistics, 2017 , 2017, CA: a cancer journal for clinicians.

[8]  Ludmila V. Danilova,et al.  Tumor immune microenvironment characterization in clear cell renal cell carcinoma identifies prognostic and immunotherapeutically relevant messenger RNA signatures , 2016, Genome Biology.

[9]  Ludmila V. Danilova,et al.  Erratum to: Tumor immune microenvironment characterization in clear cell renal cell carcinoma identifies prognostic and immunotherapeutically relevant messenger RNA signatures , 2016, Genome Biology.

[10]  K. Gardner,et al.  Targeting renal cell carcinoma with a HIF-2 antagonist , 2016, Nature.

[11]  Hyejin Cho,et al.  On-target efficacy of a HIF-2α antagonist in preclinical kidney cancer models , 2016, Nature.

[12]  H. Verheul,et al.  Novel drugs that target the metabolic reprogramming in renal cell cancer , 2016, Cancer & Metabolism.

[13]  M. Voss,et al.  Phase 1 study of CB-839, a small molecule inhibitor of glutaminase (GLS), alone and in combination with everolimus (E) in patients (pts) with renal cell cancer (RCC). , 2016 .

[14]  J. Lewis,et al.  Metabolic Modulation of Clear-cell Renal Cell Carcinoma with Dichloroacetate, an Inhibitor of Pyruvate Dehydrogenase Kinase. , 2016, European urology.

[15]  David C. Smith,et al.  Survival, Durable Response, and Long-Term Safety in Patients With Previously Treated Advanced Renal Cell Carcinoma Receiving Nivolumab. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[16]  R. Motzer,et al.  Nivolumab for Metastatic Renal Cell Carcinoma: Results of a Randomized Phase II Trial. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[17]  M. Mcnamara,et al.  OX40 Agonists and Combination Immunotherapy: Putting the Pedal to the Metal , 2015, Front. Oncol..

[18]  K. Syrigos,et al.  mTOR pathway: A current, up-to-date mini-review (Review) , 2014, Oncology letters.

[19]  B. Rini,et al.  Randomized phase III trial of temsirolimus and bevacizumab versus interferon alfa and bevacizumab in metastatic renal cell carcinoma: INTORACT trial. , 2014, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[20]  J. Reeves,et al.  Pazopanib versus sunitinib in metastatic renal-cell carcinoma. , 2013, The New England journal of medicine.

[21]  J. Brugarolas.  PBRM1 and BAP1 as novel targets for renal cell carcinoma. , 2013, Cancer journal.

[22]  J. Trent,et al.  Targeting 6-Phosphofructo-2-Kinase (PFKFB3) as a Therapeutic Strategy against Cancer , 2013, Molecular Cancer Therapeutics.

[23]  P. Kapur,et al.  Effects on survival of BAP1 and PBRM1 mutations in sporadic clear-cell renal-cell carcinoma: a retrospective analysis with independent validation. , 2013, The Lancet. Oncology.

[24]  Shiyong Wu,et al.  A Small-Molecule Inhibitor of Glucose Transporter 1 Downregulates Glycolysis, Induces Cell-Cycle Arrest, and Inhibits Cancer Cell Growth In Vitro and In Vivo , 2012, Molecular Cancer Therapeutics.

[25]  N. Grishin,et al.  BAP1 loss defines a new class of renal cell carcinoma , 2012, Nature Genetics.

[26]  D. Sabatini,et al.  mTOR Signaling in Growth Control and Disease , 2012, Cell.

[27]  A. Jemal,et al.  Cancer statistics, 2012 , 2012, CA: a cancer journal for clinicians.

[28]  P. Sutphin,et al.  Targeting GLUT1 and the Warburg Effect in Renal Cell Carcinoma by Chemical Synthetic Lethality , 2011, Science Translational Medicine.

[29]  N. Rothschild,et al.  Metabolic features of clear-cell renal cell carcinoma: mechanisms and clinical implications. , 2011, Canadian Urological Association journal = Journal de l'Association des urologues du Canada.

[30]  A. Jemal,et al.  Cancer statistics, 2011 , 2011, CA: a cancer journal for clinicians.

[31]  D. Sabatini,et al.  mTOR: from growth signal integration to cancer, diabetes and ageing , 2010, Nature Reviews Molecular Cell Biology.

[32]  Arianna Di Napoli,et al.  Patterns of gene expression and copy-number alterations in von-hippel lindau disease-associated and sporadic clear cell carcinoma of the kidney. , 2009, Cancer research.

[33]  M. Thompson.  Polybromo-1: the chromatin targeting subunit of the PBAF complex. , 2009, Biochimie.

[34]  B. Guillonneau,et al.  Renal cell carcinoma in young and old patients--is there a difference? , 2008, The Journal of urology.

[35]  R. Motzer,et al.  Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial , 2008, The Lancet.

[36]  F. Waldman,et al.  Improved Identification of von Hippel-Lindau Gene Alterations in Clear Cell Renal Tumors , 2008, Clinical Cancer Research.

[37]  S. Steinberg,et al.  High‐dose interleukin‐2 for the treatment of metastatic renal cell carcinoma , 2008, Cancer.

[38]  John O Trent,et al.  Small-molecule inhibition of 6-phosphofructo-2-kinase activity suppresses glycolytic flux and tumor growth , 2008, Molecular Cancer Therapeutics.

[39]  R. Figlin,et al.  Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. , 2007, The New England journal of medicine.

[40]  N. Denko,et al.  HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. , 2006, Cell metabolism.

[41]  W. Kaelin,et al.  Role of VHL gene mutation in human cancer. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[42]  W. Krek,et al.  The von Hippel-Lindau tumour suppressor: a multi-faceted inhibitor of tumourigenesis. , 2004, Trends in molecular medicine.

[43]  V. Janout,et al.  Epidemiology and risk factors of kidney cancer. , 2004, Biomedical papers of the Medical Faculty of the University Palacky, Olomouc, Czechoslovakia.

[44]  P. Ratcliffe,et al.  Regulation of angiogenesis by hypoxia: role of the HIF system , 2003, Nature Medicine.

[45]  Kazuki Kobayashi,et al.  VHL tumor suppressor gene alterations associated with good prognosis in sporadic clear-cell renal carcinoma. , 2002, Journal of the National Cancer Institute.

[46]  W. Kaelin,et al.  Molecular basis of the VHL hereditary cancer syndrome , 2002, Nature Reviews Cancer.

[47]  P. Ratcliffe,et al.  Activation of the HIF pathway in cancer. , 2001, Current opinion in genetics & development.

[48]  R. Fisher,et al.  Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. , 1995, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[49]  M. Ferguson-Smith,et al.  Somatic mutations of the von Hippel-Lindau disease tumour suppressor gene in non-familial clear cell renal carcinoma. , 1994, Human molecular genetics.

[50]  J. Brooks,et al.  Mutations of the VHL tumour suppressor gene in renal carcinoma , 1994, Nature Genetics.

[51]  N. Dubrawsky.  Cancer statistics , 1989, CA: a cancer journal for clinicians.

[52]  M. Karno,et al.  Renal cell carcinoma. , 1956, Bulletin. Tufts-New England Medical Center.

[53]  S. Weinhouse.  On respiratory impairment in cancer cells. , 1956, Science.