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Non–Clear Cell Renal Cell Carcinoma: How New Biological Insight May Lead to New Therapeutic Modalities

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Abstract

Treatment for patients with metastatic non–clear cell renal cancer (RCC), who constitute 25% of all RCC patients, is largely undefined and tested algorithms remain unsatisfactory. Response rates to targeted therapy are not as high as in patients with clear cell subtypes, but novel agents provide a clinically meaningful response in some individuals. The research leading to characterization of the pathways involved in clear cell renal cancer has been recognized as a role model for the development of therapies based on genetic and molecular tumor characteristics. Similar research now provides increasing insight into signal transduction in non–clear cell subtypes. This review will present and discuss the current evidence of pathways involved in the most common non–clear cell subtypes. In addition, we will review how this may lead to the development of new treatment modalities. New targets and clinical trials will be highlighted.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2009. CA Cancer J Clin. 2009;59:225–49.

    Article  PubMed  Google Scholar 

  2. Ferlay J, Autier P, Boniol M, et al. Estimates of the cancer incidence and mortality in Europe in 2006. Ann Oncol. 2001;18:581–92.

    Article  Google Scholar 

  3. Lopez-Beltran A, Scarpelli M, Montironi R, Kirkali Z. 2004 WHO classification of the renal tumors of the adults. Eur Urol. 2006;49:798–805.

    Article  PubMed  Google Scholar 

  4. Flanigan RC, Yonover PM. The role of radical nephrectomy in metastatic renal cell carcinoma. Semin Urol Oncol. 2001;19:98–102.

    PubMed  CAS  Google Scholar 

  5. Hutson TE, Bukowski RM, Cowey CL, et al. Sequential use of targeted agents in the treatment of renal cell carcinoma. Crit Rev Oncol Hematol. 2011 Jan;77(1):48–62.

  6. Vogelzang NJ, Samlowski W, Weissman A. Long-term response in primary renal cancer to sequential antiangiogenic therapy. J Clin Oncol. 2009;27:e106–7.

    Article  PubMed  Google Scholar 

  7. Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356:115–24.

    Article  PubMed  CAS  Google Scholar 

  8. • Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007;356:2271–81. Data from a randomized controlled trial including patients with papillary RCC.

    Article  PubMed  CAS  Google Scholar 

  9. • Stadler WM, Figlin RA, McDermott DF, et al. Safety and efficacy results of the advanced renal cell carcinoma sorafenib expanded access program in North America. Cancer 2010;116:1272–80. Data of retrospective subgroup analyses of non–clear cell RCC treated with sorafenib.

    Article  PubMed  CAS  Google Scholar 

  10. • Gore ME, Szczylik C, Porta C, et al. Safety and efficacy of sunitinib for metastatic renal-cell carcinoma: an expanded-access trial. Lancet Oncol. 2009;10:757–63. Data of retrospective subgroup analyses of non–clear cell RCC treated with sunitinib.

    Article  PubMed  CAS  Google Scholar 

  11. Molina AM, Feldman DR, Ginsberg MS, et al. Phase II trial of sunitinib in patients with metastatic non-clear cell renal cell carcinoma. Invest New Drugs. 2010. doi:10.1007/s10637-010-9491-6.

  12. Choueiri TK, Plantade A, Elson P, et al. Efficacy of sunitinib and sorafenib in metastatic papillary and chromophobe renal cell carcinoma. J Clin Oncol. 2008;26:127–31.

    Article  PubMed  CAS  Google Scholar 

  13. Gordon MS, Hussey M, Nagle RB, et al. Phase II study of erlotinib in patients with locally advanced or metastatic papillary histology renal cell cancer: SWOG S0317. J Clin Oncol. 2009;27:5788–93.

    Article  PubMed  CAS  Google Scholar 

  14. Dutcher JP, de Souza P, McDermott D, et al. Effect of temsirolimus versus interferon-alpha on outcome of patients with advanced renal cell carcinoma of different tumor histologies. Med Oncol. 2009;26:202–9.

    Article  PubMed  CAS  Google Scholar 

  15. • Plimack ER, Jonasch E, Bekele BN, et al.: Sunitinib in papillary renal cell carcinoma (pRCC): results from a single-arm phase II study. J Clin Oncol. 2010:28:4604. Prospective study involving patients with pRCC treated with sunitinib, only available as abstract.

    Google Scholar 

  16. Delahunt B, Eble JN. Papillary renal cell carcinoma: a clinicopathologic and immunohistochemical study of 105 tumors. Mod Pathol. 1997;10:537–44.

    PubMed  CAS  Google Scholar 

  17. Furge KA, MacKeigan JP, Teh BT. Kinase targets in renal-cell carcinomas: reassessing the old and discovering the new. Lancet Oncol. 2010;11:571–8.

    Article  PubMed  CAS  Google Scholar 

  18. Schmidt L, Duh FM, Chen F, et al. Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. Nat Genet. 1997;16:68–73.

    Article  PubMed  CAS  Google Scholar 

  19. Lubensky IA, Schmidt L, Zhuang Z, et al. Hereditary and sporadic papillary renal carcinomas with c-met mutations share a distinct morphological phenotype. Am J Pathol. 1999;155:517–26.

    Article  PubMed  CAS  Google Scholar 

  20. Morris MR, Gentle D, Abdulrahman M, et al. Tumor suppressor activity and epigenetic inactivation of hepatocyte growth factor activator inhibitor type 2/SPINT2 in papillary and clear cell renal cell carcinoma. Cancer Res. 2005;65:4598–606.

    Article  PubMed  CAS  Google Scholar 

  21. Morris MR, Maher ER. Epigenetics of renal cell carcinoma: the path towards new diagnostics and therapeutics. Genome Med. 2010;2:59.

    Article  PubMed  Google Scholar 

  22. Giubellino A, Linehan WM, Bottaro DP. Targeting the Met signaling pathway in renal cancer. Expert Rev Anticancer Ther. 2009;9:785–93.

    Article  PubMed  CAS  Google Scholar 

  23. Burgess TL, Sun J, Meyer S, et al. Biochemical characterization of AMG 102: a neutralizing, fully human monoclonal antibody to human and nonhuman primate hepatocyte growth factor. Mol Cancer Ther. 2010;9:400–9.

    Article  PubMed  CAS  Google Scholar 

  24. • Gordon MS, Sweeney CS, Mendelson DS, et al. Safety, pharmacokinetics, and pharmacodynamics of AMG 102, a fully human hepatocyte growth factor-neutralizing monoclonal antibody, in a first-in-human study of patients with advanced solid tumors. Clin Cancer Res. 2010;16:699–710. Publication describing adverse events of AMG 102.

    Article  PubMed  CAS  Google Scholar 

  25. Jin H, Yang R, Zheng Z, et al. MetMAb, the one-armed 5D5 anti-c-Met antibody, inhibits orthotopic pancreatic tumor growth and improves survival. Cancer Res. 2008;68:4360–8.

    Article  PubMed  CAS  Google Scholar 

  26. Munshi N, Jeay S, Li Y, et al. ARQ 197, a novel and selective inhibitor of the human c-Met receptor tyrosine kinase with antitumor activity. Mol Cancer Ther. 2010;9:1544–53.

    Article  PubMed  CAS  Google Scholar 

  27. Yap TA, de Bono JS. Targeting the HGF/c-Met axis: state of play. Mol Cancer Ther. 2010;9:1077–9.

    Article  PubMed  CAS  Google Scholar 

  28. • Srinivasan R, Choueiri TK, Vaishampayan U, et al. A phase II study of the dual MET/VEGFR2 inhibitor XL880 in patients (pts) with papillary renal carcinoma (PRC). J Clin Oncol. 2008;26:5103.

    Google Scholar 

  29. • Srinivasan R, Linehan W, Vaishampayan U, et al. A phase II study of two dosing regimens of GSK 1363089 (GSK089), a dual MET/VEGFR2 inhibitor, in patients (pts) with papillary renal carcinoma (PRC). J Clin Oncol. 2009;27:5103. Prospective study [28•, 29•] involving patients with pRCC treated with foretinib, only available as abstract. Patients will be stratified according to MET status to evaluate an association with outcome.

    Google Scholar 

  30. Zhang Y, Guessous F, Kofman A, et al. XL-184, a MET, VEGFR-2 and RET kinase inhibitor for the treatment of thyroid cancer, glioblastoma multiforme and NSCLC. IDrugs. 2010;13:112–21.

    PubMed  Google Scholar 

  31. Ma PC, Schaefer E, Christensen JG, Salgia R. A selective small molecule c-MET Inhibitor, PHA665752, cooperates with rapamycin. Clin Cancer Res. 2005;11:2312–9.

    Article  PubMed  CAS  Google Scholar 

  32. • Caglio S, Slimane K, May C, Escudier B. Open-label phase II trial of everolimus monotherapy in treatment-naive patients with advanced papillary renal cell carcinoma. J Clin Oncol. 2010;28:15s. Describes the design of the RAPTOR trial.

    Google Scholar 

  33. Garcia-Echeverria C, Sellers WR. Drug discovery approaches targeting the PI3K/Akt pathway in cancer. Oncogene. 2008;27:5511–26.

    Article  PubMed  CAS  Google Scholar 

  34. Serra V, Markman B, Scaltriti M, et al. NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations. Cancer Res. 2008;68:8022–30.

    Article  PubMed  CAS  Google Scholar 

  35. Schnell CR, Stauffer F, Allegrini PR, et al. Effects of the dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235 on the tumor vasculature: implications for clinical imaging. Cancer Res. 2008;68:6598–607.

    Article  PubMed  CAS  Google Scholar 

  36. Toro JR, Nickerson ML, Wei MH, et al. Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America. Am J Hum Genet. 2003;73:95–106.

    Article  PubMed  CAS  Google Scholar 

  37. Ricketts C, Woodward ER, Killick P, et al. Germline SDHB mutations and familial renal cell carcinoma. J Natl Cancer Inst. 2008;100:1260–2.

    Article  PubMed  CAS  Google Scholar 

  38. Isaacs JS, Jung YJ, Mole DR, et al. HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: novel role of fumarate in regulation of HIF stability. Cancer Cell. 2005;8:143–53.

    Article  PubMed  CAS  Google Scholar 

  39. Selak MA, Armour SM, MacKenzie ED, et al. Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. Cancer Cell. 2005;7:77–85.

    Article  PubMed  CAS  Google Scholar 

  40. Jung CR, Hwang KS, Yoo J, et al. E2-EPF UCP targets pVHL for degradation and associates with tumor growth and metastasis. Nat Med. 2006;12:809–16.

    Article  PubMed  CAS  Google Scholar 

  41. Furge KA, Chen J, Koeman J, et al. Detection of DNA copy number changes and oncogenic signaling abnormalities from gene expression data reveals MYC activation in high-grade papillary renal cell carcinoma. Cancer Res. 2007;67:3171–6.

    Article  PubMed  CAS  Google Scholar 

  42. Yusenko MV, Kuiper RP, Boethe T, et al. High-resolution DNA copy number and gene expression analyses distinguish chromophobe renal cell carcinomas and renal oncocytomas. BMC Cancer. 2009;9:152.

    Article  PubMed  Google Scholar 

  43. Yusenko MV. Molecular pathology of chromophobe renal cell carcinoma: a review. Int J Urol. 2010;17:592–600.

    Article  PubMed  Google Scholar 

  44. Yusenko MV, Kovacs G. Identifying CD82 (KAI1) as a marker for human chromophobe renal cell carcinoma. Histopathology. 2009;55:687–95.

    Article  PubMed  Google Scholar 

  45. Tan MH, Wong CF, Tan HL, et al. Genomic expression and single-nucleotide polymorphism profiling discriminates chromophobe renal cell carcinoma and oncocytoma. BMC Cancer. 2010;10:196.

    Article  PubMed  Google Scholar 

  46. Nickerson ML, Warren MB, Toro JR, et al. Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dube syndrome. Cancer Cell. 2002;2:157–64.

    Article  PubMed  CAS  Google Scholar 

  47. Baba M, Hong SB, Sharma N, et al. Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling. Proc Natl Acad Sci USA. 2006;103:15552–7.

    Article  PubMed  CAS  Google Scholar 

  48. Baba M, Furihata M, Hong SB, et al. Kidney-targeted Birt-Hogg-Dube gene inactivation in a mouse model: Erk1/2 and Akt-mTOR activation, cell hyperproliferation, and polycystic kidneys. J Natl Cancer Inst. 2008;100:140–54.

    Article  PubMed  CAS  Google Scholar 

  49. Woodward ER, Ricketts C, Killick P, et al. Familial non-VHL clear cell (conventional) renal cell carcinoma: clinical features, segregation analysis, and mutation analysis of FLCN. Clin Cancer Res. 2008;14:5925–30.

    Article  PubMed  CAS  Google Scholar 

  50. Stec R, Grala B, Maczewski M, et al. Chromophobe renal cell cancer–review of the literature and potential methods of treating metastatic disease. J Exp Clin Cancer Res. 2009;28:134.

    Article  PubMed  Google Scholar 

  51. Yamazaki K, Sakamoto M, Ohta T, et al. Overexpression of KIT in chromophobe renal cell carcinoma. Oncogene. 2003;22:847–52.

    Article  PubMed  CAS  Google Scholar 

  52. Pan CC, Chen PC, Chiang H. Overexpression of KIT (CD117) in chromophobe renal cell carcinoma and renal oncocytoma. Am J Clin Pathol. 2004;121:878–83.

    Article  PubMed  Google Scholar 

  53. Kruger S, Sotlar K, Kausch I, Horny HP. Expression of KIT (CD117) in renal cell carcinoma and renal oncocytoma. Oncology. 2005;68:269–75.

    Article  PubMed  Google Scholar 

  54. Rix U, Hantschel O, Durnberger G, et al. Chemical proteomic profiles of the BCR-ABL inhibitors imatinib, nilotinib, and dasatinib reveal novel kinase and nonkinase targets. Blood. 2007;110:4055–63.

    Article  PubMed  CAS  Google Scholar 

  55. Carvajal RD, Chapman PB, Wolchok JD, et al. A phase II study of imatinib mesylate (IM) for patients with advanced melanoma harboring somatic alterations of KIT. J Clin Oncol. 2009;27:9001.

    Google Scholar 

  56. Vuky J, Fotoohy M, Isacson C, et al. Phase II trial of imatinib mesylate (formerly known as STI-571) in patients with metastatic renal cell carcinoma (RCC). Proc Am Soc Clin Oncol. 2003;22:abstr 1672.

  57. Eble JN, Sauter G, Epstein JI, Sesterhenn IA. World health organization classification of tumours. Pathology and genetics of tumours of the urinary system and male genital organs. Lyon: IARC; 2004.

    Google Scholar 

  58. Martignoni G, Pea M, Gobbo S, et al. Cathepsin-K immunoreactivity distinguishes MiTF/TFE family renal translocation carcinomas from other renal carcinomas. Mod Pathol. 2009;22:1016–22.

    Article  PubMed  CAS  Google Scholar 

  59. Ross H, Argani P. Xp11 translocation renal cell carcinoma. Pathology. 2010;42:369–73.

    Article  PubMed  CAS  Google Scholar 

  60. Argani P, Hicks J, De Marzo AM, et al. Xp11 translocation renal cell carcinoma (RCC): extended immunohistochemical profile emphasizing novel RCC markers. Am J Surg Pathol. 2010;34:1295–303.

    Article  PubMed  Google Scholar 

  61. Tsuda M, Davis IJ, Argani P, et al. TFE3 fusions activate MET signaling by transcriptional up-regulation, defining another class of tumors as candidates for therapeutic MET inhibition. Cancer Res. 2007;67:919–29.

    Article  PubMed  CAS  Google Scholar 

  62. • Choueiri TK, Lim ZD, Hirsch MS, et al. Vascular endothelial growth factor-targeted therapy for the treatment of adult metastatic Xp11.2 translocation renal cell carcinoma. Cancer 2010;116:5219–25. A retrospective review demonstrating effect of targeted therapy for translocation tumors.

    Article  PubMed  CAS  Google Scholar 

  63. • Malouf GG, Camparo P, Oudard S, et al. Targeted agents in metastatic Xp11 translocation/TFE3 gene fusion renal cell carcinoma (RCC): a report from the Juvenile RCC Network. Ann Oncol. 2010;21:1834–8. A retrospective review demonstrating effect of first and second-line targeted therapy in 21 translocation tumors.

    Article  PubMed  CAS  Google Scholar 

  64. Srigley JR, Eble JN. Collecting duct carcinoma of kidney. Semin Diagn Pathol. 1998;15:54–67.

    PubMed  CAS  Google Scholar 

  65. Oudard S, Banu E, Vieillefond A, et al. Prospective multicenter phase II study of gemcitabine plus platinum salt for metastatic collecting duct carcinoma: results of a GETUG (Groupe d’Etudes des Tumeurs Uro-Genitales) study. J Urol. 2007;177:1698–702.

    Article  PubMed  CAS  Google Scholar 

  66. Larkin J, Fisher R, Pickering L, et al. Metastatic mucinous tubular and spindle cell carcinoma of the kidney responding to sunitinib. J Clin Oncol. 2010;28:e539–40.

    Article  PubMed  Google Scholar 

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Disclosure

A. Bex: consultant for Pfizer, Novartis, GlaxoSmithKline, and Bayer; J. Larkin: research funding from Pfizer and Novartis and consulting from GSK, Pfizer, Novartis and Bayer; C. Blank: consultant for Pfizer, Bayer, and GlaxoSmithKline.

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Authors and Affiliations

  1. Division of Surgical Oncology, Department of Urology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands

    Axel Bex

  2. Renal Cancer Unit, Medical Oncology, Royal Marsden Hospital, Fulham Road, London, SW3 6JJ, UK

    James Larkin

  3. Medical Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands

    Christian Blank

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  1. Axel Bex
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  2. James Larkin
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Correspondence to Axel Bex.

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Bex, A., Larkin, J. & Blank, C. Non–Clear Cell Renal Cell Carcinoma: How New Biological Insight May Lead to New Therapeutic Modalities. Curr Oncol Rep 13, 240–248 (2011). https://doi.org/10.1007/s11912-011-0159-y

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