Skip to main content
SpringerLink
Log in

Perspectives in drug development for metastatic renal cell cancer

  • Perspectives
  • Published:
Targeted Oncology Aims and scope Submit manuscript

Abstract

Patients with renal cell carcinoma (RCC) exhibit a spectrum of clinical outcomes, with some patients following an indolent clinical course and others displaying rapidly advancing disease. As evidence points to RCC being largely refractory to traditional chemotherapy and radiotherapy strategies, immunotherapeutic approaches played a dominant role in the management of metastatic RCC for a quarter of a century. Management of this challenging tumor has been revolutionized by the incorporation of molecularly targeted therapies such as inhibitors of pathways involving tyrosine kinase signaling and the mammalian target of rapamycin (mTOR). The improvements in disease stabilization and survival seen with these agents has meant that molecularly targeted therapy now forms the foundation for treating RCC and has resulted in a multitude of studies investigating similar compounds for efficacy in RCC. Despite this, the rationale for using immunomodulatory regimens remains strong and its ongoing place in this era of targeted treatments continues to pose interesting clinical questions. The challenge of maintaining durable responses from our current therapies persists and this review highlights the plethora of options now available in RCC treatment and the directions in which modern management are heading.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Landis SH, Murray T, Bolden S, Wingo PA (1999) Cancer statistics, 1999. CA Cancer J Clin 49:8–31

    Article  PubMed  CAS  Google Scholar 

  2. Pantuck AJ, Zisman A, Belldegrun AS (2001) The changing natural history of renal cell carcinoma. J Urol 166:1611–1623

    Article  PubMed  CAS  Google Scholar 

  3. Selli C, Hinshaw WM, Woodard BH, Paulson DF (1983) Stratification of risk factors in renal cell carcinoma. Cancer 52:899–903

    Article  PubMed  CAS  Google Scholar 

  4. Hermanek P, Schrott KM (1990) Evaluation of the new tumor, nodes and metastases classification of renal cell carcinoma. J Urol 144:238–241, discussion 241–232

    PubMed  CAS  Google Scholar 

  5. Motzer RJ, Bacik J, Mariani T, Russo P, Mazumdar M, Reuter V (2002) Treatment outcome and survival associated with metastatic renal cell carcinoma of non-clear-cell histology. J Clin Oncol 20:2376–2381

    Article  PubMed  Google Scholar 

  6. Motzer RJ, Mazumdar M, Bacik J, Berg W, Amsterdam A, Ferrara J (1999) Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma. J Clin Oncol 17:2530–2540

    PubMed  CAS  Google Scholar 

  7. Mekhail TM, Abou-Jawde RM, Boumerhi G, Malhi S, Wood L, Elson P, Bukowski R (2005) Validation and extension of the Memorial Sloan-Kettering prognostic factors model for survival in patients with previously untreated metastatic renal cell carcinoma. J Clin Oncol 23:832–841

    Article  PubMed  Google Scholar 

  8. Heng DY, Xie W, Regan MM, Warren MA, Golshayan AR, Sahi C, Eigl BJ, Ruether JD, Cheng T, North S, Venner P, Knox JJ, Chi KN, Kollmannsberger C, McDermott DF, Oh WK, Atkins MB, Bukowski RM, Rini BI, Choueiri TK (2009) Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter study. J Clin Oncol 27:5794–5799

    Article  PubMed  CAS  Google Scholar 

  9. Leppert J, Pantuck A, Figlin R, Belldegrun A (2007) The role of molecular markers in the staging of renal cell carcinoma. BJU Int 99:1208–1211

    Article  PubMed  CAS  Google Scholar 

  10. Cheville JC, Lohse CM, Zincke H, Weaver AL, Blute ML (2003) Comparisons of outcome and prognostic features among histologic subtypes of renal cell carcinoma. Am J Surg Pathol 27:612–624

    Article  PubMed  Google Scholar 

  11. Beck SD, Patel MI, Snyder ME, Kattan MW, Motzer RJ, Reuter VE, Russo P (2004) Effect of papillary and chromophobe cell type on disease-free survival after nephrectomy for renal cell carcinoma. Ann Surg Oncol 11:71–77

    Article  PubMed  Google Scholar 

  12. Furge K, Lucas K, Takhashi M, Sugimura J, Kort E, Kanayama H, Kagawa S, Hoekstra P, Curry J, Yang X, Teh B (2004) Robust classification of renal cell carcinoma based on gene expression data and predicted cytogenetic profiles. Cancer Res 64:4117–4121

    Article  PubMed  CAS  Google Scholar 

  13. Liao S, Aurelio O, Jan K, Zavada J, Stanbridge E (1997) Identification of the MN/Ca9 protein as a reliable diagnostic biomarker of clear cell carcinoma of the kidney. Cancer Res 57:2827–2831

    PubMed  CAS  Google Scholar 

  14. Bui M, Seligson D, Han K, Pantuck A, Dorey F, Huang Y, Horvath S, Leibovitch B, Chopra S, Liao S, Stanbridge E, Lerman M, Palotie A, Figlin R, Belldegrun A (2003) Carbonic anhydrase IX is an independent predictor of survival in advanced renal clear cell carcinoma: implications for prognosis and therapy. Clin Cancer Res 9:802–811

    PubMed  CAS  Google Scholar 

  15. Kim H, Seligson D, Liu X, Janzen N, Bui M, Yu H, Shi T, Belldegrun A, Horvath S, Figlin R (2005) Using tumor markers to predict the survival of patients with metastatic renal cell carcinoma. J Urol 173:1496–1501

    Article  PubMed  CAS  Google Scholar 

  16. Kim H, Seligson D, Liu X, Janzen N, Bui M, Yu H, Shi T, Horvath S, Figlin R, Belldegrun A (2004) Using protein expression to predict survival in clear cell renal carcinoma. Clin Cancer Res 10:5464–5471

    Article  PubMed  CAS  Google Scholar 

  17. Vesselli J, Shih J, Iyengar S, Marenchie J, Riss J, Worrell R, Torres-Cabala C, Tabios R, Mariotti A, Stearman R, Merino M, Walther M, Simon R, Klausner R, Linehan W (2003) Predicting survival in patients with metastatic kidney cancer by gene-expression profiling in the primary tumor. Proc Natl Acad Sci U S A 100:6958–6963

    Article  CAS  Google Scholar 

  18. Takahashi M, Teh B, Kanayama H (2006) Elucidation of the molecular signatures of renal cell carcinoma by gene expression profiling. J Med Invest 53:9–19

    Article  PubMed  Google Scholar 

  19. Semenza GL (2003) Targeting HIF-1 for cancer therapy. Nat Rev Cancer 3:721–732

    Article  PubMed  CAS  Google Scholar 

  20. Brauch H, Weirich G, Brieger J, Glavac D, Rodl H, Eichinger M, Feurer M, Weidt E, Puranakanitstha C, Neuhaus C, Pomer S, Brenner W, Schirmacher P, Storkel S, Rotter M, Masera A, Gugeler N, Decker HJ (2000) VHL alterations in human clear cell renal cell carcinoma: association with advanced tumor stage and a novel hot spot mutation. Cancer Res 60:1942–1948

    PubMed  CAS  Google Scholar 

  21. Yao M, Yoshida M, Kishida T, Nakaigawa N, Baba M, Kobayashi K, Miura T, Moriyama M, Nagashima Y, Nakatani Y, Kubota Y, Kondo K (2002) VHL tumor suppressor gene alterations associated with good prognosis in sporadic clear-cell renal carcinoma. J Natl Cancer Inst 94:1569–1575

    PubMed  CAS  Google Scholar 

  22. Yoshida M, Yao M, Ishikawa I, Kishida T, Nagashima Y, Kondo K, Nakaigawa N, Hosaka M (2002) Somatic von Hippel-Lindau disease gene mutation in clear-cell renal carcinomas associated with end-stage renal disease/acquired cystic disease of the kidney. Genes Chromosomes Cancer 35:359–364

    Article  PubMed  CAS  Google Scholar 

  23. Kondo K, Yao M, Yoshida M, Kishida T, Shuin T, Miura T, Moriyama M, Kobayashi K, Sakai N, Kaneko S, Kawakami S, Baba M, Nakaigawa N, Nagashima Y, Nakatani Y, Hosaka M (2002) Comprehensive mutational analysis of the VHL gene in sporadic renal cell carcinoma: relationship to clinicopathological parameters. Genes Chromosomes Cancer 34:58–68

    Article  PubMed  CAS  Google Scholar 

  24. Ivan M, Kaelin WG Jr (2001) The von Hippel-Lindau tumor suppressor protein. Curr Opin Genet Dev 11:27–34

    Article  PubMed  CAS  Google Scholar 

  25. Gupta K, Kshirsagar S, Li W, Gui L, Ramakrishnan S, Gupta P, Law PY, Hebbel RP (1999) VEGF prevents apoptosis of human microvascular endothelial cells via opposing effects on MAPK/ERK and SAPK/JNK signaling. Exp Cell Res 247:495–504

    Article  PubMed  CAS  Google Scholar 

  26. Nor JE, Christensen J, Liu J, Peters M, Mooney DJ, Strieter RM, Polverini PJ (2001) Up-Regulation of Bcl-2 in microvascular endothelial cells enhances intratumoral angiogenesis and accelerates tumor growth. Cancer Res 61:2183–2188

    PubMed  CAS  Google Scholar 

  27. Zundel W, Schindler C, Haas-Kogan D, Koong A, Kaper F, Chen E, Gottschalk AR, Ryan HE, Johnson RS, Jefferson AB, Stokoe D, Giaccia AJ (2000) Loss of PTEN facilitates HIF-1-mediated gene expression. Genes Dev 14:391–396

    PubMed  CAS  Google Scholar 

  28. Richard DE, Berra E, Gothie E, Roux D, Pouyssegur J (1999) p42/p44 mitogen-activated protein kinases phosphorylate hypoxia-inducible factor 1alpha (HIF-1alpha) and enhance the transcriptional activity of HIF-1. J Biol Chem 274:32631–32637

    Article  PubMed  CAS  Google Scholar 

  29. Fresno Vara JA, Casado E, de Castro J, Cejas P, Belda-Iniesta C, Gonzalez-Baron M (2004) PI3K/Akt signalling pathway and cancer. Cancer Treat Rev 30:193–204

    Article  PubMed  CAS  Google Scholar 

  30. Sabatini DM (2006) mTOR and cancer: insights into a complex relationship. Nat Rev Cancer 6:729–734

    Article  PubMed  CAS  Google Scholar 

  31. Dormond O, Madsen JC, Briscoe DM (2007) The effects of mTOR-Akt interactions on anti-apoptotic signaling in vascular endothelial cells. J Biol Chem 282:23679–23686

    Article  PubMed  CAS  Google Scholar 

  32. Land SC, Tee AR (2007) Hypoxia-inducible factor 1alpha is regulated by the mammalian target of rapamycin (mTOR) via an mTOR signaling motif. J Biol Chem 282:20534–20543

    Article  PubMed  CAS  Google Scholar 

  33. Brenner W, Farber G, Herget T, Lehr HA, Hengstler JG, Thuroff JW (2002) Loss of tumor suppressor protein PTEN during renal carcinogenesis. Int J Cancer 99:53–57

    Article  PubMed  CAS  Google Scholar 

  34. Hara S, Oya M, Mizuno R, Horiguchi A, Marumo K, Murai M (2005) Akt activation in renal cell carcinoma: contribution of a decreased PTEN expression and the induction of apoptosis by an Akt inhibitor. Ann Oncol 16:928–933

    Article  PubMed  CAS  Google Scholar 

  35. Loughna S, Sato TN (2001) Angiopoietin and Tie signaling pathways in vascular development. Matrix Biol 20:319–325

    Article  PubMed  CAS  Google Scholar 

  36. Singh H, Milner CS, Aguilar Hernandez MM, Patel N, Brindle NP (2009) Vascular endothelial growth factor activates the Tie family of receptor tyrosine kinases. Cell Signal 21:1346–1350

    Article  PubMed  CAS  Google Scholar 

  37. Maisonpierre PC, Suri C, Jones PF, Bartunkova S, Wiegand SJ, Radziejewski C, Compton D, McClain J, Aldrich TH, Papadopoulos N, Daly TJ, Davis S, Sato TN, Yancopoulos GD (1997) Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science 277:55–60

    Article  PubMed  CAS  Google Scholar 

  38. Findley CM, Cudmore MJ, Ahmed A, Kontos CD (2007) VEGF induces Tie2 shedding via a phosphoinositide 3-kinase/Akt dependent pathway to modulate Tie2 signaling. Arterioscler Thromb Vasc Biol 27:2619–2626

    Article  PubMed  CAS  Google Scholar 

  39. Yamakawa M, Liu LX, Belanger AJ, Date T, Kuriyama T, Goldberg MA, Cheng SH, Gregory RJ, Jiang C (2004) Expression of angiopoietins in renal epithelial and clear cell carcinoma cells: regulation by hypoxia and participation in angiogenesis. Am J Physiol Renal Physiol 287:F649–657

    Article  PubMed  CAS  Google Scholar 

  40. Hara S, Nakashiro K, Klosek SK, Ishikawa T, Shintani S, Hamakawa H (2006) Hypoxia enhances c-Met/HGF receptor expression and signaling by activating HIF-1alpha in human salivary gland cancer cells. Oral Oncol 42:593–598

    Article  PubMed  CAS  Google Scholar 

  41. Baldewijns MM, van Vlodrop IJ, Vermeulen PB, Soetekouw PM, van Engeland M, de Bruine AP (2010) VHL and HIF signaling in renal cell carcinogenesis. J Pathol 221(2):125–138

    PubMed  CAS  Google Scholar 

  42. Yagoda A, Bander NH (1989) Failure of cytotoxic chemotherapy, 1983–1988, and the emerging role of monoclonal antibodies for renal cancer. Urol Int 44:338–345

    Article  PubMed  CAS  Google Scholar 

  43. Horoszewicz JS, Murphy GP (1989) An assessment of the current use of human interferons in therapy of urological cancers. J Urol 142:1173–1180

    PubMed  CAS  Google Scholar 

  44. Coppin C, Porzsolt F, Awa A, Kumpf J, Coldman A, Wilt T (2005) Immunotherapy for advanced renal cell cancer. Cochrane Database Syst Rev:CD001425

  45. Pyrhonen S, Salminen E, Ruutu M, Lehtonen T, Nurmi M, Tammela T, Juusela H, Rintala E, Hietanen P, Kellokumpu-Lehtinen PL (1999) Prospective randomized trial of interferon alfa-2a plus vinblastine versus vinblastine alone in patients with advanced renal cell cancer. J Clin Oncol 17:2859–2867

    PubMed  CAS  Google Scholar 

  46. Mickisch GH, Garin A, van Poppel H, de Prijck L, Sylvester R (2001) Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: a randomised trial. Lancet 358:966–970

    Article  PubMed  CAS  Google Scholar 

  47. Flanigan RC, Mickisch G, Sylvester R, Tangen C, Van Poppel H, Crawford ED (2004) Cytoreductive nephrectomy in patients with metastatic renal cancer: a combined analysis. J Urol 171:1071–1076

    Article  PubMed  Google Scholar 

  48. Flanigan RC, Salmon SE, Blumenstein BA, Bearman SI, Roy V, McGrath PC, Caton JR Jr, Munshi N, Crawford ED (2001) Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. N Engl J Med 345:1655–1659

    Article  PubMed  CAS  Google Scholar 

  49. Rosenberg SA, Yang JC, White DE, Steinberg SM (1998) Durability of complete responses in patients with metastatic cancer treated with high-dose interleukin-2: identification of the antigens mediating response. Ann Surg 228:307–319

    Article  PubMed  CAS  Google Scholar 

  50. Klapper JA, Downey SG, Smith FO, Yang JC, Hughes MS, Kammula US, Sherry RM, Royal RE, Steinberg SM, Rosenberg S (2008) High-dose interleukin-2 for the treatment of metastatic renal cell carcinoma: a retrospective analysis of response and survival in patients treated in the surgery branch at the National Cancer Institute between 1986 and 2006. Cancer 113:293–301

    Article  PubMed  CAS  Google Scholar 

  51. Fyfe G, Fisher RI, Rosenberg SA, Sznol M, Parkinson DR, Louie AC (1995) Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. J Clin Oncol 13:688–696

    PubMed  CAS  Google Scholar 

  52. Negrier S, Escudier B, Lasset C, Douillard JY, Savary J, Chevreau C, Ravaud A, Mercatello A, Peny J, Mousseau M, Philip T, Tursz T (1998) Recombinant human interleukin-2, recombinant human interferon alfa-2a, or both in metastatic renal-cell carcinoma. Groupe Francais d'Immunotherapie. N Engl J Med 338:1272–1278

    Article  PubMed  CAS  Google Scholar 

  53. Atkins MB, Sparano J, Fisher RI, Weiss GR, Margolin KA, Fink KI, Rubinstein L, Louie A, Mier JW, Gucalp R et al (1993) Randomized phase II trial of high-dose interleukin-2 either alone or in combination with interferon alfa-2b in advanced renal cell carcinoma. J Clin Oncol 11:661–670

    PubMed  CAS  Google Scholar 

  54. Upton MP, Parker RA, Youmans A, McDermott DF, Atkins MB (2005) Histologic predictors of renal cell carcinoma response to interleukin-2-based therapy. J Immunother 28:488–495

    Article  PubMed  CAS  Google Scholar 

  55. Atkins M, Regan M, McDermott D, Mier J, Stanbridge E, Youmans A, Febbo P, Upton M, Lechpammer M, Signoretti S (2005) Carbonic anhydrase IX expression predicts outcome of interleukin 2 therapy for renal cancer. Clin Cancer Res 11:3714–3721

    Article  PubMed  CAS  Google Scholar 

  56. Kamba T, McDonald DM (2007) Mechanisms of adverse effects of anti-VEGF therapy for cancer. Br J Cancer 96:1788–1795

    Article  PubMed  CAS  Google Scholar 

  57. Imai K, Takaoka A (2006) Comparing antibody and small-molecule therapies for cancer. Nat Rev Cancer 6:714–727

    Article  PubMed  CAS  Google Scholar 

  58. Ivy SP, Wick JY, Kaufman BM (2009) An overview of small-molecule inhibitors of VEGFR signaling. Nat Rev Clin Oncol 6:569–579

    Article  PubMed  CAS  Google Scholar 

  59. Chen HX, Cleck JN (2009) Adverse effects of anticancer agents that target the VEGF pathway. Nat Rev Clin Oncol 6:465–477

    Article  PubMed  CAS  Google Scholar 

  60. Ainsworth NL, Lee JS, Eisen T (2009) Impact of anti-angiogenic treatments on metastatic renal cell carcinoma. Expert Rev Anticancer Ther 9:1793–1805

    Article  PubMed  CAS  Google Scholar 

  61. Jain RK (2001) Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat Med 7:987–989

    Article  PubMed  CAS  Google Scholar 

  62. Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335–2342

    Article  PubMed  CAS  Google Scholar 

  63. Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, Johnson DH (2006) Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 355:2542–2550

    Article  PubMed  CAS  Google Scholar 

  64. Giantonio BJ, Catalano PJ, Meropol NJ, O’Dwyer PJ, Mitchell EP, Alberts SR, Schwartz MA, Benson AB 3rd (2007) Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol 25:1539–1544

    Article  PubMed  CAS  Google Scholar 

  65. Miller K, Wang M, Gralow J, Dickler M, Cobleigh M, Perez EA, Shenkier T, Cella D, Davidson NE (2007) Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 357:2666–2676

    Article  PubMed  CAS  Google Scholar 

  66. Yang JC, Haworth L, Sherry RM, Hwu P, Schwartzentruber DJ, Topalian SL, Steinberg SM, Chen HX, Rosenberg SA (2003) A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 349:427–434

    Article  PubMed  CAS  Google Scholar 

  67. Escudier B, Pluzanska A, Koralewski P, Ravaud A, Bracarda S, Szczylik C, Chevreau C, Filipek M, Melichar B, Bajetta E, Gorbunova V, Bay JO, Bodrogi I, Jagiello-Gruszfeld A, Moore N (2007) Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet 370:2103–2111

    Article  PubMed  Google Scholar 

  68. Escudier B, Bellmunt J, Negrier S, Melichar B, Bracarda S, Ravaud A, Golding S, Jethwa S (2009) Final results of the phase III, randomized, double-blind AVOREN trial of first-line bevacizumab (BEV) + interferon-α2a (IFN) in metastatic renal cell carcinoma (mRCC). J Clin Oncol 27:Abstract 5020

  69. Rini BI, Halabi S, Rosenberg JE, Stadler WM, Vaena DA, Ou SS, Archer L, Atkins JN, Picus J, Czaykowski P, Dutcher J, Small EJ (2008) Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. J Clin Oncol 26:5422–5428

    Article  PubMed  CAS  Google Scholar 

  70. Rini B, Halabi S, Rosenberg J, Stadler W, Vaena D, Atkins J, Picus J, Czaykowski P, Dutcher J, Small E (2009) Bevacizumab plus interferon-alpha versus interferon-alpha monotherapy in patients with metastatic renal cell carcinoma: Results of overall survival for CALGB 90206. J Clin Oncol 27:Abstract LBA5019

  71. Motzer RJ, Michaelson MD, Redman BG, Hudes GR, Wilding G, Figlin RA, Ginsberg MS, Kim ST, Baum CM, DePrimo SE, Li JZ, Bello CL, Theuer CP, George DJ, Rini BI (2006) Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol 24:16–24

    Article  PubMed  CAS  Google Scholar 

  72. Motzer RJ, Rini BI, Bukowski RM, Curti BD, George DJ, Hudes GR, Redman BG, Margolin KA, Merchan JR, Wilding G, Ginsberg MS, Bacik J, Kim ST, Baum CM, Michaelson MD (2006) Sunitinib in patients with metastatic renal cell carcinoma. Jama 295:2516–2524

    Article  PubMed  CAS  Google Scholar 

  73. Motzer R, Figlin R, Hutson T, Tomczak P, Bukowski R, Rixe O, Bjarnason G, Kim S, Chen I, Michaelson D (2007) Sunitinib versus interferon-alfa (IFN-α) as first-line treatment of metastatic renal cell carcinoma (mRCC): Updated results and analysis of prognostic factors. J Clin Oncol 25:Abstract 5024

  74. Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Oudard S, Negrier S, Szczylik C, Pili R, Bjarnason GA, Garcia-del-Muro X, Sosman JA, Solska E, Wilding G, Thompson JA, Kim ST, Chen I, Huang X, Figlin RA (2009) Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol 27:3584–3590

    Article  PubMed  CAS  Google Scholar 

  75. Mizukami Y, Kohgo Y, Chung DC (2007) Hypoxia inducible factor-1 independent pathways in tumor angiogenesis. Clin Cancer Res 13:5670–5674

    Article  PubMed  CAS  Google Scholar 

  76. Huang D, Ding Y, Luo WM, Bender S, Qian CN, Kort E, Zhang ZF, VandenBeldt K, Duesbery NS, Resau JH, Teh BT (2008) Inhibition of MAPK kinase signaling pathways suppressed renal cell carcinoma growth and angiogenesis in vivo. Cancer Res 68:81–88

    Article  PubMed  CAS  Google Scholar 

  77. Newman DJ, Cragg GM (2007) Natural products as sources of new drugs over the last 25 years. J Nat Prod 70:461–477

    Article  PubMed  CAS  Google Scholar 

  78. Wan PT, Garnett MJ, Roe SM, Lee S, Niculescu-Duvaz D, Good VM, Jones CM, Marshall CJ, Springer CJ, Barford D, Marais R (2004) Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell 116:855–867

    Article  PubMed  CAS  Google Scholar 

  79. Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, Negrier S, Chevreau C, Solska E, Desai AA, Rolland F, Demkow T, Hutson TE, Gore M, Freeman S, Schwartz B, Shan M, Simantov R, Bukowski RM (2007) Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 356:125–134

    Article  PubMed  CAS  Google Scholar 

  80. Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Staehler M, Negrier S, Chevreau C, Desai AA, Rolland F, Demkow T, Hutson TE, Gore M, Anderson S, Hofilena G, Shan M, Pena C, Lathia C, Bukowski RM (2009) Sorafenib for treatment of renal cell carcinoma: Final efficacy and safety results of the phase III treatment approaches in renal cancer global evaluation trial. J Clin Oncol 27:3312–3318

    Article  PubMed  CAS  Google Scholar 

  81. Hutson TE, Davis ID, Machiels JP, De Souza PL, Rottey S, Hong BF, Epstein RJ, Baker KL, McCann L, Crofts T, Pandite L, Figlin RA (2010) Efficacy and safety of pazopanib in patients with metastatic renal cell carcinoma. J Clin Oncol 28:475–480

    Article  PubMed  CAS  Google Scholar 

  82. Sternberg CN, Davis ID, Mardiak J, Szczylik C, Lee E, Wagstaff J, Barrios CH, Salman P, Gladkov OA, Kavina A, Zarba JJ, Chen M, McCann L, Pandite L, Roychowdhury DF, Hawkins RE (2010) Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol 28:1061–1068

    Article  PubMed  CAS  Google Scholar 

  83. Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, Staroslawska E, Sosman J, McDermott D, Bodrogi I, Kovacevic Z, Lesovoy V, Schmidt-Wolf IG, Barbarash O, Gokmen E, O’Toole T, Lustgarten S, Moore L, Motzer RJ (2007) Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 356:2271–2281

    Article  PubMed  CAS  Google Scholar 

  84. Atkins MB, Hidalgo M, Stadler WM, Logan TF, Dutcher JP, Hudes GR, Park Y, Liou SH, Marshall B, Boni JP, Dukart G, Sherman ML (2004) Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma. J Clin Oncol 22:909–918

    Article  PubMed  CAS  Google Scholar 

  85. Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, Grunwald V, Thompson JA, Figlin RA, Hollaender N, Urbanowitz G, Berg WJ, Kay A, Lebwohl D, Ravaud A (2008) Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 372:449–456

    Article  PubMed  CAS  Google Scholar 

  86. Jain RK, Xu L (2007) alphaPlGF: a new kid on the antiangiogenesis block. Cell 131:443–445

    Article  PubMed  CAS  Google Scholar 

  87. Matsumoto K, Suzuki K, Koike H, Okamura K, Tsuchiya K, Uchida T, Takezawa Y, Kobayashi M, Yamanaka H (2003) Prognostic significance of plasma placental growth factor levels in renal cell cancer: an association with clinical characteristics and vascular endothelial growth factor levels. Anticancer Res 23:4953–4958

    PubMed  CAS  Google Scholar 

  88. Fischer C, Jonckx B, Mazzone M, Zacchigna S, Loges S, Pattarini L, Chorianopoulos E, Liesenborghs L, Koch M, De Mol M, Autiero M, Wyns S, Plaisance S, Moons L, van Rooijen N, Giacca M, Stassen JM, Dewerchin M, Collen D, Carmeliet P (2007) Anti-PlGF inhibits growth of VEGF(R)-inhibitor-resistant tumors without affecting healthy vessels. Cell 131:463–475

    Article  PubMed  CAS  Google Scholar 

  89. Garcia J, Hudes G, Choueiri T, Stadler W, Wood L, Bhatia S, Youssoufian H, Rowinsky E, Schwartz J, Thompson J (2010) Phase II study of IMC-1121B in patients with metastatic renal cancer (mRCC) following VEGFR-2 tyrosine kinase inhibitor (TKI) therapy (IMCL CP12-0605/NCT00515697). 2010 Genitourinary Cancers Symposium: Abstract 326

  90. Holash J, Davis S, Papadopoulos N, Croll SD, Ho L, Russell M, Boland P, Leidich R, Hylton D, Burova E, Ioffe E, Huang T, Radziejewski C, Bailey K, Fandl JP, Daly T, Wiegand SJ, Yancopoulos GD, Rudge JS (2002) VEGF-Trap: a VEGF blocker with potent antitumor effects. Proc Natl Acad Sci U S A 99:11393–11398

    Article  PubMed  CAS  Google Scholar 

  91. Lawrence DS, Niu J (1998) Protein kinase inhibitors: the tyrosine-specific protein kinases. Pharmacol Ther 77:81–114

    Article  PubMed  CAS  Google Scholar 

  92. Borzilleri RM, Zheng X, Qian L, Ellis C, Cai ZW, Wautlet BS, Mortillo S, Jeyaseelan R Sr, Kukral DW, Fura A, Kamath A, Vyas V, Tokarski JS, Barrish JC, Hunt JT, Lombardo LJ, Fargnoli J, Bhide RS (2005) Design, synthesis, and evaluation of orally active 4-(2, 4-difluoro-5-(methoxycarbamoyl)phenylamino)pyrrolo[2, 1-f][1, 2, 4]triaz ines as dual vascular endothelial growth factor receptor-2 and fibroblast growth factor receptor-1 inhibitors. J Med Chem 48:3991–4008

    Article  PubMed  CAS  Google Scholar 

  93. Rixe O, Bukowski RM, Michaelson MD, Wilding G, Hudes GR, Bolte O, Motzer RJ, Bycott P, Liau KF, Freddo J, Trask PC, Kim S, Rini BI (2007) Axitinib treatment in patients with cytokine-refractory metastatic renal-cell cancer: a phase II study. Lancet Oncol 8:975–984

    Article  PubMed  Google Scholar 

  94. Rini B, Wilding G, Hudes H (2007) Axitinib (AGO13736:AG) in patients with metastatic clear cell renal cell cancer (RCC) refractory to sorafenib. Eur J Cancer 5:Abstract 300

  95. Bhargava P, Esteves B, Nosov D, Lipatov O, Lyulko A, Anischenko A, Chacko R, Lee P, Al-Adhami M, Ryan J (2009) Updated activity and safety results of a phase II randomized discontinuation trial (RDT) of AV-951, a potent and selective VEGFR1, 2, and 3 kinase inhibitor, in patients with renal cell carcinoma (RCC). J Clin Oncol 27:Abstract 5032

    Google Scholar 

  96. Emoto N, Isozaki O, Ohmura E, Ito F, Tsushima T, Shizume K, Demura H, Toma H (1994) Basic fibroblast growth factor (FGF-2) in renal cell carcinoma, which is indistinguishable from that in normal kidney, is involved in renal cell carcinoma growth. J Urol 152:1626–1631

    PubMed  CAS  Google Scholar 

  97. Takahashi A, Sasaki H, Kim SJ, Kakizoe T, Miyao N, Sugimura T, Terada M, Tsukamoto T (1999) Identification of receptor genes in renal cell carcinoma associated with angiogenesis by differential hybridization technique. Biochem Biophys Res Commun 257:855–859

    Article  PubMed  CAS  Google Scholar 

  98. Angevin E, Lopez J, Pande A, Moldovan C, Shi M, Soria J, Wang X, Harzstark A, Saro J, Escudier B (2009) TKI258 (dovitinib lactate) in metastatic renal cell carcinoma (mRCC) patients refractory to approved targeted therapies: A phase I/II dose finding and biomarker study. J Clin Oncol 27:Abstract 3563

  99. Choueiri TK, Plantade A, Elson P, Negrier S, Ravaud A, Oudard S, Zhou M, Rini BI, Bukowski RM, Escudier B (2008) Efficacy of sunitinib and sorafenib in metastatic papillary and chromophobe renal cell carcinoma. J Clin Oncol 26:127–131

    Article  PubMed  CAS  Google Scholar 

  100. Yap T, Patnaik A, Fearen I, Olmos D, Papadopoulos K, Tunariu N, Sullivan D, Yan L, Bono JD, Tolcher A (2010) First-in-class phase I trial of a selective Akt inhibitor, MK2206 (MK), evaluating alternate day (QOD) and once weekly (QW) doses in advanced cancer patients (pts) with evidence of target modulation and antitumor activity. J Clin Oncol 28:Abstr 3009

    Google Scholar 

  101. Gills JJ, Dennis PA (2009) Perifosine: update on a novel Akt inhibitor. Curr Oncol Rep 11:102–110

    Article  PubMed  CAS  Google Scholar 

  102. Cho D, Figlin R, Flaherty K, Michaelson D, Sosman J, Ghebremichael M, Bowers M, Mier J, Atkins M, McDermott D (2009) A phase II trial of perifosine in patients with advanced renal cell carcinoma (RCC) who have failed tyrosine kinase inhibitors (TKI). J Clin Oncol 27:Abstract 5101

  103. Vogelzang N, Hutson T, Samlowski W, Somer B, Richey S, Alemany C, Loesch D, Richards P, Gardner L, Sportelli P (2009) Phase II study of perifosine in metastatic renal cell carcinoma (RCC) progressing after prior therapy (Rx) with a VEGF receptor inhibitor. J Clin Oncol 27:Abstract 5034

  104. Curti BD (2006) Immunomodulatory and antitumor effects of interleukin-21 in patients with renal cell carcinoma. Expert Rev Anticancer Ther 6:905–909

    Article  PubMed  CAS  Google Scholar 

  105. Kumano M, Hara I, Furukawa J, Oniki S, Nagai H, Miyake H, Fujisawa M (2007) Interleukin-21 activates cytotoxic T lymphocytes and natural killer cells to generate antitumor response in mouse renal cell carcinoma. J Urol 178:1504–1509

    Article  PubMed  Google Scholar 

  106. Thompson JA, Curti BD, Redman BG, Bhatia S, Weber JS, Agarwala SS, Sievers EL, Hughes SD, DeVries TA, Hausman DF (2008) Phase I study of recombinant interleukin-21 in patients with metastatic melanoma and renal cell carcinoma. J Clin Oncol 26:2034–2039

    Article  PubMed  CAS  Google Scholar 

  107. Bleumer I, Knuth A, Oosterwijk E, Hofmann R, Varga Z, Lamers C, Kruit W, Melchior S, Mala C, Ullrich S, De Mulder P, Mulders PF, Beck J (2004) A phase II trial of chimeric monoclonal antibody G250 for advanced renal cell carcinoma patients. Br J Cancer 90:985–990

    Article  PubMed  CAS  Google Scholar 

  108. Liu Z, Smyth FE, Renner C, Lee FT, Oosterwijk E, Scott AM (2002) Anti-renal cell carcinoma chimeric antibody G250: cytokine enhancement of in vitro antibody-dependent cellular cytotoxicity. Cancer Immunol Immunother 51:171–177

    Article  PubMed  CAS  Google Scholar 

  109. Dohlsten M, Abrahmsen L, Bjork P, Lando PA, Hedlund G, Forsberg G, Brodin T, Gascoigne NR, Forberg C, Lind P et al (1994) Monoclonal antibody-superantigen fusion proteins: tumor-specific agents for T-cell-based tumor therapy. Proc Natl Acad Sci U S A 91:8945–8949

    Article  PubMed  CAS  Google Scholar 

  110. Erlandsson E, Andersson K, Cavallin A, Nilsson A, Larsson-Lorek U, Niss U, Sjoberg A, Wallen-Ohman M, Antonsson P, Walse B, Forsberg G (2003) Identification of the antigenic epitopes in staphylococcal enterotoxins A and E and design of a superantigen for human cancer therapy. J Mol Biol 333:893–905

    Article  PubMed  CAS  Google Scholar 

  111. Shaw DM, Connolly NB, Patel PM, Kilany S, Hedlund G, Nordle O, Forsberg G, Zweit J, Stern PL, Hawkins RE (2007) A phase II study of a 5 T4 oncofoetal antigen tumour-targeted superantigen (ABR-214936) therapy in patients with advanced renal cell carcinoma. Br J Cancer 96:567–574

    Article  PubMed  CAS  Google Scholar 

  112. Srivastava PK, Amato RJ (2001) Heat shock proteins: the ‘Swiss Army Knife’ vaccines against cancers and infectious agents. Vaccine 19:2590–2597

    Article  PubMed  CAS  Google Scholar 

  113. Jonasch E, Wood C, Tamboli P, Pagliaro LC, Tu SM, Kim J, Srivastava P, Perez C, Isakov L, Tannir N (2008) Vaccination of metastatic renal cell carcinoma patients with autologous tumour-derived vitespen vaccine: clinical findings. Br J Cancer 98:1336–1341

    Article  PubMed  CAS  Google Scholar 

  114. Wood C, Srivastava P, Bukowski R, Lacombe L, Gorelov AI, Gorelov S, Mulders P, Zielinski H, Hoos A, Teofilovici F, Isakov L, Flanigan R, Figlin R, Gupta R, Escudier B (2008) An adjuvant autologous therapeutic vaccine (HSPPC-96; vitespen) versus observation alone for patients at high risk of recurrence after nephrectomy for renal cell carcinoma: a multicentre, open-label, randomised phase III trial. Lancet 372:145–154

    Article  PubMed  CAS  Google Scholar 

  115. Yang JC (2008) Vitespen: a vaccine for renal cancer? Lancet 372:92–93

    Article  PubMed  Google Scholar 

  116. Staehler M, Stenzl A, Dietrich PY, Eisen T, Haferkamp A, Beck J, Mayer A, Walter S, Singh-Jasuja H, Stief C (2007) A phase I study to evaluate safety, immunogenicity and anti-tumor activity of the multi-peptide vaccine IMA901 in renal cell carcinoma patients (RCC). J Clin Oncol 25:Abstract 5098

  117. Laber D, Taft B, Kloecker G, Bates P, Trent J, Miller D (2006) Extended phase I study of AS1411 in renal and non-small cell lung cancers. J Clin Oncol 24:Abstract 13098

  118. Marshall J, Posey J, Hwang J, Malik S, Shen R, Kazempour K, White L, Fraser K, Chang C, Ahn C (2007) A phase I trial of RX-0201 (AKT anti-sense) in patients with an advanced cancer. J Clin Oncol 25:Abstract 3564

  119. Patnaik A, Chiorean E, Tolcher A, Papadopoulos K, Beeram M, Kee D, Waddell M, Gilles E, Buchbinder A (2009) EZN-2968, a novel hypoxia-inducible factor-1α (HIF-1α) messenger ribonucleic acid (mRNA) antagonist: Results of a phase I, pharmacokinetic (PK), dose-escalation study of daily administration in patients (pts) with advanced malignancies. J Clin Oncol 27:Abstract 2564

    Google Scholar 

  120. Hewitson KS, Schofield CJ (2004) The HIF pathway as a therapeutic target. Drug Discov Today 9:704–711

    Article  PubMed  CAS  Google Scholar 

  121. Semenza GL (2007) Evaluation of HIF-1 inhibitors as anticancer agents. Drug Discov Today 12:853–859

    Article  PubMed  CAS  Google Scholar 

  122. Ellis L, Hammers H, Pili R (2009) Targeting tumor angiogenesis with histone deacetylase inhibitors. Cancer Lett 280:145–153

    Article  PubMed  CAS  Google Scholar 

  123. Liu T, Kuljaca S, Tee A, Marshall GM (2006) Histone deacetylase inhibitors: multifunctional anticancer agents. Cancer Treat Rev 32:157–165

    Article  PubMed  CAS  Google Scholar 

  124. Sasakawa Y, Naoe Y, Inoue T, Sasakawa T, Matsuo M, Manda T, Mutoh S (2002) Effects of FK228, a novel histone deacetylase inhibitor, on human lymphoma U-937 cells in vitro and in vivo. Biochem Pharmacol 64:1079–1090

    Article  PubMed  CAS  Google Scholar 

  125. Rossig L, Li H, Fisslthaler B, Urbich C, Fleming I, Forstermann U, Zeiher AM, Dimmeler S (2002) Inhibitors of histone deacetylation downregulate the expression of endothelial nitric oxide synthase and compromise endothelial cell function in vasorelaxation and angiogenesis. Circ Res 91:837–844

    Article  PubMed  Google Scholar 

  126. Kwon HJ, Kim MS, Kim MJ, Nakajima H, Kim KW (2002) Histone deacetylase inhibitor FK228 inhibits tumor angiogenesis. Int J Cancer 97:290–296

    Article  PubMed  CAS  Google Scholar 

  127. Qian DZ, Kachhap SK, Collis SJ, Verheul HM, Carducci MA, Atadja P, Pili R (2006) Class II histone deacetylases are associated with VHL-independent regulation of hypoxia-inducible factor 1 alpha. Cancer Res 66:8814–8821

    Article  PubMed  CAS  Google Scholar 

  128. Pili R (2009) Recent investigations of histone deacetylase inhibitors in renal cell carcinoma. Clin Adv Hematol Oncol 7:252–254

    PubMed  Google Scholar 

  129. Kelly WK, O'Connor OA, Krug LM, Chiao JH, Heaney M, Curley T, MacGregore-Cortelli B, Tong W, Secrist JP, Schwartz L, Richardson S, Chu E, Olgac S, Marks PA, Scher H, Richon VM (2005) Phase I study of an oral histone deacetylase inhibitor, suberoylanilide hydroxamic acid, in patients with advanced cancer. J Clin Oncol 23:3923–3931

    Article  PubMed  CAS  Google Scholar 

  130. Samlowski WE, Wong B, Vogelzang NJ (2008) Management of renal cancer in the tyrosine kinase inhibitor era: a view from 3 years on. BJU Int 102:162–165

    Article  PubMed  CAS  Google Scholar 

  131. Di Lorenzo G, Carteni G, Autorino R, Bruni G, Tudini M, Rizzo M, Aieta M, Gonnella A, Rescigno P, Perdona S, Giannarini G, Pignata S, Longo N, Palmieri G, Imbimbo C, De Laurentiis M, Mirone V, Ficorella C, De Placido S (2009) Phase II study of sorafenib in patients with sunitinib-refractory metastatic renal cell cancer. J Clin Oncol 27:4469–4474

    Article  PubMed  Google Scholar 

  132. Shepard R, Rini B, Garcia J (2008) A multicenter prospective trial of sorafenib in patients (pts) with metastatic clear cell renal cell carcinoma (mccRCC) refractory to prior sunitinib or bevacizumab. J Clin Oncol 26:Abstract 5123

  133. Paglino C, Porta C (2010) Sequencing or not sequencing multikinase inhibitors in kidney cancer: this is the dilemma. Oncol Rev 4:1–3

    Article  Google Scholar 

  134. Deprimo SE, Bello CL, Smeraglia J, Baum CM, Spinella D, Rini BI, Michaelson MD, Motzer RJ (2007) Circulating protein biomarkers of pharmacodynamic activity of sunitinib in patients with metastatic renal cell carcinoma: modulation of VEGF and VEGF-related proteins. J Transl Med 5:32

    Article  PubMed  CAS  Google Scholar 

  135. O'Reilly KE, Rojo F, She QB, Solit D, Mills GB, Smith D, Lane H, Hofmann F, Hicklin DJ, Ludwig DL, Baselga J, Rosen N (2006) mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res 66:1500–1508

    Article  PubMed  CAS  Google Scholar 

  136. Feldman DR, Baum MS, Ginsberg MS, Hassoun H, Flombaum CD, Velasco S, Fischer P, Ronnen E, Ishill N, Patil S, Motzer RJ (2009) Phase I trial of bevacizumab plus escalated doses of sunitinib in patients with metastatic renal cell carcinoma. J Clin Oncol 27:1432–1439

    Article  PubMed  CAS  Google Scholar 

  137. Motzer RJ, Hudes G, Wilding G, Schwartz LH, Hariharan S, Kempin S, Fayyad R, Figlin RA (2009) Phase I trial of sunitinib malate plus interferon-alpha for patients with metastatic renal cell carcinoma. Clin Genitourin Cancer 7:28–33

    Article  PubMed  CAS  Google Scholar 

  138. Patel PH, Senico PL, Curiel RE, Motzer RJ (2009) Phase I study combining treatment with temsirolimus and sunitinib malate in patients with advanced renal cell carcinoma. Clin Genitourin Cancer 7:24–27

    Article  PubMed  CAS  Google Scholar 

  139. Biswas S, Kelly J, Eisen T (2009) Cytoreductive nephrectomy in metastatic clear-cell renal cell carcinoma: perspectives in the tyrosine kinase inhibitor era. Oncologist 14:52–59

    Article  PubMed  Google Scholar 

Download references

Conflict of interest statement

Professor Eisen has received research support and honoraria from Bayer and Pfizer, and honoraria from Weth, Novartis and Roche. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Author information

Authors and Affiliations

  1. University Department of Oncology, Addenbrooke’s Hospital, University of Cambridge, Cambridge, CB2 2QQ, UK

    Bristi Basu & Tim Eisen

  2. Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK

    Tim Eisen

Authors
  1. Bristi Basu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tim Eisen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tim Eisen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Basu, B., Eisen, T. Perspectives in drug development for metastatic renal cell cancer. Targ Oncol 5, 139–156 (2010). https://doi.org/10.1007/s11523-010-0149-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11523-010-0149-2

Keywords

Search

Navigation