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Targeted Therapy in Renal Cell Carcinoma

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Targeted Cancer Therapy

Part of the book series: Current Clinical Oncology™ ((CCO))

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Abstract

Renal cell carcinoma affects close to 40,000 people per year in the United States; and once it is metastatic, treatment options have historically been limited. With our emerging understanding of the molecular biology of renal cell carcinoma, we have recently acquired an expanding armamentarium of agents that target vascular and intracellular pathways involved in renal carcinogenesis. This chapter describes the key agents and the clinical data supporting their use. The chapter concludes with several of the key dilemmas we will face over the next decade when approaching the treatment of renal cell carcinoma.

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References

  1. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2006. CA Cancer J Clin 2006;56(2):106–30.

    Google Scholar 

  2. Patel PH, Chaganti RS, Motzer RJ. Targeted therapy for metastatic renal cell carcinoma. Br J Cancer 2006;94(5):614–9.

    PubMed  CAS  Google Scholar 

  3. Chow WH, Devesa SS, Warren JL, et al. Rising incidence of renal cell cancer in the United States. JAMA 1999;281(17):1628–31.

    Article  PubMed  CAS  Google Scholar 

  4. Pantuck AJ, Zisman A, Belldegrun AS. The changing natural history of renal cell carcinoma. J Urol 2001;166(5):1611–23.

    Article  PubMed  CAS  Google Scholar 

  5. Presti JC Jr, Rao PH, Chen Q, et al. Histopathological, cytogenetic, and molecular characterization of renal cortical tumors. Cancer Res 1991;51(5):1544–52.

    PubMed  Google Scholar 

  6. Weiss GR, Margolin KA, Sznol M, et al. A phase II study of the continuous intravenous infusion of interleukin-6 for metastatic renal cell carcinoma. J Immunother Emphasis Tumor Immunol 1995;18(1):52–6.

    PubMed  CAS  Google Scholar 

  7. Fuhrman SA, Lasky LC, Limas C. Prognostic significance of morphologic parameters in renal cell carcinoma. Am J Surg Pathol 1982;6(7):655–63.

    PubMed  CAS  Google Scholar 

  8. Mancilla-Jimenez R, Stanley RJ, Blath RA. Papillary renal cell carcinoma: a clinical, radiologic, and pathologic study of 34 cases. Cancer 1976;38(6):2469–80.

    Article  PubMed  CAS  Google Scholar 

  9. Kovacs G, Wilkens L, Papp T, et al. Differentiation between papillary and nonpapillary renal cell carcinomas by DNA analysis. J Natl Cancer Inst 1989;81(7):527–30.

    Article  PubMed  CAS  Google Scholar 

  10. Kovacs G, Fuzesi L, Emanual A, et al. Cytogenetics of papillary renal cell tumors. Genes Chromosomes Cancer 1991;3(4):249–55.

    Article  PubMed  CAS  Google Scholar 

  11. Sene AP, Hunt L, McMahon RF, et al. Renal carcinoma in patients undergoing nephrectomy: analysis of survival and prognostic factors. Br J Urol 1992;70(2):125–34.

    PubMed  CAS  Google Scholar 

  12. Motzer RJ, Bacik J, Mariani T, et al. Treatment outcome and survival associated with metastatic renal cell carcinoma of non-clear-cell histology. J Clin Oncol 2002;20(9):2376–81.

    Article  PubMed  Google Scholar 

  13. Akhtar M, Kardar H, Linjawi T, et al. Chromophobe cell carcinoma of the kidney: a clinicopathologic study of 21 cases. Am J Surg Pathol 1995;19(11):1245–56.

    Article  PubMed  CAS  Google Scholar 

  14. Speicher MR, Schoell B, du Manoir S, et al. Specific loss of chromosomes 1, 2, 6, 10, 13, 17, and 21 in chromophobe renal cell carcinomas revealed by comparative genomic hybridization. Am J Pathol 1994;145(2):356–64.

    PubMed  CAS  Google Scholar 

  15. Kovacs A, Kovacs G. Low chromosome number in chromophobe renal cell carcinomas. Genes Chromosomes Cancer 1992;4(3):267–8.

    Article  PubMed  CAS  Google Scholar 

  16. Kennedy SM, Merino MJ, Linehan WM, et al. Collecting duct carcinoma of the kidney. Hum Pathol 1990;21(4):449–56.

    Article  PubMed  CAS  Google Scholar 

  17. Davis CJ Jr, Mostofi FK, Sesterhenn IA. Renal medullary carcinoma: the seventh sickle cell nephropathy. Am J Surg Pathol 1995;19(1):1–11.

    PubMed  Google Scholar 

  18. Laissy JP, Menegazzo D, Debray MP, et al. Renal carcinoma: diagnosis of venous invasion with Gd-enhanced MR venography. Eur Radiol 2000;10(7):1138–43.

    Article  PubMed  CAS  Google Scholar 

  19. Stahlschmidt J, Cullinane C, Roberts P, et al. Renal medullary carcinoma: prolonged remission with chemotherapy, immunohistochemical characterisation and evidence of bcr/abl rearrangement. Med Pediatr Oncol 1999;33(6):551–7.

    Article  PubMed  CAS  Google Scholar 

  20. Simpson L, He X, Pins M, et al. Renal medullary carcinoma and ABL gene amplification. J Urol 2005;173(6):1883–8.

    Article  PubMed  Google Scholar 

  21. Tomlinson GE, Nisen PD, Timmons CF, et al. Cytogenetics of a renal cell carcinoma in a 17-month-old child: evidence for Xp11.2 as a recurring breakpoint. Cancer Genet Cytogenet 1991;57(1):11–7.

    Article  PubMed  CAS  Google Scholar 

  22. Heimann P, El Housni H, Ogur G, et al. Fusion of a novel gene, RCC17, to the TFE3 gene in t(X;17)(p11.2;q25.3)-bearing papillary renal cell carcinomas. Cancer Res 2001;61(10):4130–5.

    PubMed  CAS  Google Scholar 

  23. Gnarra JR, Glenn GM, Latif F, et al. Molecular genetic studies of sporadic and familial renal cell carcinoma. Urol Clin North Am 1993;20(2):207–16.

    PubMed  CAS  Google Scholar 

  24. Lonser RR, Glenn GM, Walther M, et al. von Hippel-Lindau disease. Lancet 2003;361(9374):2059–67.

    Article  PubMed  CAS  Google Scholar 

  25. Kaelin WG Jr. Molecular basis of the VHL hereditary cancer syndrome. Nat Rev Cancer 2002;2(9):673–82.

    Article  PubMed  CAS  Google Scholar 

  26. Semenza GL. HIF-1 and human disease: one highly involved factor. Genes Dev 2000;14(16):1983–91.

    PubMed  CAS  Google Scholar 

  27. Masson N, William C, Maxwell PH, et al. Independent function of two destruction domains in hypoxia-inducible factor-alpha chains activated by prolyl hydroxylation. EMBO J 2001;20:5197–206.

    Article  PubMed  CAS  Google Scholar 

  28. Lonergan KM, Iliopoulos O, Ohh M, et al. Regulation of hypoxia-inducible mRNAs by the von Hippel-Lindau tumor suppressor protein requires binding to complexes containing elongins B/C and Cul2. Mol Cell Biol 1998;18(2):732–41.

    PubMed  CAS  Google Scholar 

  29. Jaakkola P, Mole DR, Tian Y-M, et al. Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2s-regulated prolyl hydroxylation. Science 2001;292(5516):468–72.

    Article  PubMed  CAS  Google Scholar 

  30. Yu F, White SB, Zhao Q, et al. HIF-1alpha binding to VHL is regulated by stimulus-sensitive proline hydroxylation. Proc Natl Acad Sci U S A 2001;98(17):9630–5.

    Article  PubMed  CAS  Google Scholar 

  31. Bruick RK, McKnight SL. A conserved family of prolyl-4-hydroxylases that modify HIF. Science 2001;294(5545):1337–40.

    Article  PubMed  CAS  Google Scholar 

  32. 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(1):68–73.

    Article  PubMed  CAS  Google Scholar 

  33. Comoglio PM, Tamagnone L, Boccaccio C. Plasminogen-related growth factor and semaphorin receptors: a gene superfamily controlling invasive growth. Exp Cell Res 1999;253(1):88–99.

    Article  PubMed  CAS  Google Scholar 

  34. Stella MC, Comoglio PM. HGF: a multifunctional growth factor controlling cell scattering. Int J Biochem Cell Biol 1999;31(12):1357–62.

    Article  PubMed  CAS  Google Scholar 

  35. Van der Voort R, Taher T, Derksen P, et al. The hepatocyte growth factor/MET pathway in development, tumorigenesis, and B-cell differentiation. Adv Cancer Res 2000;79:39–90.

    PubMed  Google Scholar 

  36. Alam NA, Rowan AJ, Wortham NC, et al. Genetic and functional analyses of FH mutations in multiple cutaneous and uterine leiomyomatosis, hereditary leiomyomatosis and renal cancer, and fumarate hydratase deficiency. Hum Mol Genet 2003;12(11):1241–52.

    Article  PubMed  CAS  Google Scholar 

  37. Kiuru M, Launonen V, Hietala M, et al. Familial cutaneous leiomyomatosis is a two-hit condition associated with renal cell cancer of characteristic histopathology. Am J Pathol 2001;159(3):825–9.

    PubMed  CAS  Google Scholar 

  38. Launonen V, Vierimaa O, Kiuru M, et al. Inherited susceptibility to uterine leiomyomas and renal cell cancer. Proc Natl Acad Sci U S A 2001;98(6):3387–92.

    Article  PubMed  CAS  Google Scholar 

  39. Tomlinson IP, Alam NA, Rowan AJ, et al. Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat Genet 2002;30(4):406–10.

    Article  PubMed  CAS  Google Scholar 

  40. 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(1):95–106.

    Article  PubMed  CAS  Google Scholar 

  41. Pavlovich CP, Walther MM, Eyler RA, et al. Renal tumors in the Birt-Hogg-Dube syndrome. Am J Surg Pathol 2002;26(12):1542–52.

    Article  PubMed  Google Scholar 

  42. Zbar B, Alvord WG, Glenn G, et al. Risk of renal and colonic neoplasms and spontaneous pneumothorax in the Birt-Hogg-Dube syndrome. Cancer Epidemiol Biomarkers Prev 2002;11(4):393–400.

    PubMed  Google Scholar 

  43. Pavlovich CP, Grubb RL 3rd, Hurley K, et al. Evaluation and management of renal tumors in the Birt-Hogg-Dube syndrome. J Urol 2005;173(5):1482–6.

    Article  PubMed  Google Scholar 

  44. Nickerson M, Warren M, Toro J, 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(2):157.

    Article  PubMed  CAS  Google Scholar 

  45. Van Slegtenhorst M, de Hoogt R, Hermans C, et al. Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science 1997;277(5327):805–8.

    Article  PubMed  Google Scholar 

  46. Dabora SL, Jozwiak S, Franz DN, et al. Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs. Am J Hum Genet 2001;68(1):64–80.

    Article  PubMed  CAS  Google Scholar 

  47. Roach ES, Gomez MR, Northrup H. Tuberous sclerosis complex consensus conference: revised clinical diagnostic criteria. J Child Neurol 1998;13(12):624–8.

    Article  PubMed  CAS  Google Scholar 

  48. Yang XJ, Sugimura J, Tretiakova MS, et al. Gene expression profiling of renal medullary carcinoma: potential clinical relevance. Cancer 2004;100(5):976–85.

    Article  PubMed  Google Scholar 

  49. Rini BI, Jaeger E, Weinberg V, et al. Clinical response to therapy targeted at vascular endothelial growth factor in metastatic renal cell carcinoma: impact of patient characteristics and Von Hippel-Lindau gene status. BJU Int 2006;98(4):756–62.

    Article  PubMed  CAS  Google Scholar 

  50. Yang JC, Haworth S, Steinberg SM, et al. A randomized double-blind placebo-controlled trial of bevacizumab (anti-VEGF antibody) demonstrating a prolongation in time to progression in patients with metastatic renal cancer. Proc Am Soc Clin Oncol 2002;21(1):15.

    Google Scholar 

  51. Escudier B, Koralewski P, Pluzanska A, et al. A randomized, controlled, double-blind phase III study (AVOREN) of bevacizumab/interferon-α2a vs placebo/interferon- α2a as first-line therapy in metastatic renal cell carcinoma. J Clin Oncol 2007;25(18S):3.

    Google Scholar 

  52. Hainsworth JD, Sosman JA, Spigel DR, et al. Treatment of metastatic renal cell carcinoma with a combination of bevacizumab and erlotinib. J Clin Oncol 2005;23(31):7889–96.

    Article  PubMed  CAS  Google Scholar 

  53. Bukowski RM, Kabbinavar F, Figlin RA, et al. Bevacizumab with or without erlotinib in metastatic renal cell carcinoma (RCC). In: ASCO, 2006, p 4523.

    Google Scholar 

  54. Ratain MJ, Eisen T, Stadler WM, et al. Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol 2006;24(16):2505–12.

    Article  PubMed  CAS  Google Scholar 

  55. Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007;356(2):125–34.

    Article  PubMed  CAS  Google Scholar 

  56. Szcylik C, Dermkow T, Staehler M, et al. Randomized phase II trial of first-line treatment with sorafenib versus interferon in patients with advanced renal cell carcinoma: final results. J Clin Oncol 2007;25(18S):241s.

    Google Scholar 

  57. Amato RJ, Harris P, Dalton M, et al. A phase II trial of intra-patient dose-esclated sorafenib in patients(pts) with metastatic renal cell cancer (MRCC). J Clin Oncol 2007;25(18S):241s.

    Google Scholar 

  58. Motzer RJ, Michaelson MD, Redman BG, et al. 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 2006;24(1):16–24.

    Article  PubMed  CAS  Google Scholar 

  59. Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007;356(2):115–24.

    Article  PubMed  CAS  Google Scholar 

  60. Motzer RJ, Figlin R, Hutson TE, et al. Sunitinib versus interferon alfa as first-line treatment of metastatic renal cell carcinoma (mRCC): updated results and analysis of prognostic factors. In: ASCO, 2007, p 5024.

    Google Scholar 

  61. George DJ, Michaelson D, Rosenberg SA, et al. Phase II trial of sunitinib in bevacizumab-refractory metastatic renal cell carcinoama (mRCC): updated results and analysis of circulating biomarkers. In: ASCO, 2007, p 5035.

    Google Scholar 

  62. Rini B, Rixe O, Bukowski R, et al. AG-013736, a multi-target tyrosine kinase receptor inhibitor, demonstrates anti-tumor activity in a Phase 2 study of cytokine-refractory, metastatic renal cell cancer (RCC). In: 2005; 2005. p. 4509.

    Google Scholar 

  63. Rini BI, Wilding GT, Hudes G, et al. Axitinib (AG-013736; AG) in patients (pts) with metastatic renal cell cancer (RCC) refractory to sorafenib. J Clin Oncol 2007;25(18s):242s.

    Google Scholar 

  64. Atkins MB, Hidalgo M, Stadler WM, et al. A randomized double-blind phase 2 study of intravenous CCI-779 administered weekly to patients with advanced renal cell carcinoma. In: Proc Am Soc Clin Oncol; 2002; 2002. p. 36.

    Google Scholar 

  65. Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 2007;356(22):2271–81.

    Article  PubMed  CAS  Google Scholar 

  66. Motzer RJ, Bacik J, Murphy BA, et al. Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol, 2002; 20:289.

    Article  PubMed  CAS  Google Scholar 

  67. Motzer RJ, Amato R, Todd M, et al. Phase II trial of antiepidermal growth factor receptor antibody C225 in patients with advanced renal cell carcinoma. Invest New Drugs 2003;21(1):99–101.

    Article  PubMed  CAS  Google Scholar 

  68. Rowinsky EK, Schwartz GH, Gollob JA, et al. Safety, pharmacokinetics, and activity of ABX-EGF, a fully human anti-epidermal growth factor receptor monoclonal antibody in patients with metastatic renal cell cancer. J Clin Oncol 2004;22(15):3003–15.

    Article  PubMed  CAS  Google Scholar 

  69. Druker BJ, Schwartz L, Marion S, et al. Phase II trial of ZD 1839 (Iressa), and EGF receptor inhibitor, in patients with renal cell carcinoma. Proc Am Soc Clin Oncol 2002;720. No. 150.

    Google Scholar 

  70. Dawson NA, Guo C, Zak R, et al. A phase II trial of gefitinib (Iressa, ZD1839) in stage IV and recurrent renal cell carcinoma. Clin Cancer Res 2004;10(23):7812–9.

    Article  PubMed  CAS  Google Scholar 

  71. Jermann M, Stahel RA, Salzberg M, et al. A phase II, open-label study of gefitinib (IRESSA) in patients with locally advanced, metastatic, or relapsed renal-cell carcinoma. Cancer Chemother Pharmacol 2005;1–7.

    Google Scholar 

  72. Ravaud A, Gardner J, Hawkins R, et al. Efficacy of lapatinib in patients with high tumor EGFR expression: results of a phase III trial in advanced renal cell carcinoma (RCC). In: ASCO 2006;4502.

    Google Scholar 

  73. Heinrich MC, Corless CL, Demetri GD, et al. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol 2003;21(23):4342–9.

    Article  PubMed  CAS  Google Scholar 

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Authors
  1. Eric Jonasch MD
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  2. Nizar Tannir MD
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Editors and Affiliations

  1. Department of Investigational Cancer Therapeutics Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX

    Razelle Kurzrock MD

  2. Department of Clinical Research, The University of Texas MD Anderson Cancer Center, Houston, TX

    Maurie Markman

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© 2008 Humana Press, Totowa, NJ

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Jonasch, E., Tannir, N. (2008). Targeted Therapy in Renal Cell Carcinoma. In: Kurzrock, R., Markman, M. (eds) Targeted Cancer Therapy. Current Clinical Oncology™. Humana Press. https://doi.org/10.1007/978-1-60327-424-1_15

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  • DOI: https://doi.org/10.1007/978-1-60327-424-1_15

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-60327-423-4

  • Online ISBN: 978-1-60327-424-1

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