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Renal cell carcinoma (RCC) is a heterogeneous disease as reflected in its presentation and clinical course, pathological subtypes, nuclear grades and molecular biology. Emerging data indicate that renal tumors express a variety of molecular tumor markers and unique patterns of gene expression. Clinically the disease behaves quite heterogeneously, with courses ranging from indolent to highly aggressive. Surgical monotherapy or as part of a multimodal approach remains the standard of care for most cases of RCC. Radical or partial nephrectomy is associated with a 5-year cancer specific survival (CSS) of 85–97% for pT1 tumors. Unfortunately, 20% of patients have either locally advanced or node positive (N+) RCC while another 22% have metastatic RCC (mRCC) at presentation. Unlike the outcomes in early localized disease, survival rates for N+ patients are poor and patients with mRCC are rarely cured despite aggressive multimodal therapy. Classic cytotoxic chemotherapy has repeatedly been shown to have little effect and only 5–20% of patients with mRCC respond to immunologic agents such as interferon and/or interleukin. Cytoreductive nephrectomy with systemic immunotherapy is associated with few cures with median survivals of 12–24 months. Recent advances in our understanding of the molecular origins and pathways of RCC have led to the development of more effective targeted therapies. Here we review the molecular pathways that define the pertinent therapeutic targets in RCC and the clinical data for these new and promising agents.
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References and Recommended Reading
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Jemal A, Murray T, Ward E, et al.: Cancer statistics. CA Cancer J Clin 2005, 55:10–30
Cohen HT, McGovern FJ: Renal-cell carcinoma. N Engl J Med 2005, 353:2477–2490
Chawla SN, Crispen PL, Hanlon AL, Greenberg RE, Chen DYT, Uzzo RG: The natural history of observed enhancing renal masses: meta-analysis and review of the world literature. J Urol 2006, 175:425–431
Coppin C, Porzsolt F, Awa A, Kumpf J, Coldman A, Wilt T: Immunotherapy for advanced renal cell carcinoma. Cochrane Database Syst Rev 2005, 25(1):CD001425
Frank I, Blute ML, Leibovich BC, et al.: Independent validation of the 2002 American Joint Committee on cancer primary tumor classification for renal cell carcinoma using a large, single institution cohort. J Urol 2005, 173:1889–1892
Moinzadeh A, Gill IS, Finelli A, Kaouk J, Desai M: Laparoscopic partial nephrectomy: 3-year followup. J Urol 2006, 175:459–462
Gill IS, Remer EM, Hasan WA, et al.: Renal cryoablation: outcome at 3 years. J Urol 2005, 173:1903–1907
Yagoda A, Petrylak D, Thompson S: Cytotoxic chemotherapy for advanced renal cell carcinoma. Urol Clin North Am 1993, 20(2):303–321
Flanigan RC, Salmon SE, Blumenstein BA, et al.: Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal cell cancer. N Engl J Med 2001, 345:1655–1659
Enquist E, Zambrano N, Zbar B, et al: Molecular genetics of renal cell carcinoma. In Bukowski RM, Novick AC (eds). Renal Cell Carcinoma: Molecular biology, Immunology, and Clinical Management. Totowa, N.J.: Humana Press Inc, 2000;pp 79–93
Knudson AG Jr.: Genetics of human cancer. Annu Rev Genet 1986, 20:231–251
Uzzo RG, Novick AC: von Hippel Lindau syndrome: clinical and molecular considerations for the urologist. AUA Update Ser 1999, 18:137–144
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, 155:517–526
Uzzo RG, Cairns P, Al-Saleem T, Hudes G, Haas N, Greenberg RE, Kolenko V: The basic biology and immunobiology of renal cell carcinoma: considerations for the clinician. Urol Clin North Am 2003, 30:423–436
Baylin SB, Herman JG, Graff JR, et al.: Alterations in DNA methylation: a fundamental aspects of neoplasia. Adv Cancer Res 1998, 72:141–196
Gnarra JR, Lerman MI, Zbar B, et al.: Genetics of renal-cell carcinoma and evidence for a critical role for von Hippel-Lindau in renal tumorigenesis. Semin Oncol 1995, 22:3–8
Linehan WM, Lerman MI, Zbar B: Identification of the von Hippel-Lindau (VHL) gene. Its role in renal cancer. JAMA 1995, 273:564–570
Foster K, Prowse A, van den Berg A, et al.: Somatic mutations of the von Hippel-Lindau disease tumour suppressor gene in non-familial clear cell renal carcinoma. Hum Mol Genet 1994, 3:2169–2173
Hatano N, Nishikawa NS, McElgunn C, et al.: A comprehensive analysis of loss of heterozygosity caused by hemizygous deletions in renal cell carcinoma using a subtraction library. Mol Carcinog 2001, 31:161–170
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
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, 145:356–364
Stadler WM: Targeted agents for the treatment of advanced renal cell carcinoma. Cancer 2005, 104(11):2323–2333
Mendel DB, Laird AD, Xin X, Louie SG, Christensen JG, Li G, Schreck RE, Abrams TJ, Ngai TJ, Lee LB, Murray LJ, Carver J, Chan E, Moss KG, Haznedar JO, Sukbuntherng J, Blake RA, Sun L, Tang C, Miller T, Shirazian S, McMahon G, Cherrington JM: In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res 2003, 9(1):327–337
O’Farrel AM, et al.: SU 11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in␣vitro and in␣vivo. Blood 2003, 101:3597
Fiedler W, et al.: A phase I study of SU11248 in the treatment of patients with refractory or resistant acute myeloid leukemia or not amenable to conventional therapy for the disease. Blood 2004, 5:1846
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: Sunitinib in patients with metastatic renal cell carcinoma. JAMA 2006, 295(21):2516–2524
Motzer RJ, et al.: SU011248, a novel tyrosine kinase inhibitor, shows antitumor activity in second line therapy for patients with metastatic renal cell carcinoma: results of a phase II study. Proc Am Soc Clin Oncol 2004, Abs#4500
Demetri GD, van Oosterom AT, Garrett CR, Blackstein ME, Shah MH, Verweij J, McArthur G, Judson IR, Heinrich MC, Morgan JA, Desai J, Fletcher CD, George S, Bello CL, Huang X, Baum CM, Casali PG: Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet. 2006, 368(9544):1329–1338
Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, Oudard S, Kim ST, Baum CM, Figlin RA: Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007, 356(2):115–124
Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, Chen C, Zhang X, Vincent P, McHugh M, Cao Y, Shujath J, Gawlak S, Eveleigh D, Rowley B, Liu L, Adnane L, Bollag G, Lynch M, Auclair D, Taylor I, Gedrich R, Voznesensky A, Riedl B, Post LE, Trail PA: BAY 43–9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 2004, 64(19):7099–7109
Escudier B, Eisen T. Stadler W, et al.: Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007, 356(2):125–134
Szczylik C, Demkow 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 ASCO Annual Meeting Proceedings Part I 2007, 25(18S):5025
Amato RJ, Harris P, Dalton M, et al.: A phase II trial of intra-patient dose-escalated sorafenib in patients (pts) with metastatic renal cell cancer (MRCC). J Clin Oncol, 2007 ASCO Annual Meeting Proceedings Part I 2007, 25(18S):5026
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). J Clin Oncol, 2005 ASCO Annual Meeting Proceedings 2005, 23(16S) Part I of II (June 1 Supplement):4509
Hurwitz H, Dowlati A, Savage S, et al.: Safety, tolerability and pharmacokinetics of oral administration of GW786034 in pts with solid tumors. J Clin Oncol, 2005 ASCO Annual Meeting Proceedings 2005, 23(16S) Part I of II (June 1 Supplement):3012
Albert DH, Tapang P, Magoc TJ, et al.: Preclinical activity of ABT-869, a multitargeted receptor tyrosine kinase inhibitor. Mol Cancer Ther 2006, 5(4):995–1006
Van Cruijsen H, Voest EE, Van Herpen CM, et al.: Phase I evaluation of AZD2171, a highly potent, selective VEGFR signaling inhibitor, in combination with gefitinib, in patients with advanced tumors. J Clin Oncol, 2006 ASCO Annual Meeting Proceedings Part I 2006, 24(18S):3017
Albers MW, Williams RT, Brown EJ, Tanaka A, Hall FL, Schreiber SL: FKBP-rapamycin inhibits a cyclin-dependent kinase activity and a cyclin D1-Cdk association in early G1 of an osteosarcoma cell line. J Biol Chem 1993, 268:22825–22829
Hidalgo M, Rowinsky EK: The rapamycin-sensitive signal transduction pathway as a target for cancer therapy. Oncogene 2000, 19(56):6680–6686
Brown EJ, Albers MW, Shin TB, Ocjlawa K, Keith CT, Lane WS, Schreiber SLA: Mammalian protein targeted by G1-arresting rapamycin receptor complex. Nature 1994, 369:756–758
Del Bufalo D, Ciuffreda L, Trisciuoglio D, Desideri M, Cognetti F, Zupi G, Milella M: Antiangiogenic potential of the mammalian target of rapamycin inhibitor temsirolimus. Cancer Res 2006, 66(11):5549–5554
Hudes G, Carducci M, Tomczak P, et al.: Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 2007, 356(22):2271–2281
Figlin RA, Seligson D, Wu H, et al.: Characterization of the mTOR pathway in renal cell carcinoma and its use in predicting patient selection for agents targeting this pathway. J Clin Oncol, 2005 ASCO Annual Meeting Proceedings 2005, 23(16S) Part I of II (June 1 Supplement):4539
Amato RJ, Misellati A, Khan M, Chiang S: A phase II trial of RAD001 in patients (Pts) with metastatic renal cell carcinoma (MRCC). J Clin Oncol, 2006 ASCO Annual Meeting Proceedings Part I 2006, 24(18S):4530
Yang JC, Haworth L, Sherry RM, Hwu P, Schwartzentruber DJ, Topalian SL, Steinberg SM, Chen HX, Rosenberg SA: A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 2003, 349(5):427–434.
Rini B, Halabi S, Taylor J, et al.: Cancer and leukemia group B 90206: a randomized phase III trial of interferon-alpha or interferon-alpha plus anti-vascular endothelial growth factor antibody (bevacizumab) in metastatic renal cell carcinoma. Clin Cancer Res 2004, 10(8):2584–2586.
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 ASCO Annual Meeting Proceedings Part I, 2007, 25(18S):3
Veronese ML, Mosenkis A, Flaherty KT, et al.: Mechanisms of hypertension associated with BAY 43–9006. J Clin Oncol 2006, 24(9):1363–1369
Govindarajan R, Adusumilli J, Baxter DL, et al.: Reversible posterior leukoencephalopathy syndrome induced by RAF kinase inhibitor BAY 43–9006. J Clin Oncol 2006, 24(28):e48
Ewer MS, Lippman SM: Type II chemotherapy-related cardiac dysfunction: time to recognize a new entity. J Clin Oncol 2005, 23(13):2900–2922
Robert C, Soria JC, Spatz A, et al.: Cutaneous side-effects of kinase inhibitors and blocking antibodies. Lancet Oncol 2005, 6(7):491–500
Lokich JJ, Moore C: Chemotherapy-associated palmar-plantar erythrodysesthesia syndrome. Ann Intern Med 1984, 101(6):798–799
Robert C, Faivre S, Raymond E, et al.: Subungual splinter hemorrhages: a clinical window to inhibition of vascular endothelial growth factor receptors? Ann Intern Med 2005, 143(4):313–314
Routhouska S, Gilliam AC, Mirmirani P: Hair depigmentation during chemotherapy with a class III/V receptor tyrosine kinase inhibitor. Arch Dermatol 2006, 142(11):1477–1479
Desai J, Yassa L, Marqusee E, et al.: Hypothyroidism after sunitinib treatment for patients with gastrointestinal stromal tumors. Ann Intern Med 2006, 145(9):660–664
Sandler A, Gray R, Perry MC, et al.: Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006, 355(24):2542–2550
Investigator Safety Report for CCI-779, Investigator’s Brochure April, 2005
Duran I, Sin LL, Oza Am, et al.: Characterisation of the lung toxicity of the cell cycle inhibitor temsirolimus. Eur J Cancer 2006, 42(12):1875–1880
Galanis E, Buckner JC, Maurer MJ, et al.: Phase II trial of temsirolimus (CCI-779) in recurrent glioblastoma multiforme: a North Central Cancer Treatment Group Study. J Clin Oncol 2005, 23(23):5294–5304
Chang SM, Wen P, Cloughesy T, et al.: Phase II study of CCI-779 in patients with recurrent glioblastoma multiforme. Invest New Drugs 2005, 23(4):357–361
Huffman TA, Mothe-Satney I, Lawrence JC Jr.: Insulin-stimulated phosphorylation of lipin mediated by the mammalian target of rapamycin. Proc Natl Acad Sci USA 2002, 99(2):1047–1052
Kunkle DA, Haas NB, Uzzo RG: Adjuvant strategies for high risk renal cell carcinoma patients. Curr Urol Rep 2007, 8(1):19–30
Jocham D, Richter A, Hoffman L, et al.: Adjuvant autologous renal tumour cell vaccine and risk of tumour progression in patients with renal-cell carcinoma after radical nephrectomy: phase III, randomized controlled trial. Lancet 2004, 363:594–599
Uzzo RG, Novick AC: The role of nephrectomy and metastasectomy in advanced renal cell carcinoma. In: Bukowski RM, Novick AC (eds) Renal Cell Carcinoma: Molecular Biology, Immunology, and Clinical Management. Totowa, NJ: The Humana Press, (2000); pp 215–228
Mickisch GA, van Poppel H, de Prijck L, Sylvester R, European Organisation for Research and Treatment of Cancer (EORTC) Genitourinary Group. Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: a randomised trial. Lancet 2001, 358(9286):966–970
Halbert RJ, Figlin RA, Atkin MB, Bernal M, Hutson TE, Uzzo RG, Bukowski RM, Khan KD, Wood CG, Dubois R: Treatments for patients with metastatic renal cell cancer: a rand appropriateness panel. Cancer 2006, 107(10):2375–2383
Scappaticci FA, Fehrenbacher L, Cartwright T, et al.: Surgical wound healing complications in metastatic colorectal cancer patients treated with bevacizumab. J Surg Oncol 2005, 91(3):173–180
D’Angelica M, Kornprat P, Gonen M, et al.: Lack of evidence for increased operative morbidity after hepatectomy with perioperative use of bevacizumab: a matched case–control study. Ann Surg Oncol 2007, 14:759–765
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Haas, N.B., Uzzo, R.G. Tyrosine Kinase Inhibitors and Anti-Angiogenic Therapies in Kidney Cancer. Curr. Treat. Options in Oncol. 8, 211–226 (2007). https://doi.org/10.1007/s11864-007-0031-3
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DOI: https://doi.org/10.1007/s11864-007-0031-3