Skip to main content
SpringerLink
Log in

Targeted Therapy in Melanoma

  • Chapter
Book cover Targeted Cancer Therapy

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

  • 1055 Accesses

Summary

Melanoma is notorious for its resistance to cytotoxic and radiation therapy, and patients with advanced melanoma has a poor prognosis. Despite development of new cytotoxic drugs, immunotherapies, and treatment strategies combining the two, overall survival of patients with metastatic melanoma has not improved significantly. Recent studies provide a modicum of optimism regarding our understanding of the biology of melanoma and potentially regarding targeted therapy for this disease. Genomic mutations in N-Ras, BRaf, and PTEN have demonstrated intimate involvement in the progression, invasion,and survival of neoplastic cells in most cutaneous melanomas. An increasing number ofdrugs inhibit the signal transduction pathways activated by these aberrations, and recent clinical studies have shown cautiously promising responses to these drugs. Many of these studies are also elucidating the role of angiogenesis and immunoregulation in melanoma, opening the door to a wide variety of new strategies for tumor environment modulation and immunostimulation for more effective melanoma therapy. Because of the complicated signal transduction pathways in melanoma cells and the complex interactions of these tumors with the surrounding environment and immune system, combining these drugs with other targeted therapies, cytotoxic agents, or immunotherapies will likely be required for successful treatment of melanoma.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2007. CA Cancer J Clin 2007;57:43–66.

    PubMed  Google Scholar 

  2. Balch CM, Soong SJ, Gershenwald JE, et al. Prognostic factors analysis of 17,600 melanoma patients: validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol 2001;19:3622–34.

    PubMed  CAS  Google Scholar 

  3. Tsao H, Atkins MB, Sober AJ. Management of cutaneous melanoma. N Engl J Med 2004;351:998–1012.

    Article  PubMed  CAS  Google Scholar 

  4. Atkins MB, Kunkel L, Sznol M, et al. High-dose recombinant interleukin-2 therapy in patients with metastatic melanoma: long-term survival update. Cancer J Sci Am 2000;6(Suppl 1):S11–4.

    PubMed  Google Scholar 

  5. National Cancer Institute. 51-year trends in U.S. cancer death rates. In SEER cancer statistics review -AD, 2007, at http://seer.cancer.gov/csr/1975_2000/results_merged/topic_inc_mor_trends.pdf.

    Google Scholar 

  6. Demetri GD, von Mehren M, Blanke CD, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 2002;347:472–80.

    Article  PubMed  CAS  Google Scholar 

  7. Druker BJ, Talpaz M, Resta DJ, et al. NB Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001;344:1031–7.

    Article  PubMed  CAS  Google Scholar 

  8. Choueiri TK, Bukowski RM, Rini BI. The current role of angiogenesis inhibitors in the treatment of renal cell carcinoma. Semin Oncol 2006;33:596–606.

    Article  PubMed  CAS  Google Scholar 

  9. Davies M, Hennessy B, Mills GB. Point mutations of protein kinases and individualised cancer therapy. Expert Opin Pharmacother 2006;7:2243–61.

    Article  PubMed  CAS  Google Scholar 

  10. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005;353:1659–72.

    Article  PubMed  CAS  Google Scholar 

  11. Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005;353:1673–84.

    Article  PubMed  CAS  Google Scholar 

  12. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001;344:783–92.

    Article  PubMed  CAS  Google Scholar 

  13. Mass RD, Press MF, Anderson S, et al. Evaluation of clinical outcomes according to HER2 detection by fluorescence in situ hybridization in women with metastatic breast cancer treated with trastuzumab. Clin Breast Cancer 2005;6:240–6.

    PubMed  Google Scholar 

  14. Colicelli J. Human RAS superfamily proteins and related GTPases. Sci STKE 2004;2004:RE13.

    Google Scholar 

  15. Giehl K. Oncogenic Ras in tumour progression and metastasis. Biol Chem 2005;386:193–205.

    Article  PubMed  CAS  Google Scholar 

  16. Rubinfeld H, Seger R. The ERK cascade: a prototype of MAPK signaling. Mol Biotechnol 2005;31:151–74.

    Article  PubMed  CAS  Google Scholar 

  17. Wellbrock C, Karasarides M, Marais R. The RAF proteins take centre stage. Nat Rev Mol Cell Biol 2004;5:875–85.

    Article  PubMed  CAS  Google Scholar 

  18. Cohen C, Zavala-Pompa A, Sequeira JH, et al. Mitogen-actived protein kinase activation is an early event in melanoma progression. Clin Cancer Res 2002;8:3728–33.

    PubMed  CAS  Google Scholar 

  19. Lebedeva IV, Sarkar D, Su ZZ, et al. Molecular target-based therapy of pancreatic cancer. Cancer Res 2006;66:2403–13.

    Article  PubMed  CAS  Google Scholar 

  20. Grady WM, Markowitz SD. Genetic and epigenetic alterations in colon cancer. Annu Rev Genomics Hum Genet 2002;3:101–28.

    Article  PubMed  CAS  Google Scholar 

  21. Smalley KS. A pivotal role for ERK in the oncogenic behaviour of malignant melanoma? Int J Cancer 2003;104:527–32.

    Google Scholar 

  22. Goydos JS, Mann B, Kim HJ, et al. Detection of B-RAF and N-RAS mutations in human melanoma. J Am Coll Surg 2005;200:362–70.

    Article  PubMed  Google Scholar 

  23. Goel VK, Lazar AJ, Warneke CL, et al. Examination of mutations in BRAF, NRAS, and PTEN in primary cutaneous melanoma. J Invest Dermatol 2006;126:154–60.

    Google Scholar 

  24. Gray-Schopfer VC, da Rocha Dias S, Marais R. The role of B-RAF in melanoma. Cancer Metastasis Rev 2005;24:165–83.

    Article  PubMed  CAS  Google Scholar 

  25. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature 2002;417:949–54.

    Article  PubMed  CAS  Google Scholar 

  26. Rimoldi D, Salvi S, Lienard D, et al. Lack of BRAF mutations in uveal melanoma. Cancer Res 2003;63:5712–15.

    PubMed  CAS  Google Scholar 

  27. Curtin JA, Fridlyand J, Kageshita T, et al. Distinct sets of genetic alterations in melanoma. N Engl J Med 2005;353:2135–47.

    Article  PubMed  CAS  Google Scholar 

  28. Wong CW, Fan YS, Chan TL, et al. BRAF and NRAS mutations are uncommon in melanomas arising in diverse internal organs. J Clin Pathol 2005;58:640–4.

    Article  PubMed  CAS  Google Scholar 

  29. Zuidervaart W, van Nieuwpoort F, Stark M, et al. Activation of the MAPK pathway is a common event in uveal melanomas although it rarely occurs through mutation of BRAF or RAS. Br J Cancer 2005;92:2032–8.

    Article  PubMed  CAS  Google Scholar 

  30. Pollock PM, Harper UL, Hansen KS, et al. High frequency of BRAF mutations in nevi. Nat Genet 2003;33:19–20.

    Article  PubMed  CAS  Google Scholar 

  31. Yazdi AS, Palmedo G, Flaig MJ, et al. Mutations of the BRAF gene in benign and malignant melanocytic lesions. J Invest Dermatol 2003;121:1160–2.

    Article  PubMed  CAS  Google Scholar 

  32. Patton EE, Widlund HR, Kutok JL, et al. BRAF mutations are sufficient to promote nevi formation and cooperate with p53 in the genesis of melanoma. Curr Biol 2005;15:249–54.

    Article  PubMed  CAS  Google Scholar 

  33. Lazar-Molnar E, Hegyesi H, Toth S, et al. Autocrine and paracrine regulation by cytokines and growth factors in melanoma. Cytokine 2000;12:547–54.

    Article  PubMed  CAS  Google Scholar 

  34. Hingorani SR, Jacobetz MA, Robertson GP, et al. Suppression of BRAF(V599E) in human melanoma abrogates transformation. Cancer Res 2003;63:5198–202.

    PubMed  CAS  Google Scholar 

  35. Strumberg D. Preclinical and clinical development of the oral multikinase inhibitor sorafenib in cancer treatment. Drugs Today (Barc) 2005;41:773–84.

    Article  CAS  Google Scholar 

  36. Strumberg D, Voliotis D, Moeller JG, et al. Results of phase I pharmacokinetic and pharmacodynamic studies of the Raf kinase inhibitor BAY 43–9006 in patients with solid tumors. Int J Clin Pharmacol Ther 2002;40:580–1.

    PubMed  CAS  Google Scholar 

  37. Eisen T, Ahmad T, Flaherty KT, et al. Sorafenib in advanced melanoma: a Phase II randomised discontinuation trial analysis. Br J Cancer 2006;95:581–6.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  39. Flaherty KT, Brose M, Schuchter L, et al. Phase I/II trial of BAY 43–9006, carboplatin (C) and paclitaxel (P) demonstrates preliminary antitumor activity in the expansion cohort of patients with metastatic melanoma. In Proceedings of Am Soc Clin Oncol; New Orleans, LA. 2004: No 14S (July 15 Supplement), 7507.

    Google Scholar 

  40. Lorigan P, Corrie P, Chao D, et al. Phase II trial of sorafenib combined with dacarbazine in metastatic melanoma patients. In Proceedings of Am Soc Clin Oncol; Atlanta, GA. 2006: No 18S (June 20 Supplement), 8012.

    Google Scholar 

  41. McDermott DF, Sosman JA, Hodi FS, et al. Randomized phase II study of dacarbazine with or without sorafenib in patients with advanced melanoma. In Proceedings of Am Soc Clin Oncol; Chicago, IL. 2007: No 18S (June 20 Supplement), 8511.

    Google Scholar 

  42. Amaravadi RK, Schuchter LM, Kramer A, et al. Preliminary results of a randomized phase II study comparing two schedules of temozolomide in combination with sorafenib in patients with advanced melanoma. In Proceedings of Am Soc Clin Oncol; Atlanta, GA. 2006: No 18S (June 20 Supplement), 8009.

    Google Scholar 

  43. Caponigro F, Casale M, Bryce J. Farnesyl transferase inhibitors in clinical development. Expert Opin Investig Drugs 2003;12:943–54.

    Article  PubMed  CAS  Google Scholar 

  44. Rinehart J, Adjei AA, Lorusso PM, et al. Multicenter phase II study of the oral MEK inhibitor, CI-1040, in patients with advanced non-small-cell lung, breast, colon, and pancreatic cancer. J Clin Oncol 2004;22:4456–62.

    Article  PubMed  CAS  Google Scholar 

  45. Lorusso PM, Adjei AA, Varterasian M, et al. Phase I and pharmacodynamic study of the oral MEK inhibitor CI-1040 in patients with advanced malignancies. J Clin Oncol 2005;23:5281–93.

    Article  PubMed  CAS  Google Scholar 

  46. Wallace EM, Lyssikatos JP, Yeh T, et al. Progress towards therapeutic small molecule MEK inhibitors for use in cancer therapy. Curr Top Med Chem 2005;5:215–29.

    Article  PubMed  CAS  Google Scholar 

  47. Lorusso P, Krishnamurthi S, Rinehart JR, et al. A phase I-II clinical study of a second generation oral MEK inhibitor, PD 0325901 in patients with advanced cancer. In Proceedings of Am Soc Clin Oncol; Orlando, FL. 2005.

    Google Scholar 

  48. Downward J. PI 3-kinase, Akt and cell survival. Semin Cell Dev Biol 2004;15:177–82.

    Article  PubMed  CAS  Google Scholar 

  49. Robertson GP. Functional and therapeutic significance of Akt deregulation in malignant melanoma. Cancer Metastasis Rev 2005;24:273–85.

    Article  PubMed  CAS  Google Scholar 

  50. Brunet A, Bonni A, Zigmond MJ, et al. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 1999;96:857–68.

    Article  PubMed  CAS  Google Scholar 

  51. Romashkova JA, Makarov SS. NF-kappaB is a target of AKT in anti-apoptotic PDGF signalling. Nature 1999;401:86–90.

    Article  PubMed  CAS  Google Scholar 

  52. Dhawan P, Singh AB, Ellis DL, et al. Constitutive activation of Akt/protein kinase B in melanoma leads to up-regulation of nuclear factor-kappaB and tumor progression. Cancer Res 2002;62:7335–42.

    PubMed  CAS  Google Scholar 

  53. Datta SR, Dudek H, Tao X, et al. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 1997;91:231–41.

    Article  PubMed  CAS  Google Scholar 

  54. Sekulic A, Hudson CC, Homme JL, et al. A direct linkage between the phosphoinositide 3-kinase-AKT signaling pathway and the mammalian target of rapamycin in mitogen-stimulated and transformed cells. Cancer Res 2000;60:3504–13.

    PubMed  CAS  Google Scholar 

  55. Cross DA, Alessi DR, Cohen P, et al. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 1995;378:785–9.

    Article  PubMed  CAS  Google Scholar 

  56. Datta SR, Brunet A, Greenberg ME. Cellular survival: a play in three Akts. Genes Dev 1999;13:2905–27.

    Article  PubMed  CAS  Google Scholar 

  57. Testa JR, Bellacosa A. AKT plays a central role in tumorigenesis. Proc Natl Acad Sci U S A 2001;98:10983–5.

    Article  PubMed  CAS  Google Scholar 

  58. Scheid MP, Woodgett JR. Unravelling the activation mechanisms of protein kinase B/Akt. FEBS Lett 2003;546:108–12.

    Article  PubMed  CAS  Google Scholar 

  59. Bellacosa A, Testa JR, Staal SP, et al. A retroviral oncogene, akt, encoding a serine-threonine kinase containing an SH2-like region. Science 1991;254:274–7.

    Article  PubMed  CAS  Google Scholar 

  60. Brazil DP, Park J, Hemmings BA. PKB binding proteins. Getting in on the Akt. Cell 2002;111:293–303.

    Article  PubMed  CAS  Google Scholar 

  61. Stahl JM, Sharma A, Cheung M, et al. Deregulated Akt3 activity promotes development of malignant melanoma. Cancer Res 2004;64:7002–10.

    Article  PubMed  CAS  Google Scholar 

  62. Maehama T, Dixon JE. The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem 1998;273:13375–8.

    Article  PubMed  CAS  Google Scholar 

  63. Lin H, Bondy ML, Langford LA, et al. Allelic deletion analyses of MMAC/PTEN and DMBT1 loci in gliomas: relationship to prognostic significance. Clin Cancer Res 1998;4:2447–54.

    PubMed  CAS  Google Scholar 

  64. Stambolic V, Suzuki A, de la Pompa JL, et al. Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell 1998;95:29–39.

    Article  PubMed  CAS  Google Scholar 

  65. Davies MA, Lu Y, Sano T, et al. Adenoviral transgene expression of MMAC/PTEN in human glioma cells inhibits Akt activation and induces anoikis. Cancer Res 1998;58:5285–90.

    PubMed  CAS  Google Scholar 

  66. Davies MA, Koul D, Dhesi H, et al. Regulation of Akt/PKB activity, cellular growth, and apoptosis in prostate carcinoma cells by MMAC/PTEN. Cancer Res 1999;59:2551–6.

    PubMed  CAS  Google Scholar 

  67. Hwang PH, Yi HK, Kim DS, et al. Suppression of tumorigenicity and metastasis in B16F10 cells by PTEN/MMAC1/TEP1 gene. Cancer Lett 2001;172:83–91.

    Article  PubMed  CAS  Google Scholar 

  68. Dahia PL, Aguiar RC, Alberta J, et al. PTEN is inversely correlated with the cell survival factor Akt/PKB and is inactivated via multiple mechanismsin haematological malignancies. Hum Mol Genet 1999;8:185–93.

    Article  PubMed  CAS  Google Scholar 

  69. Cheney IW, Johnson DE, Vaillancourt MT, et al. Suppression of tumorigenicity of glioblastoma cells by adenovirus-mediated MMAC1/PTEN gene transfer. Cancer Res 1998;58:2331–4.

    PubMed  CAS  Google Scholar 

  70. Boni R, Vortmeyer AO, Burg G, et al. The PTEN tumour suppressor gene and malignant melanoma. Melanoma Res 1998, 8:300–302.

    Article  PubMed  CAS  Google Scholar 

  71. Celebi JT, Shendrik I, Silvers DN, Peacocke M. Identification of PTEN mutations in metastatic melanoma specimens. J Med Genet 2000;37:653–7.

    Article  PubMed  CAS  Google Scholar 

  72. Guldberg P, thor Straten P, Birck A, et al. Disruption of the MMAC1/PTEN gene by deletion or mutation is a frequent event in malignant melanoma. Cancer Res 1997;57:3660–3.

    PubMed  CAS  Google Scholar 

  73. Robertson GP, Furnari FB, Miele ME, et al. In vitro loss of heterozygosity targets the PTEN/MMAC1 gene in melanoma. Proc Natl Acad Sci U S A 1998;95:9418–9423.

    Article  PubMed  CAS  Google Scholar 

  74. Birck A, Ahrenkiel V, Zeuthen J, et al. Mutation and allelic loss of the PTEN/MMAC1 gene in primary and metastatic melanoma biopsies. J Invest Dermatol 2000;114:277–80.

    Article  PubMed  CAS  Google Scholar 

  75. Reifenberger J, Wolter M, Bostrom J, et al. Allelic losses on chromosome arm 10q and mutation of the PTEN (MMAC1) tumour suppressor gene in primary and metastatic malignant melanomas. Virchows Arch 2000;436:487–93.

    Article  PubMed  CAS  Google Scholar 

  76. Poetsch M, Dittberner T, Woenckhaus C. PTEN/MMAC1 in malignant melanoma and its importance for tumor progression. Cancer Genet Cytogenet 2001;125:21–6.

    Article  PubMed  CAS  Google Scholar 

  77. Tsao H, Zhang X, Benoit E, et al. Identification of PTEN/MMAC1 alterations in uncultured melanomas and melanoma cell lines. Oncogene 1998;16:3397–402.

    Article  PubMed  CAS  Google Scholar 

  78. Zhou XP, Gimm O, Hampel H, et al. Epigenetic PTEN silencing in malignant melanomas without PTEN mutation. Am J Pathol 2000;157:1123–8.

    PubMed  CAS  Google Scholar 

  79. Tsao H, Goel V, Wu H, et al. Genetic interaction between NRAS and BRAF mutations and PTEN/MMAC1 inactivation in melanoma. J Invest Dermatol 2004;122:337–41.

    Article  PubMed  CAS  Google Scholar 

  80. Dai DL, Martinka M, Li G. Prognostic significance of activated Akt expression in melanoma: a clinicopathologic study of 292 cases. J Clin Oncol 2005;23:1473–82.

    Article  PubMed  CAS  Google Scholar 

  81. Kondapaka SB, Singh SS, Dasmahapatra GP, et al. Perifosine, a novel alkylphospholipid, inhibits protein kinase B activation. Mol Cancer Ther 2003;2:1093–103.

    PubMed  CAS  Google Scholar 

  82. Ernst DS, Eisenhauer E, Wainman N, et al. Phase II study of perifosine in previously untreated patients with metastatic melanoma. Invest New Drugs 2005;23:569–75.

    Article  PubMed  CAS  Google Scholar 

  83. Investigators Brochure CCI-779. Wyeth.

    Google Scholar 

  84. Raymond E, Alexandre J, Faivre S, et al. Safety and pharmacokinetics of escalated doses of weekly intravenous infusion of CCI-779, a novel mTOR inhibitor, in patients with cancer. J Clin Oncol 2004;22:2336–47.

    Article  PubMed  CAS  Google Scholar 

  85. Atkins MB, Lotze MT, Dutcher JP, et al. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol 1999;17:2105–16.

    Google Scholar 

  86. Amiri KI, Richmond A. Role of nuclear factor-kappa B in melanoma. Cancer Metastasis Rev 2005;24:301–13.

    Article  PubMed  CAS  Google Scholar 

  87. Wang CY, Mayo MW, Korneluk RG, et al. NF-kappaB antiapoptosis: induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 to suppress caspase-8 activation. Science 1998;281:1680–3.

    Article  PubMed  CAS  Google Scholar 

  88. Catz SD, Johnson JL. Transcriptional regulation of bcl-2 by nuclear factor kappa B and its significance in prostate cancer. Oncogene 2001;20:7342–51.

    Article  PubMed  CAS  Google Scholar 

  89. Kunz M, Hartmann A, Flory E, et al. Anoxia-induced up-regulation of interleukin-8 in human malignant melanoma. A potential mechanism for high tumor aggressiveness. Am J Pathol 1999;155:753–63.

    PubMed  CAS  Google Scholar 

  90. Cusack JC, Liu R, Baldwin AS. NF-kappa B and chemoresistance: potentiation of cancer drugs via inhibition of NF-kappa B. Drug Resist Updat 1999;2:271–3.

    Article  PubMed  CAS  Google Scholar 

  91. Meyskens FL, Jr., Buckmeier JA, McNulty SE, et al. Activation of nuclear factor-kappa B in human metastatic melanomacells and the effect of oxidative stress. Clin Cancer Res 1999;5:1197–202.

    PubMed  CAS  Google Scholar 

  92. McNulty SE, Tohidian NB, Meyskens FL, Jr. RelA, p50 and inhibitor of kappa B alpha are elevated in human metastatic melanoma cells and respond aberrantly to ultraviolet light B. Pigment Cell Res 2001;14:456–65.

    Article  PubMed  CAS  Google Scholar 

  93. McNulty SE, del Rosario R, Cen D, et al. Comparative expression of NFkappaB proteins in melanocytes of normal skin vs. benign intradermal naevus and human metastatic melanoma biopsies. Pigment Cell Res 2004;17:173–80.

    Article  PubMed  CAS  Google Scholar 

  94. Koul D, Yao Y, Abbruzzese JL, et al. Tumor suppressor MMAC/PTEN inhibits cytokine-induced NFkappaB activation without interfering with the IkappaB degradation pathway. J Biol Chem 2001;276:11402–8.

    Article  PubMed  CAS  Google Scholar 

  95. Madrid LV, Mayo MW, Reuther JY, et al. Akt stimulates the transactivation potential of the RelA/p65 Subunit of NF-kappa B through utilization of the Ikappa B kinase and activation of the mitogen-activated protein kinase p38. J Biol Chem 2001;276:18934–40.

    Article  PubMed  CAS  Google Scholar 

  96. Troppmair J, Hartkamp J, Rapp UR. Activation of NF-kappa B by oncogenic Raf in HEK 293 cells occurs through autocrine recruitment of the stress kinase cascade. Oncogene 1998;17:685–90.

    Article  PubMed  CAS  Google Scholar 

  97. Jo H, Zhang R, Zhang H, et al. NF-kappa B is required for H-ras oncogene induced abnormal cell proliferation and tumorigenesis. Oncogene 2000;19:841–9.

    Article  PubMed  CAS  Google Scholar 

  98. Belch A, Kouroukis CT, Crump M, et al. A phase II study of bortezomib in mantle cell lymphoma: the National Cancer Institute of Canada Clinical Trials Group trial IND.150. Ann Oncol 2007;18:116–21.

    Article  PubMed  CAS  Google Scholar 

  99. Richardson PG, Hideshima T, Anderson KC. Bortezomib (PS-341): a novel, first-in-class proteasome inhibitor for the treatment of multiple myeloma and other cancers. Cancer Control 2003;10:361–9.

    PubMed  Google Scholar 

  100. Markovic SN, Geyer SM, Dawkins F, et al. A phase II study of bortezomib in the treatment of metastatic malignant melanoma. Cancer 2005;103:2584–9.

    Article  PubMed  CAS  Google Scholar 

  101. Yang J, Amiri KI, Burke JR, et al. BMS-345541 targets inhibitor of kappaB kinase and induces apoptosis in melanoma: involvement of nuclear factor kappaB and mitochondria pathways. Clin Cancer Res 2006, 12:950–60.

    Article  PubMed  CAS  Google Scholar 

  102. Druker BJ, Lydon NB. Lessons learned from the development of an abl tyrosine kinase inhibitor for chronic myelogenous leukemia. J Clin Invest 2000, 105:3–7.

    Article  PubMed  CAS  Google Scholar 

  103. Okuda K, Weisberg E, Gilliland DG, et al. ARG tyrosine kinase activity is inhibited by STI571. Blood 2001, 97:2440–8.

    Article  PubMed  CAS  Google Scholar 

  104. Schindler T, Bornmann W, Pellicena P, et al. Structural mechanism for STI-571 inhibition of abelson tyrosine kinase. Science 2000, 289:1938–42.

    Article  PubMed  CAS  Google Scholar 

  105. Easty DJ, Bennett DC. Protein tyrosine kinases in malignant melanoma. Melanoma Res 2000, 10:401–11.

    Article  PubMed  CAS  Google Scholar 

  106. Barnhill RL, Xiao M, Graves D, et al. Expression of platelet-derived growth factor (PDGF)-A, PDGF-B and the PDGF-alpha receptor, but not the PDGF-beta receptor, in human malignant melanoma in vivo. Br J Dermatol 1996, 135:898–904.

    Article  PubMed  CAS  Google Scholar 

  107. Shen SS, Zhang PS, Eton O, et al. Analysis of protein tyrosine kinase expression in melanocytic lesions by tissue array. J Cutan Pathol 2003, 30:539–47.

    Article  PubMed  Google Scholar 

  108. Wyman K, Atkins MB, Prieto V, et al. Multicenter Phase II trial of high-dose imatinib mesylate in metastatic melanoma: significant toxicity with no clinical efficacy. Cancer 2006, 106:2005–11.

    Article  PubMed  CAS  Google Scholar 

  109. Eton O, Billings L, Kim K, et al. Phase II trial of imatinib mesylate (STI-571) in metastatic melanoma (MM). In Proceedings of Am Soc Clin Oncol; New Orleans, LA. 2004: No.14S (July 15 Supplement), 7528.

    Google Scholar 

  110. Mendel DB, Laird AD, Xin X, et al. 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, 9:327–37.

    PubMed  CAS  Google Scholar 

  111. O’Farrell AM, Abrams TJ, Yuen HA, et al. SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo. Blood 2003, 101:3597–605.

    Article  PubMed  CAS  Google Scholar 

  112. 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 

  113. Atkins M, Jones CA, Kirkpatrick P. Sunitinib maleate. Nat Rev Drug Discov 2006, 5:279–80.

    Article  PubMed  CAS  Google Scholar 

  114. Demetri GD, van Oosterom AT, Garrett CR, et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet 2006, 368:1329–38.

    Article  PubMed  CAS  Google Scholar 

  115. Vaux DL, Cory S, Adams JM. Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature 1988, 335:440–2.

    Article  PubMed  CAS  Google Scholar 

  116. Tsujimoto Y, Finger LR, Yunis J, et al. Cloning of the chromosome breakpoint of neoplastic B cells with the t(14;18) chromosome translocation. Science 1984, 226:1097–99.

    Article  PubMed  CAS  Google Scholar 

  117. Bakhshi A, Jensen JP, Goldman P, et al. Cloning the chromosomal breakpoint of t(14;18) human lymphomas: clustering around JH on chromosome 14 and near a transcriptional unit on 18. Cell 1985, 41:899–906.

    Article  PubMed  CAS  Google Scholar 

  118. Konopleva M, Zhao S, Xie Z, et al. Apoptosis. Molecules and mechanisms. Adv Exp Med Biol 1999, 457:217–36.

    PubMed  CAS  Google Scholar 

  119. Maung ZT, MacLean FR, Reid MM, et al. The relationship between bcl-2 expression and response to chemotherapy in acute leukaemia. Br J Haematol 1994, 88:105–09.

    PubMed  CAS  Google Scholar 

  120. Bedner E, Li X, Gorczyca W, et al. Analysis of apoptosis by laser scanning cytometry. Cytometry 1999, 35:181–95.

    Article  PubMed  CAS  Google Scholar 

  121. Jansen B, Schlagbauer-Wadl H, Brown BD, et al. Bcl-2 antisense therapy chemosensitizes human melanoma in SCID mice. Nat Med 1998, 4:232–4.

    Article  PubMed  CAS  Google Scholar 

  122. Utikal J, Leiter U, Udart M, et al. Expression of c-myc and bcl-2 in primary and advanced cutaneous melanoma. Cancer Invest 2002, 20:914–21.

    Article  PubMed  CAS  Google Scholar 

  123. Korsmeyer SJ. BCL-2 gene family and the regulation of programmed cell death. Cancer Res 1999, 59:1693s–1700s.

    Google Scholar 

  124. Leiter U, Schmid RM, Kaskel P, et al. Antiapoptotic bcl-2 and bcl-xL in advanced malignant melanoma. Arch Dermatol Res 2000, 292:225–32.

    Article  PubMed  CAS  Google Scholar 

  125. Jansen B, Wacheck V, Heere-Ress E, et al. Chemosensitisation of malignant melanoma by BCL2 antisense therapy. Lancet 2000, 356:1728–33.

    Article  PubMed  CAS  Google Scholar 

  126. Bedikian AY, Millward M, Pehamberger H, et al. Bcl-2 antisense (oblimersen sodium) plus dacarbazine in patients with advanced melanoma: the Oblimersen Melanoma Study Group. J Clin Oncol 2006, 24:4738–45.

    Article  PubMed  CAS  Google Scholar 

  127. Boulton S, Pemberton LC, Porteous JK, et al. Potentiation of temozolomide-induced cytotoxicity: a comparative study of the biological effects of poly(ADP-ribose) polymerase inhibitors. Br J Cancer 1995, 72:849–56.

    PubMed  CAS  Google Scholar 

  128. Trucco C, Oliver FJ, de Murcia G, et al. DNA repair defect in poly(ADP-ribose) polymerase-deficient cell lines. Nucleic Acids Res 1998, 26:2644–9.

    Article  PubMed  CAS  Google Scholar 

  129. Malanga M, Pleschke JM, Kleczkowska HE et al. Poly(ADP-ribose) binds to specific domains of p53 and alters its DNA binding functions. J Biol Chem 1998, 273:11839–43.

    Article  PubMed  CAS  Google Scholar 

  130. Agarwal ML, Agarwal A, Taylor WR, et al. Defective induction but normal activation and function of p53 in mouse cells lacking poly-ADP-ribose polymerase. Oncogene 1997, 15:1035–41.

    Article  PubMed  CAS  Google Scholar 

  131. Pieper AA, Verma A, Zhang J, et al. Poly (ADP-ribose) polymerase, nitric oxide and cell death. Trends Pharmacol Sci 1999, 20:171–81.

    Article  PubMed  CAS  Google Scholar 

  132. Burkle A. Physiology and pathophysiology of poly(ADP-ribosyl)ation. Bioessays 2001, 23:795–806.

    Article  PubMed  CAS  Google Scholar 

  133. Tentori L, Leonetti C, Scarsella M, et al. Combined treatment with temozolomide and poly(ADP-ribose) polymerase inhibitor enhances survival of mice bearing hematologic malignancy at the central nervous system site. Blood 2002, 99:2241–44.

    Article  PubMed  CAS  Google Scholar 

  134. Plummer R, Lorigan P, Evans J, et al. First and final report of a phase II study of the poly(ADP-ribose) polymerase (PARP) inhibitor, AG014699, in combination with temozolomide (TMZ) in patients with metastatic malignant melanoma (MM). In Proceedings of Am Soc Clin Oncol; Atlanta, GA. 2006: No. 18S (June 20 Supplement), 8013.

    Google Scholar 

  135. Srivastava A, Laidler P, Hughes LE, et al. Neovascularization in human cutaneous melanoma: a quantitative morphological and Doppler ultrasound study. Eur J Cancer Clin Oncol 1986, 22:1205–9.

    Article  PubMed  CAS  Google Scholar 

  136. Marcoval J, Moreno A, Graells J, et al. Angiogenesis and malignant melanoma. Angiogenesis is related to the development of vertical (tumorigenic) growth phase. J Cutan Pathol 1997, 24:212–8.

    Article  PubMed  CAS  Google Scholar 

  137. Straume O, Akslen LA. Expresson of vascular endothelial growth factor, its receptors (FLT-1, KDR) and TSP-1 related to microvessel density and patient outcome in vertical growth phase melanomas. Am J Pathol 2001, 159:223–35.

    PubMed  CAS  Google Scholar 

  138. Erhard H, Rietveld FJ, van Altena MC, et al. Transition of horizontal to vertical growth phase melanoma is accompanied by induction of vascular endothelial growth factor expression and angiogenesis. Melanoma Res 1997, 7 Suppl 2:S19–26.

    PubMed  CAS  Google Scholar 

  139. Srivastava A, Laidler P, Davies RP, et al. The prognostic significance of tumor vascularity in intermediate-thickness (0.76–4.0 mm thick) skin melanoma. A quantitative histologic study. Am J Pathol 1988, 133:419–23.

    PubMed  CAS  Google Scholar 

  140. Denijn M, Ruiter DJ. The possible role of angiogenesis in the metastatic potential of human melanoma. Clinicopathological aspects. Melanoma Res 1993, 3:5–14.

    Article  PubMed  CAS  Google Scholar 

  141. Graham CH, Rivers J, Kerbel RS, et al. Extent of vascularization as a prognostic indicator in thin ( 0.76 mm) malignant melanomas. Am J Pathol 1994, 145:510–4.

    PubMed  CAS  Google Scholar 

  142. Demirkesen C, Buyukpinarbasili N, Ramazanoglu R, et al. The correlation of angiogenesis with metastasis in primary cutaneous melanoma: a comparative analysis of microvessel density, expression of vascular endothelial growth factor and basic fibroblastic growth factor. Pathology 2006, 38:132–7.

    Article  PubMed  CAS  Google Scholar 

  143. Potgens AJ, Lubsen NH, van Altena MC, et al. Vascular permeability factor expression influences tumor angiogenesis in human melanoma lines xenografted to nude mice. Am J Pathol 1995, 146:197–209.

    PubMed  CAS  Google Scholar 

  144. Oku T, Tjuvajev JG, Miyagawa T, et al. Tumor growth modulation by sense and antisense vascular endothelial growth factor gene expression: effects on angiogenesis, vascular permeability, blood volume, blood flow, fluorodeoxyglucose uptake, and proliferation of human melanoma intracerebral xenografts. Cancer Res 1998, 58:4185–92.

    PubMed  CAS  Google Scholar 

  145. Claffey KP, Brown LF, del Aguila LF, et al. Expression of vascular permeability factor/vascular endothelial growth factor by melanoma cells increases tumor growth, angiogenesis, and experimental metastasis. Cancer Res 1996, 56:172–81.

    PubMed  CAS  Google Scholar 

  146. Rofstad EK, Danielsen T. Hypoxia-induced angiogenesis and vascular endothelial growth factor secretion in human melanoma. Br J Cancer 1998, 77:897–902.

    PubMed  CAS  Google Scholar 

  147. Halaban R, Kwon BS, Ghosh S, et al. bFGF as an autocrine growth factor for human melanomas. Oncogene Res 1988, 3:177–86.

    PubMed  CAS  Google Scholar 

  148. Becker D, Meier CB, Herlyn M. Proliferation of human malignant melanomas is inhibited by antisense oligodeoxynucleotides targeted against basic fibroblast growth factor. Embo J 1989, 8:3685–91.

    PubMed  CAS  Google Scholar 

  149. Li J, Yen C, Liaw D, Podsypanina K, et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 1997, 275:1943–7.

    Article  PubMed  CAS  Google Scholar 

  150. Zachariae CO, Thestrup-Pedersen K, Matsushima K. Expression and secretion of leukocyte chemotactic cytokines by normal human melanocytes and melanoma cells. J Invest Dermatol 1991, 97:593–599.

    Article  PubMed  CAS  Google Scholar 

  151. Dvorak HF, Brown LF, Detmar M, et al. Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. Am J Pathol 1995, 146:1029–39.

    PubMed  CAS  Google Scholar 

  152. Ferrara N. Vascular endothelial growth factor. Eur J Cancer 1996, 32A:2413–22.

    Google Scholar 

  153. Slavin J. Fibroblast growth factors: at the heart of angiogenesis. Cell Biol Int 1995, 19:431–44.

    Article  PubMed  CAS  Google Scholar 

  154. Ellis LM, Fidler IJ. Angiogenesis and metastasis. Eur J Cancer 1996, 32A:2451–60.

    Google Scholar 

  155. Bikfalvi A, Klein S, Pintucci G, et al.. Biological roles of fibroblast growth factor-2. Endocr Rev 1997, 18:26–45.

    Article  PubMed  CAS  Google Scholar 

  156. Bar-Eli M. Role of interleukin-8 in tumor growth and metastasis of human melanoma. Pathobiology 1999, 67:12–8.

    Article  PubMed  CAS  Google Scholar 

  157. Li A, Dubey S, Varney ML, et al. IL-8 directly enhanced endothelial cell survival, proliferation, and matrix metalloproteinases production and regulated angiogenesis. J Immunol 2003, 170:3369–76.

    PubMed  CAS  Google Scholar 

  158. Rofstad EK, Halsor EF. Vascular endothelial growth factor, interleukin 8, platelet-derived endothelial cell growth factor, and basic fibroblast growth factor promote angiogenesis and metastasis in human melanoma xenografts. Cancer Res 2000, 60:4932–8.

    PubMed  CAS  Google Scholar 

  159. Lev DC, Ruiz M, Mills L, et al. Dacarbazine causes transcriptional up-regulation of interleukin 8 and vascular endothelial growth factor in melanoma cells: a possible escape mechanism from chemotherapy. Mol Cancer Ther 2003, 2:753–63.

    PubMed  CAS  Google Scholar 

  160. Lev DC, Onn A, Melinkova VO, et al. Exposure of melanoma cells to dacarbazine results in enhanced tumor growth and metastasis in vivo. J Clin Oncol 2004, 22:2092–100.

    Article  PubMed  CAS  Google Scholar 

  161. Terman BI, Dougher-Vermazen M, Carrion ME, et al. Identification of the KDR tyrosine kinase as a receptor for vascular endothelial cell growth factor. Biochem Biophys Res Commun 1992, 187:1579–86.

    Article  PubMed  CAS  Google Scholar 

  162. de Vries C, Escobedo JA, Ueno H, et al. The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor. Science 1992, 255:989–91.

    Article  PubMed  Google Scholar 

  163. Hwu WJ, Krown SE, Menell JH, et al. Phase II study of temozolomide plus thalidomide for the treatment of metastatic melanoma. J Clin Oncol 2003, 21:3351–6.

    Article  PubMed  CAS  Google Scholar 

  164. Kaipainen A, Korhonen J, Pajusola K, et al. The related FLT4, FLT1, and KDR receptor tyrosine kinases show distinct expression patterns in human fetal endothelial cells. J Exp Med 1993, 178:2077–88.

    Article  PubMed  CAS  Google Scholar 

  165. Salven P, Heikkila P, Joensuu H. Enhanced expression of vascular endothelial growth factor in metastatic melanoma. Br J Cancer 1997, 76:930–4.

    PubMed  CAS  Google Scholar 

  166. Bayer-Garner IB, Hough AJ, Jr., Smoller BR. Vascular endothelial growth factor expression in malignant melanoma: prognostic versus diagnostic usefulness. Mod Pathol 1999, 12:770–4.

    PubMed  CAS  Google Scholar 

  167. Birck A, Kirkin AF, Zeuthen J, et al. Expression of basic fibroblast growth factor and vascular endothelial growth factor in primary and metastatic melanoma from the same patients. Melanoma Res 1999, 9:375–81.

    Article  PubMed  CAS  Google Scholar 

  168. Lacal PM, Failla CM, Pagani E, et al. Human melanoma cells secrete and respond to placenta growth factor and vascular endothelial growth factor. J Invest Dermatol 2000, 115:1000–7.

    Article  PubMed  CAS  Google Scholar 

  169. Simonetti O, Lucarini G, Brancorsini D, et al. Immunohistochemical expression of vascular endothelial growth factor, matrix metalloproteinase 2, and matrix metalloproteinase 9 in cutaneous melanocytic lesions. Cancer 2002, 95:1963–70.

    Article  PubMed  CAS  Google Scholar 

  170. Ugurel S, Rappl G, Tilgen W et al. Increased serum concentration of angiogenic factors in malignant melanoma patients correlates with tumor progression and survival. J Clin Oncol 2001, 19:577–83.

    PubMed  CAS  Google Scholar 

  171. Vlaykova T, Laurila P, Muhonen T, . Prognostic value of tumour vascularity in metastatic melanoma and association of blood vessel density with vascular endothelial growth factor expression. Melanoma Res 1999, 9:59–68.

    Article  PubMed  CAS  Google Scholar 

  172. Gitay-Goren H, Halaban R, Neufeld G. Human melanoma cells but not normal melanocytes express vascular endothelial growth factor receptors. Biochem Biophys Res Commun 1993, 190:702–708.

    Article  PubMed  CAS  Google Scholar 

  173. Carson WE, Biber J, Shah N, et al. A phase 2 trial of a recombinant humanized monoclonal anti-vascular endothelial growth factor (VEGF) antibody in patients with malignant melanoma In Proceedings of Am Soc Clin Oncol; Chicago, IL. 2003: (abstr 2873).

    Google Scholar 

  174. D’Amato RJ, Loughnan MS, Flynn E, et al.. Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci U S A 1994, 91:4082–5.

    Article  PubMed  CAS  Google Scholar 

  175. Kruse FE, Joussen AM, Rohrschneider K, et al. Thalidomide inhibits corneal angiogenesis induced by vascular endothelial growth factor. Graefes Arch Clin Exp Ophthalmol 1998, 236:461–6.

    Article  PubMed  CAS  Google Scholar 

  176. Marriott JB, Clarke IA, Dredge K, et al. Thalidomide and its analogues have distinct and opposing effects on TNF-alpha and TNFR2 during co-stimulation of both CD4(+) and CD8(+) T cells. Clin Exp Immunol 2002, 130:75–84.

    Article  PubMed  CAS  Google Scholar 

  177. Shannon EJ, Sandoval F. Thalidomide increases the synthesis of IL-2 in cultures of human mononuclear cells stimulated with Concanavalin-A, Staphylococcal enterotoxin A, and purified protein derivative. Immunopharmacology 1995, 31:109–16.

    Article  PubMed  CAS  Google Scholar 

  178. Verbon A, Juffermans NP, Speelman P, et al. A single oral dose of thalidomide enhances the capacity of lymphocytes to secrete gamma interferon in healthy humans. Antimicrob Agents Chemother 2000, 44:2286–90.

    Article  PubMed  CAS  Google Scholar 

  179. Keifer JA, Guttridge DC, Ashburner BP, et al. Inhibition of NF-kappa B activity by thalidomide through suppression of IkappaB kinase activity. J Biol Chem 2001, 276:22382–7.

    Article  PubMed  CAS  Google Scholar 

  180. Cavenagh JD, Oakervee H. Thalidomide in multiple myeloma: current status and future prospects. Br J Haematol 2003, 120:18–26.

    Article  PubMed  CAS  Google Scholar 

  181. Dimopoulos MA, Anagnostopoulos A, Weber D. Treatment of plasma cell dyscrasias with thalidomide and its derivatives. J Clin Oncol 2003, 21:4444–54.

    Article  PubMed  CAS  Google Scholar 

  182. Glasmacher A, Hahn C, Hoffmann F, et al. A systematic review of phase-II trials of thalidomide monotherapy in patients with relapsed or refractory multiple myeloma. Br J Haematol 2006, 132:584–93.

    Article  PubMed  CAS  Google Scholar 

  183. Eisen T, Boshoff C, Mak I, et al. Continuous low dose Thalidomide: a phase II study in advanced melanoma, renal cell, ovarian and breast cancer. Br J Cancer 2000, 82:812–7.

    Article  PubMed  CAS  Google Scholar 

  184. Pawlak WZ, Legha SS. Phase II study of thalidomide in patients with metastatic melanoma. Melanoma Res 2004, 14:57–62.

    Article  PubMed  CAS  Google Scholar 

  185. Reiriz AB, Richter MF, Fernandes S, et al. Phase II study of thalidomide in patients with metastatic malignant melanoma. Melanoma Res 2004, 14:527–31.

    Article  PubMed  CAS  Google Scholar 

  186. Hwu WJ, Lis E, Menell JH, et al. Temozolomide plus thalidomide in patients with brain metastases from melanoma: a phase II study. Cancer 2005, 103:2590–7.

    Article  PubMed  CAS  Google Scholar 

  187. Laber DA, Okeke RI, Arce-Lara C, et al. A phase II study of extended dose temozolomide and thalidomide in previously treated patients with metastatic melanoma. J Cancer Res Clin Oncol 2006, 132:611–6.

    Article  PubMed  CAS  Google Scholar 

  188. Krown SE, Niedzwiecki D, Hwu WJ, et al. Phase II study of temozolomide and thalidomide in patients with metastatic melanoma in the brain: high rate of thromboembolic events (CALGB 500102). Cancer 2006, 107:1883–90.

    Article  PubMed  CAS  Google Scholar 

  189. Raje N, Anderson KC. Thalidomide and immunomodulatory drugs as cancer therapy. Curr Opin Oncol 2002, 14:635–40.

    Article  PubMed  CAS  Google Scholar 

  190. Bartlett JB, Michael A, Clarke IA, et al. Phase I study to determine the safety, tolerability and immunostimulatory activity of thalidomide analogue CC-5013 in patients with metastatic malignant melanoma and other advanced cancers. Br J Cancer 2004, 90:955–61.

    Article  PubMed  CAS  Google Scholar 

  191. Brooks PC, Montgomery AM, Rosenfeld M, et al. Integrin alpha v beta 3 antagonists promote tumor regression by inducing apoptosis of angiogenic blood vessels. Cell 1994, 79:1157–64.

    Article  PubMed  CAS  Google Scholar 

  192. Varner JA, Cheresh DA. Tumor angiogenesis and the role of vascular cell integrin alphabeta3. In Important Adv Oncol. Edited by De Vita VT, Hellman S, Rosenberg SA. Philadelphia, PA: Lippincott-Raven; 1996: 69–87.

    Google Scholar 

  193. Varner JA, Cheresh DA. Integrins and cancer. Curr Opin Cell Biol 1996, 8:724–30.

    Article  PubMed  CAS  Google Scholar 

  194. Albelda SM, Mette SA, Elder DE, et al. Integrin distribution in malignant melanoma: association of the beta 3 subunit with tumor progression. Cancer Res 1990, 50:6757–64.

    PubMed  CAS  Google Scholar 

  195. Natali PG, Hamby CV, Felding-Habermann B, et al. Clinical significance of alpha(v)beta3 integrin and intercellular adhesion molecule-1 expression in cutaneous malignant melanoma lesions. Cancer Res 1997, 57:1554–60.

    PubMed  CAS  Google Scholar 

  196. Byzova TV, Goldman CK, Pampori N, et al. A mechanism for modulation of cellular responses to VEGF: activation of the integrins. Mol Cell 2000, 6:851–60.

    PubMed  CAS  Google Scholar 

  197. Kim S, Bell K, Mousa SA, Varner JA. Regulation of angiogenesis in vivo by ligation of integrin alpha5beta1 with the central cell-binding domain of fibronectin. Am J Pathol 2000, 156:1345–62.

    PubMed  CAS  Google Scholar 

  198. Kim S, Bakre M, Yin H, et al. Inhibition of endothelial cell survival and angiogenesis by protein kinase A. J Clin Invest 2002, 110:933–41.

    PubMed  CAS  Google Scholar 

  199. Hersey P, Sosman J, O’Day S, et al. A phase II, randomized, open-label study evaluating the antitumor activity of MEDI-522, a humanized monoclonal antibody directed against the human alpha v beta 3 (avb3) integrin, ± dacarbazine (DTIC) in patients with metastatic melanoma (MM) In Proceedings of Am Soc Clin Oncol; Orlando, FL. 2005: No. 16S, Part I of II (June 11 Supplement), 7507.

    Google Scholar 

  200. Kim KB, Diwan AH, Papadopoulos NE,et al. A randomized phase II study of EMD 121974 in patients (pts) with metastatic melanoma (MM). In Proceedings of Am Soc Clin Oncol; Chicago, IL. 2007: No 18S (June 20 Supplement), 8548.

    Google Scholar 

  201. Cranmer LD, Bedikian AY, Ribas A, et al. Phase II study of volociximab (M200), an α5α1 anti-integrin antibody in metastatic melanoma. In Proceedings of Am Soc Clin Oncol; Atlanta, GA. 2006: No. 18S (June 20 Supplement), 8011.

    Google Scholar 

  202. Nathanson L.Spontaneous regression of malignant melanoma: a review of the literature on incidence, clinical features, and possible mechanisms. Natl Cancer Inst Monogr 1976, 44:67–76.

    PubMed  CAS  Google Scholar 

  203. Rosenberg SA, Yang JC, Restifo NP. Cancer immunotherapy: moving beyond current vaccines. Nat Med 2004, 10:909–15.

    Article  PubMed  CAS  Google Scholar 

  204. Rivoltini L, Canese P, Huber V, et al. Escape strategies and reasons for failure in the interaction between tumour cells and the immune system: how can we tilt the balance towards immune-mediated cancer control? Expert Opin Biol Ther 2005, 5:463–76.

    Google Scholar 

  205. Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature 1998, 392:245–52.

    Article  PubMed  CAS  Google Scholar 

  206. Korman AJ, Peggs KS, Allison JP. Checkpoint blockade in cancer immunotherapy. Adv Immunol 2006, 90:297–39.

    Article  PubMed  CAS  Google Scholar 

  207. Schwartz RH. A cell culture model for T lymphocyte clonal anergy. Science 1990, 248:1349–56.

    Article  PubMed  CAS  Google Scholar 

  208. Acuto O, Michel F. CD28-mediated co-stimulation: a quantitative support for TCR signalling. Nat Rev Immunol 2003, 3:939–51.

    Article  PubMed  CAS  Google Scholar 

  209. Alegre ML, Frauwirth KA, Thompson CB. T-cell regulation by CD28 and CTLA-4. Nat Rev Immunol 2001, 1:220–8.

    Article  PubMed  CAS  Google Scholar 

  210. Melero I, Hervas-Stubbs S, Glennie M, et al. Immunostimulatory monoclonal antibodies for cancer therapy. Nat Rev Cancer 2007, 7:95–106.

    Article  PubMed  CAS  Google Scholar 

  211. Collins AV, Brodie DW, Gilbert RJ, et al. The interaction properties of costimulatory molecules revisited. Immunity 2002, 17:201–10.

    Article  PubMed  CAS  Google Scholar 

  212. Peggs KS, Quezada SA, Korman AJ, et al. Principles and use of anti-CTLA4 antibody in human cancer immunotherapy. Curr Opin Immunol 2006, 18:206–13.

    Article  PubMed  CAS  Google Scholar 

  213. Chambers CA, Sullivan TJ, Allison JP. Lymphoproliferation in CTLA-4-deficient mice is mediated by costimulation-dependent activation of CD4+ T cells. Immunity 1997, 7:885–95.

    Article  PubMed  CAS  Google Scholar 

  214. Waterhouse P, Penninger JM, Timms E, et al. Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science 1995, 270:985–8.

    Article  PubMed  CAS  Google Scholar 

  215. Sakaguchi S, Sakaguchi N, Asano M, et al. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 1995, 155:1151–64.

    PubMed  CAS  Google Scholar 

  216. Wang HY, Lee DA, Peng G, et al. Tumor-specific human CD4+ regulatory T cells and their ligands: implications for immunotherapy. Immunity 2004, 20:107–18.

    Article  PubMed  CAS  Google Scholar 

  217. Kronenberg M, Rudensky A. Regulation of immunity by self-reactive T cells. Nature 2005, 435:598–604.

    Article  PubMed  CAS  Google Scholar 

  218. Sakaguchi S. Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self. Nat Immunol 2005, 6:345–52.

    Article  PubMed  CAS  Google Scholar 

  219. Thompson CB, Allison JP. The emerging role of CTLA-4 as an immune attenuator. Immunity 1997, 7:445–50.

    Article  PubMed  CAS  Google Scholar 

  220. Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science 1996, 271:1734–6.

    Article  PubMed  CAS  Google Scholar 

  221. Kwon ED, Hurwitz AA, Foster BA, et al. Manipulation of T cell costimulatory and inhibitory signals for immunotherapy of prostate cancer. Proc Natl Acad Sci U S A 1997, 94:8099–103.

    Article  PubMed  CAS  Google Scholar 

  222. Sotomayor EM, Borrello I, Tubb E, et al. In vivo blockade of CTLA-4 enhances the priming of responsive T cells but fails to prevent the induction of tumor antigen-specific tolerance. Proc Natl Acad Sci U S A 1999, 96:11476–81.

    Article  PubMed  CAS  Google Scholar 

  223. van Elsas A, Hurwitz AA, Allison JP. Combination immunotherapy of B16 melanoma using anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and granulocyte/macrophage colony-stimulating factor (GM-CSF)-producing vaccines induces rejection of subcutaneous and metastatic tumors accompanied by autoimmune depigmentation. J Exp Med 1999, 190:355–66.

    Article  PubMed  Google Scholar 

  224. Hurwitz AA, Foster BA, Kwon ED, etal. Combination immunotherapy of primary prostate cancer in a transgenic mouse model using CTLA-4 blockade. Cancer Res 2000, 60:2444–8.

    PubMed  CAS  Google Scholar 

  225. Sutmuller RP, van Duivenvoorde LM, van Elsas A, et al. Synergism of cytotoxic T lymphocyte-associated antigen 4 blockade and depletion of CD25(+) regulatory T cells in antitumor therapy reveals alternative pathways for suppression of autoreactive cytotoxic T lymphocyte responses. J Exp Med 2001, 194:823–32.

    Article  PubMed  CAS  Google Scholar 

  226. Demaria S, Kawashima N, Yang AM, et al. Immune-mediated inhibition of metastases after treatment with local radiation and CTLA-4 blockade in a mouse model of breast cancer. Clin Cancer Res 2005, 11:728–34.

    PubMed  CAS  Google Scholar 

  227. Mokyr MB, Kalinichenko T, Gorelik L, et al. Realization of the therapeutic potential of CTLA-4 blockade in low-dose chemotherapy-treated tumor-bearing mice. Cancer Res 1998, 58:5301–4.

    PubMed  CAS  Google Scholar 

  228. Davila E, Kennedy R, Celis E. Generation of antitumor immunity by cytotoxic T lymphocyte epitope peptide vaccination, CpG-oligodeoxynucleotide adjuvant, and CTLA-4 blockade. Cancer Res 2003, 63:3281–88.

    PubMed  CAS  Google Scholar 

  229. Hodi FS, Mihm MC, Soiffer RJ, et al. Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients. Proc Natl Acad Sci U S A 2003, 100:4712–7.

    Article  PubMed  CAS  Google Scholar 

  230. Ribas A, Camacho LH, Lopez-Berestein G, et al. Antitumor activity in melanoma and anti-self responses in a phase I trial with the anti-cytotoxic T lymphocyte-associated antigen 4 monoclonal antibody CP-675,206. J Clin Oncol 2005, 23:8968–77.

    Article  PubMed  CAS  Google Scholar 

  231. Attia P, Phan GQ, Maker AV, et al. Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4. J Clin Oncol 2005, 23:6043–53.

    Article  PubMed  CAS  Google Scholar 

  232. Fischkoff SA, Hersh E, Weber J, et al. Durable responses and long-term progression-free survival observed in a phase II study of MDX-010 alone or in combination with dacarbazine (DTIC) in metastatic melanoma. In Proceedings of Am Soc Clin Oncol; Orlando, FL. 2005: No. 16S, Part I of II (June 11 Supplement), 7525.

    Google Scholar 

  233. Maker AV, Phan GQ, Attia P, et al. Tumor regression and autoimmunity in patients treated with cytotoxic T lymphocyte-associated antigen 4 blockade and interleukin 2: a phase I/II study. Ann Surg Oncol 2005, 12:1005–16.

    Article  PubMed  Google Scholar 

  234. Beck KE, Blansfield JA, Tran KQ, et al. Enterocolitis in patients with cancer after antibody blockade of cytotoxic T-lymphocyte-associated antigen 4. J Clin Oncol 2006, 24:2283–9.

    Article  PubMed  CAS  Google Scholar 

  235. Phan GQ, Yang JC, Sherry RM, et al. Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci U S A 2003, 100:8372–7.

    Article  PubMed  CAS  Google Scholar 

  236. Robinson MR, Chan CC, Yang JC, et al. Cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma: a new cause of uveitis. J Immunother 2004, 27:478–9.

    Article  PubMed  Google Scholar 

  237. Blansfield JA, Beck KE, Tran K, et al. Cytotoxic T-lymphocyte-associated antigen-4 blockage can induce autoimmune hypophysitis in patients with metastatic melanoma and renal cancer. J Immunother 2005, 28:593–8.

    Article  PubMed  CAS  Google Scholar 

  238. Small EJ, Tchekmedyian NS, Rini BI, et al. A pilot trial of CTLA-4 blockade with human anti-CTLA-4 in patients with hormone-refractory prostate cancer. Clin Cancer Res 2007, 13:1810–5.

    Article  PubMed  CAS  Google Scholar 

  239. Curtin JA, Busam K, Pinkel D, et al. Somatic activation of KIT in distinct subtypes of melanoma. J Clin Oncol 2006, 24:4340–6.

    Article  PubMed  CAS  Google Scholar 

Download references

Authors
  1. Michael Davies MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sunil Patel MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kevin B. Kim MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

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

Rights and permissions

Reprints and permissions

Copyright information

© 2008 Humana Press, Totowa, NJ

About this chapter

Cite this chapter

Davies, M., Patel, S., Kim, K.B. (2008). Targeted Therapy in Melanoma. In: Kurzrock, R., Markman, M. (eds) Targeted Cancer Therapy. Current Clinical Oncology™. Humana Press. https://doi.org/10.1007/978-1-60327-424-1_9

Download citation

  • DOI: https://doi.org/10.1007/978-1-60327-424-1_9

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-60327-423-4

  • Online ISBN: 978-1-60327-424-1

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation