Therapeutic Implications of the Emerging Molecular Biology of … · 2011. 3. 25. · Therapeutic Implications of the Emerging Molecular Biology of Uveal Melanoma Mrinali Patel MD1,
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Therapeutic Implications of the Emerging Molecular Biology of Uveal Melanoma
Mrinali Patel MD1, Elizabeth Smyth MD1, Paul B. Chapman MD,1 Jedd D. Wolchok MD
PhD,1 Gary K Schwartz, MD1, David H Abramson, MD2, Richard D Carvajal, MD1
Departments of Medicine1 and Surgery2, Memorial Sloan-Kettering Cancer Center, New
York, NY, USA
**Mrinali Patel MD and Elizabeth Smyth MD contributed equally to this manuscript.
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 28, 2011; DOI: 10.1158/1078-0432.CCR-10-3169
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 28, 2011; DOI: 10.1158/1078-0432.CCR-10-3169
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 28, 2011; DOI: 10.1158/1078-0432.CCR-10-3169
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 28, 2011; DOI: 10.1158/1078-0432.CCR-10-3169
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 28, 2011; DOI: 10.1158/1078-0432.CCR-10-3169
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 28, 2011; DOI: 10.1158/1078-0432.CCR-10-3169
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 28, 2011; DOI: 10.1158/1078-0432.CCR-10-3169
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 28, 2011; DOI: 10.1158/1078-0432.CCR-10-3169
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 28, 2011; DOI: 10.1158/1078-0432.CCR-10-3169
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 28, 2011; DOI: 10.1158/1078-0432.CCR-10-3169
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 28, 2011; DOI: 10.1158/1078-0432.CCR-10-3169
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 28, 2011; DOI: 10.1158/1078-0432.CCR-10-3169
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 28, 2011; DOI: 10.1158/1078-0432.CCR-10-3169
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 28, 2011; DOI: 10.1158/1078-0432.CCR-10-3169
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 28, 2011; DOI: 10.1158/1078-0432.CCR-10-3169
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 28, 2011; DOI: 10.1158/1078-0432.CCR-10-3169
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 28, 2011; DOI: 10.1158/1078-0432.CCR-10-3169
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 28, 2011; DOI: 10.1158/1078-0432.CCR-10-3169
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 28, 2011; DOI: 10.1158/1078-0432.CCR-10-3169
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 28, 2011; DOI: 10.1158/1078-0432.CCR-10-3169
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 28, 2011; DOI: 10.1158/1078-0432.CCR-10-3169
References 1. Chang AE, Karnell LH, Menck HR. The National Cancer Data Base report on cutaneous and noncutaneous melanoma: a summary of 84,836 cases from the past decade. The American College of Surgeons Commission on Cancer and the American Cancer Society. Cancer. 1998;83:1664-78. 2. Singh AD, Topham A. Incidence of uveal melanoma in the United States: 1973-1997. Ophthalmology. 2003;110:956-61. 3. Seddon JM, Albert DM, Lavin PT, Robinson N. A prognostic factor study of disease-free interval and survival following enucleation for uveal melanoma. Arch Ophthalmol. 1983;101:1894-9. 4. Shields CL, Shields JA, De Potter P, Cater J, Tardio D, Barrett J. Diffuse choroidal melanoma. Clinical features predictive of metastasis. Arch Ophthalmol. 1996;114:956-63. 5. Shields CL, Shields JA, Materin M, Gershenbaum E, Singh AD, Smith A. Iris melanoma - Risk factors for metastasis in 169 consecutive patients. Ophthalmology. 2001;108:172-8. 6. Singh AD, Shields CL, Shields JA. Prognostic factors in uveal melanoma. Melanoma Res. 2001;11:255-63. 7. McLean IW, Foster WD, Zimmerman LE. Uveal melanoma: location, size, cell type, and enucleation as risk factors in metastasis. Hum Pathol. 1982;13:123-32. 8. McLean MJ, Foster WD, Zimmerman LE. Prognostic factors in small malignant melanomas of choroid and ciliary body. Arch Ophthalmol. 1977;95:48-58. 9. Folberg R, Rummelt V, Parys-Van Ginderdeuren R, Hwang T, Woolson RF, Pe'er J, et al. The prognostic value of tumor blood vessel morphology in primary uveal melanoma. Ophthalmology. 1993;100:1389-98. 10. Prescher G, Bornfeld N, Hirche H, Horsthemke B, Jockel KH, Becher R. Prognostic implications of monosomy 3 in uveal melanoma. Lancet. 1996;347:1222-5. 11. Patel KA, Edmondson ND, Talbot F, Parsons MA, Rennie IG, Sisley K. Prediction of prognosis in patients with uveal melanoma using fluorescence in situ hybridisation. Br J Ophthalmol. 2001;85:1440-4. 12. Zuidervaart W, van der Velden PA, Hurks MH, van Nieuwpoort FA, Out-Luiting CJ, Singh AD, et al. Gene expression profiling identifies tumour markers potentially playing a role in uveal melanoma development. Br J Cancer. 2003;89:1914-9. 13. Onken MD, Worley LA, Ehlers JP, Harbour JW. Gene expression profiling in uveal melanoma reveals two molecular classes and predicts metastatic death. Cancer Res. 2004;64:7205-9. 14. Tschentscher F, Husing J, Holter T, Kruse E, Dresen IG, Jockel KH, et al. Tumor classification based on gene expression profiling shows that uveal melanomas with and without monosomy 3 represent two distinct entities. Cancer Res. 2003;63:2578-84. 15. Onken MD, Lin AY, Worley LA, Folberg R, Harbour JW. Association between microarray gene expression signature and extravascular matrix patterns in primary uveal melanomas. Am J Ophthalmol. 2005;140:748-9. 16. Diener-West M, Reynolds SM, Agugliaro DJ, Caldwell R, Cumming K, Earle JD, et al. Development of metastatic disease after enrollment in the COMS trials for treatment of choroidal melanoma: Collaborative Ocular Melanoma Study Group Report No. 26. Arch Ophthalmol. 2005;123:1639-43.
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 28, 2011; DOI: 10.1158/1078-0432.CCR-10-3169
17. Lorigan JG, Wallace S, Mavligit GM. The prevalence and location of metastases from ocular melanoma: imaging study in 110 patients. AJR Am J Roentgenol. 1991;157:1279-81. 18. Rietschel P, Panageas KS, Hanlon C, Patel A, Abramson DH, Chapman PB. Variates of survival in metastatic uveal melanoma. J Clin Oncol. 2005;23:8076-80. 19. Shields JA, Augsburger JJ, Donoso LA, Bernardino VB, Jr., Portenar M. Hepatic metastasis and orbital recurrence of uveal melanoma after 42 years. Am J Ophthalmol. 1985;100:666-8. 20. Assessment of metastatic disease status at death in 435 patients with large choroidal melanoma in the Collaborative Ocular Melanoma Study (COMS): COMS report no. 15. Arch Ophthalmol. 2001;119:670-6. 21. Kujala E, Makitie T, Kivela T. Very long-term prognosis of patients with malignant uveal melanoma. Invest Ophthalmol Vis Sci. 2003;44:4651-9. 22. Bedikian AY, Legha SS, Mavligit G, Carrasco CH, Khorana S, Plager C, et al. Treatment of uveal melanoma metastatic to the liver: a review of the M. D. Anderson Cancer Center experience and prognostic factors. Cancer. 1995;76:1665-70. 23. Augsburger JJ, Correa ZM, Shaikh AH. Effectiveness of treatments for metastatic uveal melanoma. Am J Ophthalmol. 2009;148:119-27. 24. Pingpank J, Hughes M, Alexander H, al. e. A Phase III Random Assignment Trial Comparing Percutaneous Hepatic Perfusion with Melphalan (PHP-mel) to Standard of Care for Patients with Hepatic Metastases from Metastatic Ocular or Cutaneous Melanoma. J Clin Oncol 28:18s (suppl; abstr 8512). 2010. 25. Weber A, Hengge UR, Urbanik D, Markwart A, Mirmohammadsaegh A, Reichel MB, et al. Absence of mutations of the BRAF gene and constitutive activation of extracellular-regulated kinase in malignant melanomas of the uvea. Lab Invest. 2003;83:1771-6. 26. Van Raamsdonk CD, Bezrookove V, Green G, Bauer J, Gaugler L, O'Brien JM, et al. Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi. Nature. 2009;457:599-602. 27. Babchia N, Calipel A, Mouriaux F, Faussat AM, Mascarelli F. 17-AAG and 17-DMAG-induced inhibition of cell proliferation through B-Raf downregulation in WT B-Raf-expressing uveal melanoma cell lines. Invest Ophthalmol Vis Sci. 2008;49:2348-56. 28. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417:949-54. 29. Zuidervaart W, van Nieuwpoort F, Stark M, Dijkman R, Packer L, Borgstein AM, 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. 30. Malaponte G, Libra M, Gangemi P, Bevelacqua V, Mangano K, D'Amico F, et al. Detection of BRAF gene mutation in primary choroidal melanoma tissue. Cancer Biol Ther. 2006;5:225-7. 31. Edmunds SC, Cree IA, Di Nicolantonio F, Hungerford JL, Hurren JS, Kelsell DP. Absence of BRAF gene mutations in uveal melanomas in contrast to cutaneous melanomas. Br J Cancer. 2003;88:1403-5. 32. Rimoldi D, Salvi S, Lienard D, Lejeune FJ, Speiser D, Zografos L, et al. Lack of BRAF mutations in uveal melanoma. Cancer Res. 2003;63:5712-5.
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 28, 2011; DOI: 10.1158/1078-0432.CCR-10-3169
33. Maat W, Kilic E, Luyten GP, de Klein A, Jager MJ, Gruis NA, et al. Pyrophosphorolysis detects B-RAF mutations in primary uveal melanoma. Invest Ophthalmol Vis Sci. 2008;49:23-7. 34. Janssen CS, Sibbett R, Henriquez FL, McKay IC, Kemp EG, Roberts F. The T1799A point mutation is present in posterior uveal melanoma. Br J Cancer. 2008;99:1673-7. 35. Calipel A, Mouriaux F, Glotin AL, Malecaze F, Faussat AM, Mascarelli F. Extracellular signal-regulated kinase-dependent proliferation is mediated through the protein kinase A/B-Raf pathway in human uveal melanoma cells. J Biol Chem. 2006;281:9238-50. 36. Calipel A, Lefevre G, Pouponnot C, Mouriaux F, Eychene A, Mascarelli F. Mutation of B-Raf in human choroidal melanoma cells mediates cell proliferation and transformation through the MEK/ERK pathway. J Biol Chem. 2003;278:42409-18. 37. Kilic E, Bruggenwirth HT, Verbiest MM, Zwarthoff EC, Mooy NM, Luyten GP, et al. The RAS-BRAF kinase pathway is not involved in uveal melanoma. Melanoma Res. 2004;14:203-5. 38. Hatzivassiliou G, Song K, Yen I, Brandhuber BJ, Anderson DJ, Alvarado R, et al. RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature. 2010;464:431-5. 39. Heidorn SJ, Milagre C, Whittaker S, Nourry A, Niculescu-Duvas I, Dhomen N, et al. Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell. 2010;140:209-21. 40. Poulikakos PI, Zhang C, Bollag G, Shokat KM, Rosen N. RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature. 2010;464:427-30. 41. Schwartz G, Robertson S, Shen A, al e. A phase I study of XL281, a selective oral RAF kinase inhibitor, in patients (pts) with advanced solid tumors. J Clin Oncol 27:15s, 2009 (suppl; abstr 3513). 2009. 42. van Elsas A, Zerp S, van der Flier S, Kruse-Wolters M, Vacca A, Ruiter DJ, et al. Analysis of N-ras mutations in human cutaneous melanoma: tumor heterogeneity detected by polymerase chain reaction/single-stranded conformation polymorphism analysis. Recent Results Cancer Res. 1995;139:57-67. 43. Onken MD, Worley LA, Long MD, Duan S, Council ML, Bowcock AM, et al. Oncogenic mutations in GNAQ occur early in uveal melanoma. Invest Ophthalmol Vis Sci. 2008;49:5230-4. 44. Van Raamsdonk CD, Griewank KG, Crosby MB, Garrido MC, Vemula S, Wiesner T, et al. Mutations in GNA11 in uveal melanoma. N Engl J Med. 2010;363:2191-9. 45. Bauer J, Kilic E, Vaarwater J, Bastian BC, Garbe C, de Klein A. Oncogenic GNAQ mutations are not correlated with disease-free survival in uveal melanoma. Br J Cancer. 2009;101:813-5. 46. Vallar L. GTPase-inhibiting mutations activate the alpha-chain of Gs in human tumours. Biochem Soc Symp. 1990;56:165-70. 47. Ambrosini G, Schwartz GK. The MEK inhibitor AZD6244 (selumetinib) is active in GNAQ mutant ocular melanoma cells. American Association for Cancer Research (abstr 5035). 2010.
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 28, 2011; DOI: 10.1158/1078-0432.CCR-10-3169
48. Adjei AA, Cohen RB, Franklin W, Morris C, Wilson D, Molina JR, et al. Phase I pharmacokinetic and pharmacodynamic study of the oral, small-molecule mitogen-activated protein kinase kinase 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancers. J Clin Oncol. 2008;26:2139-46. 49. Dummer R, Robert C, Chapman PB, al e. AZD6244 (ARRY-142886) vs temozolomide (TMZ) in patients (pts) with advanced melanoma: An open-label, randomized, multicenter, phase II study. J Clin Oncol 26:2008 (May 20 suppl; abstr 9033). 2008. 50. Romano E, Schwartz GK, Chapman PB, Wolchock JD, Carvajal RD. Treatment implications of the emerging molecular classification system for melanoma. Lancet Oncology. In press. 51. Abdel-Rahman MH, Yang Y, Zhou XP, Craig EL, Davidorf FH, Eng C. High frequency of submicroscopic hemizygous deletion is a major mechanism of loss of expression of PTEN in uveal melanoma. J Clin Oncol. 2006;24:288-95. 52. Naus NC, Zuidervaart W, Rayman N, Slater R, van Drunen E, Ksander B, et al. Mutation analysis of the PTEN gene in uveal melanoma cell lines. Int J Cancer. 2000;87:151-3. 53. Babchia N, Calipel A, Mouriaux F, Faussat AM, Mascarelli F. The PI3K/Akt and mTOR/P70S6K signaling pathways in human uveal melanoma cells: interaction with B-Raf/ERK. Invest Ophthalmol Vis Sci. 2010;51:421-9. 54. Casagrande F, Bacqueville D, Pillaire MJ, Malecaze F, Manenti S, Breton-Douillon M, et al. G1 phase arrest by the phosphatidylinositol 3-kinase inhibitor LY 294002 is correlated to up-regulation of p27Kip1 and inhibition of G1 CDKs in choroidal melanoma cells. FEBS Lett. 1998;422:385-90. 55. Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell. 2006;124:471-84. 56. Bjornsti MA, Houghton PJ. The TOR pathway: a target for cancer therapy. Nat Rev Cancer. 2004;4:335-48. 57. Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream. Cell. 2007;129:1261-74. 58. Wang L, Harris TE, Roth RA, Lawrence JC, Jr. PRAS40 regulates mTORC1 kinase activity by functioning as a direct inhibitor of substrate binding. J Biol Chem. 2007;282:20036-44. 59. Margolin K, Longmate J, Baratta T, Synold T, Christensen S, Weber J, et al. CCI-779 in metastatic melanoma: a phase II trial of the California Cancer Consortium. Cancer. 2005;104:1045-8. 60. O'Reilly KE, Rojo F, She QB, Solit D, Mills GB, Smith D, et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res. 2006;66:1500-8. 61. Wan X, Harkavy B, Shen N, Grohar P, Helman LJ. Rapamycin induces feedback activation of Akt signaling through an IGF-1R-dependent mechanism. Oncogene. 2007;26:1932-40. 62. Shi Y, Yan H, Frost P, Gera J, Lichtenstein A. Mammalian target of rapamycin inhibitors activate the AKT kinase in multiple myeloma cells by up-regulating the insulin-like growth factor receptor/insulin receptor substrate-1/phosphatidylinositol 3-kinase cascade. Mol Cancer Ther. 2005;4:1533-40.
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 28, 2011; DOI: 10.1158/1078-0432.CCR-10-3169
63. All-Ericsson C, Girnita L, Muller-Brunotte A, Brodin B, Seregard S, Ostman A, et al. c-Kit-dependent growth of uveal melanoma cells: a potential therapeutic target? Invest Ophthalmol Vis Sci. 2004;45:2075-82. 64. Pache M, Glatz K, Bosch D, Dirnhofer S, Mirlacher M, Simon R, et al. Sequence analysis and high-throughput immunohistochemical profiling of KIT (CD 117) expression in uveal melanoma using tissue microarrays. Virchows Arch. 2003;443:741-4. 65. Pereira PR, Odashiro AN, Marshall JC, Correa ZM, Belfort R, Jr., Burnier MN, Jr. The role of c-kit and imatinib mesylate in uveal melanoma. J Carcinog. 2005;4:19. 66. Lefevre G, Glotin AL, Calipel A, Mouriaux F, Tran T, Kherrouche Z, et al. Roles of stem cell factor/c-Kit and effects of Glivec/STI571 in human uveal melanoma cell tumorigenesis. J Biol Chem. 2004;279:31769-79. 67. Fiorentini G, Rossi S, Lanzanova G, Biancalani M, Palomba A, Bernardeschi P, et al. Tyrosine kinase inhibitor imatinib mesylate as anticancer agent for advanced ocular melanoma expressing immunoistochemical C-KIT (CD 117): preliminary results of a compassionate use clinical trial. J Exp Clin Cancer Res. 2003;22:17-20. 68. Penel N, Delcambre C, Durando X, Clisant S, Hebbar M, Negrier S, et al. O-Mel-Inib: a Cancero-pole Nord-Ouest multicenter phase II trial of high-dose imatinib mesylate in metastatic uveal melanoma. Invest New Drugs. 2008;26:561-5. 69. Tijani L, Luadadio M, Mastrangelo M, Sato T. Final results of a pilot study using sunitinib malate in patients with stage IV uveal melanoma. J Clin Oncol 28:15s (suppl; abstr 8577). 2010. 70. Hofmann UB, Kauczok-Vetter CS, Houben R, Becker JC. Overexpression of the KIT/SCF in uveal melanoma does not translate into clinical efficacy of imatinib mesylate. Clin Cancer Res. 2009;15:324-9. 71. Carvajal RD, Chapman PB, Wolchok JD, Cane L, Teitcher JB, Lutzky J, et al. A phase II study of imatinib mesylate (IM) for patients with advanced melanoma harboring somatic alterations of KIT. J Clin Oncol 27:15s, 2009 (suppl; abstr 9001). 2009. 72. Curtin JA, Fridlyand J, Kageshita T, Patel HN, Busam KJ, Kutzner H, et al. Distinct sets of genetic alterations in melanoma. N Engl J Med. 2005;353:2135-47. 73. Curtin JA, Busam K, Pinkel D, Bastian BC. Somatic activation of KIT in distinct subtypes of melanoma. J Clin Oncol. 2006;24:4340-6. 74. Leventhal PS, Feldman EL. Insulin-like Growth Factors as Regulators of Cell Motility Signaling Mechanisms. Trends Endocrinol Metab. 1997;8:1-6. 75. Zhang D, Bar-Eli M, Meloche S, Brodt P. Dual regulation of MMP-2 expression by the type 1 insulin-like growth factor receptor: the phosphatidylinositol 3-kinase/Akt and Raf/ERK pathways transmit opposing signals. J Biol Chem. 2004;279:19683-90. 76. Rodeck U, Melber K, Kath R, Menssen HD, Varello M, Atkinson B, et al. Constitutive expression of multiple growth factor genes by melanoma cells but not normal melanocytes. J Invest Dermatol. 1991;97:20-6. 77. All-Ericsson C, Girnita L, Seregard S, Bartolazzi A, Jager MJ, Larsson O. Insulin-like growth factor-1 receptor in uveal melanoma: a predictor for metastatic disease and a potential therapeutic target. Invest Ophthalmol Vis Sci. 2002;43:1-8. 78. Kanter-Lewensohn L, Dricu A, Girnita L, Wejde J, Larsson O. Expression of insulin-like growth factor-1 receptor (IGF-1R) and p27Kip1 in melanocytic tumors: a potential regulatory role of IGF-1 pathway in distribution of p27Kip1 between different cyclins. Growth Factors. 2000;17:193-202.
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 28, 2011; DOI: 10.1158/1078-0432.CCR-10-3169
79. Mallikarjuna K, Pushparaj V, Biswas J, Krishnakumar S. Expression of epidermal growth factor receptor, ezrin, hepatocyte growth factor, and c-Met in uveal melanoma: an immunohistochemical study. Curr Eye Res. 2007;32:281-90. 80. Economou MA, All-Ericsson C, Bykov V, Girnita L, Bartolazzi A, Larsson O, et al. Receptors for the liver synthesized growth factors IGF-1 and HGF/SF in uveal melanoma: intercorrelation and prognostic implications. Invest Ophthalmol Vis Sci. 2005;46:4372-5. 81. Girnita A, All-Ericsson C, Economou MA, Astrom K, Axelson M, Seregard S, et al. The insulin-like growth factor-I receptor inhibitor picropodophyllin causes tumor regression and attenuates mechanisms involved in invasion of uveal melanoma cells. Acta Ophthalmol. 2008;86 Thesis 4:26-34. 82. Girnita A, Girnita L, del Prete F, Bartolazzi A, Larsson O, Axelson M. Cyclolignans as inhibitors of the insulin-like growth factor-1 receptor and malignant cell growth. Cancer Res. 2004;64:236-42. 83. Economou MA, Andersson S, Vasilcanu D, All-Ericsson C, Menu E, Girnita A, et al. Oral picropodophyllin (PPP) is well tolerated in vivo and inhibits IGF-1R expression and growth of uveal melanoma. Invest Ophthalmol Vis Sci. 2008;49:2337-42. 84. Topcu-Yilmaz P, Kiratli H, Saglam A, Soylemezoglu F, Hascelik G. Correlation of clinicopathological parameters with HGF, c-Met, EGFR, and IGF-1R expression in uveal melanoma. Melanoma Res. 2010;20:126-32. 85. Fredstorp L, Werner S. Growth hormone and insulin-like growth factor-1 in blood and urine as response markers during treatment of acromegaly with octreotide: a double-blind placebo-controlled study. J Endocrinol Invest. 1993;16:253-8. 86. Pollak MN, Polychronakos C, Guyda H. Somatostatin analogue SMS 201-995 reduces serum IGF-I levels in patients with neoplasms potentially dependent on IGF-I. Anticancer Res. 1989;9:889-91. 87. Theodoropoulou M, Zhang J, Laupheimer S, Paez-Pereda M, Erneux C, Florio T, et al. Octreotide, a somatostatin analogue, mediates its antiproliferative action in pituitary tumor cells by altering phosphatidylinositol 3-kinase signaling and inducing Zac1 expression. Cancer Res. 2006;66:1576-82. 88. Gao S, Yu BP, Li Y, Dong WG, Luo HS. Antiproliferative effect of octreotide on gastric cancer cells mediated by inhibition of Akt/PKB and telomerase. World J Gastroenterol. 2003;9:2362-5. 89. Charland S, Boucher MJ, Houde M, Rivard N. Somatostatin inhibits Akt phosphorylation and cell cycle entry, but not p42/p44 mitogen-activated protein (MAP) kinase activation in normal and tumoral pancreatic acinar cells. Endocrinology. 2001;142:121-8. 90. Schmid HA. Pasireotide (SOM230): Development, mechanism of action and potential applications. Mol Cell Endocrinol. 2008;286:69-74. 91. Schmid HA, Silva AP. Short- and long-term effects of octreotide and SOM230 on GH, IGF-I, ACTH, corticosterone and ghrelin in rats. J Endocrinol Invest. 2005;28:28-35. 92. Weckbecker G, Briner U, Lewis I, Bruns C. SOM230: a new somatostatin peptidomimetic with potent inhibitory effects on the growth hormone/insulin-like growth factor-I axis in rats, primates, and dogs. Endocrinology. 2002;143:4123-30.
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 28, 2011; DOI: 10.1158/1078-0432.CCR-10-3169
93. Bruns C, Lewis I, Briner U, Meno-Tetang G, Weckbecker G. SOM230: a novel somatostatin peptidomimetic with broad somatotropin release inhibiting factor (SRIF) receptor binding and a unique antisecretory profile. Eur J Endocrinol. 2002;146:707-16. 94. Ruan W, Fahlbusch F, Clemmons DR, Monaco ME, Walden PD, Silva AP, et al. SOM230 inhibits insulin-like growth factor-I action in mammary gland development by pituitary independent mechanism: mediated through somatostatin subtype receptor 3? Mol Endocrinol. 2006;20:426-36. 95. Lum SS, Fletcher WS, O'Dorisio MS, Nance RW, Pommier RF, Caprara M. Distribution and functional significance of somatostatin receptors in malignant melanoma. World J Surg. 2001;25:407-12. 96. Ardjomand N, Schaffler G, Radner H, El-Shabrawi Y. Expression of somatostatin receptors in uveal melanomas. Invest Ophthalmol Vis Sci. 2003;44:980-7. 97. Bottaro DP, Rubin JS, Faletto DL, Chan AM, Kmiecik TE, Vande Woude GF, et al. Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product. Science. 1991;251:802-4. 98. Furge KA, Zhang YW, Vande Woude GF. Met receptor tyrosine kinase: enhanced signaling through adapter proteins. Oncogene. 2000;19:5582-9. 99. Birchmeier C, Birchmeier W, Gherardi E, Vande Woude GF. Met, metastasis, motility and more. Nat Rev Mol Cell Biol. 2003;4:915-25. 100. Zhang YW, Vande Woude GF. HGF/SF-met signaling in the control of branching morphogenesis and invasion. J Cell Biochem. 2003;88:408-17. 101. Rosario M, Birchmeier W. How to make tubes: signaling by the Met receptor tyrosine kinase. Trends Cell Biol. 2003;13:328-35. 102. Li G, Schaider H, Satyamoorthy K, Hanakawa Y, Hashimoto K, Herlyn M. Downregulation of E-cadherin and Desmoglein 1 by autocrine hepatocyte growth factor during melanoma development. Oncogene. 2001;20:8125-35. 103. Abdel-Rahman MH, Boru G, Massengill J, Salem MM, Davidorf FH. MET oncogene inhibition as a potential target of therapy for uveal melanomas. Invest Ophthalmol Vis Sci. 2010;51:3333-9. 104. Hendrix MJ, Seftor EA, Seftor RE, Kirschmann DA, Gardner LM, Boldt HC, et al. Regulation of uveal melanoma interconverted phenotype by hepatocyte growth factor/scatter factor (HGF/SF). Am J Pathol. 1998;152:855-63. 105. Ye M, Hu D, Tu L, Zhou X, Lu F, Wen B, et al. Involvement of PI3K/Akt signaling pathway in hepatocyte growth factor-induced migration of uveal melanoma cells. Invest Ophthalmol Vis Sci. 2008;49:497-504. 106. Yan D, Zhou X, Chen X, Hu DN, Dong XD, Wang J, et al. MicroRNA-34a inhibits uveal melanoma cell proliferation and migration through downregulation of c-Met. Invest Ophthalmol Vis Sci. 2009;50:1559-65. 107. Kivela T, Eskelin S, Kujala E. Metastatic uveal melanoma. Int Ophthalmol Clin. 2006;46:133-49. 108. Economou MA, All-Ericsson C, Bykov V, Girnita L, Bartolazzi A, Larsson O, et al. Receptors for the liver synthesized growth factors IGF-1 and HGF/SF in uveal melanoma: intercorrelation and prognostic implications. Acta Ophthalmol. 2008;86 Thesis 4:20-5.
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 28, 2011; DOI: 10.1158/1078-0432.CCR-10-3169
109. Harbour JW, Onken MD, Roberson ED, Duan S, Cao L, Worley LA, et al. Frequent mutation of BAP1 in metastasizing uveal melanomas. Science. 2010;330:1410-3. 110. Wilkinson KD. Regulation of ubiquitin-dependent processes by deubiquitinating enzymes. FASEB J. 1997;11:1245-56. 111. Wilkinson KD. Ubiquitination and deubiquitination: targeting of proteins for degradation by the proteasome. Semin Cell Dev Biol. 2000;11:141-8. 112. Angeloni D. Molecular analysis of deletions in human chromosome 3p21 and the role of resident cancer genes in disease. Brief Funct Genomic Proteomic. 2007;6:19-39. 113. Hershko A, Ciechanover A. The ubiquitin system. Annu Rev Biochem. 1998;67:425-79. 114. Jensen DE, Proctor M, Marquis ST, Gardner HP, Ha SI, Chodosh LA, et al. BAP1: a novel ubiquitin hydrolase which binds to the BRCA1 RING finger and enhances BRCA1-mediated cell growth suppression. Oncogene. 1998;16:1097-112. 115. Mallery DL, Vandenberg CJ, Hiom K. Activation of the E3 ligase function of the BRCA1/BARD1 complex by polyubiquitin chains. EMBO J. 2002;21:6755-62. 116. Johnston SC, Larsen CN, Cook WJ, Wilkinson KD, Hill CP. Crystal structure of a deubiquitinating enzyme (human UCH-L3) at 1.8 A resolution. EMBO J. 1997;16:3787-96. 117. Yu H, Mashtalir N, Daou S, Hammond-Martel I, Ross J, Sui G, et al. The ubiquitin carboxyl hydrolase BAP1 forms a ternary complex with YY1 and HCF-1 and is a critical regulator of gene expression. Mol Cell Biol. 2010;30:5071-85. 118. Buchhagen DL, Qiu L, Etkind P. Homozygous deletion, rearrangement and hypermethylation implicate chromosome region 3p14.3-3p21.3 in sporadic breast-cancer development. Int J Cancer. 1994;57:473-9. 119. Ventii KH, Devi NS, Friedrich KL, Chernova TA, Tighiouart M, Van Meir EG, et al. BRCA1-associated protein-1 is a tumor suppressor that requires deubiquitinating activity and nuclear localization. Cancer Res. 2008;68:6953-62. 120. Machida YJ, Machida Y, Vashisht AA, Wohlschlegel JA, Dutta A. The deubiquitinating enzyme BAP1 regulates cell growth via interaction with HCF-1. J Biol Chem. 2009;284:34179-88. 121. Nishikawa H, Wu W, Koike A, Kojima R, Gomi H, Fukuda M, et al. BRCA1-associated protein 1 interferes with BRCA1/BARD1 RING heterodimer activity. Cancer Res. 2009;69:111-9. 122. Misaghi S, Ottosen S, Izrael-Tomasevic A, Arnott D, Lamkanfi M, Lee J, et al. Association of C-terminal ubiquitin hydrolase BRCA1-associated protein 1 with cell cycle regulator host cell factor 1. Mol Cell Biol. 2009;29:2181-92.
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 28, 2011; DOI: 10.1158/1078-0432.CCR-10-3169
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 28, 2011; DOI: 10.1158/1078-0432.CCR-10-3169
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 28, 2011; DOI: 10.1158/1078-0432.CCR-10-3169
Table 1. Receptor tyrosine kinase inhibitors and inhibitors of the MAP kinase and PI3K/Akt pathways of interest in uveal melanoma. Signaling Pathway Target Agent Development Stage Trial Status
ClinicalTrials.gov Identifier
MAP Kinase
BRAF PLX4032 (RO5185426) Phase III trial in cutaneous melanoma Accrual completed NCT01006980
XL281 Phase I trial in solid tumors Ongoing NCT00451880 Sorafenib (BAY 43-9006) FDA approved for renal cell and hepatocellular carcinoma n/a n/a
MEK
AZD6244 (ARRY-142886) Phase II trial in uveal melanoma Ongoing NCT01143402 GSK1120212 Phase III trial in cutaneous melanoma Ongoing NCT01245062
AS703026 Phase I trial in hematologic malignancies Ongoing NCT00957580 MSC1936369B Phase I trial in solid tumors Ongoing NCT00982865
PI3K/Akt
mTOR
Rapamycin Approved for post-renal transplant immunosuppression n/a n/a Temsirolimus FDA approved for renal cell carcinoma n/a n/a
Everolimus (RAD001) Phase II with paclitaxel/carboplatin in Stage IV melanoma Ongoing NCT01014351 Ridaforolimus (AP23573) Phase I/II in advanced/refractory malignancies Accrual completed NCT00112372
TORC1/2 AZD8055 Phase I in advanced solid malignancies Ongoing NCT00973076 OSI027 Phase I in advanced solid malignancies/lymphoma Ongoing NCT00698243 INK128 Phase I in advanced solid malignancies Ongoing NCT01058707
PI3K
XL147 GDC0941 SF1126
Phase I in advanced solid tumors/lymphoma Phase I in patients with solid tumors Phase I in patients with solid tumors
Ongoing Ongoing Ongoing
NCT00486135 NCT00876109 NCT00907205
PI3K + mTOR
XL765 PF04691502
Phase I in patients with solid tumors Phase I in patients with solid tumors
Ongoing Ongoing
NCT00485719 NCT00927823
Akt
Perifosine Phase I in solid tumors/lymphoma Accrual completed NCT00389077 GSK2141795 Phase I in solid tumors/lymphoma Ongoing NCT00920257 GSK690693 Phase I in solid tumors/lymphoma Ongoing NCT00493818
MK2206 Phase I in locally advanced or metastatic solid tumors Ongoing NCT01071018
IMC-A12 Phase I with temsirolimus in advanced cancers Ongoing NCT00678769 R1507 Phase I in advanced solid tumors Ongoing NCT00400361
MK0646 Phase I in advanced solid tumors Accrual completed NCT00635778 OSI-906 Phase I in advanced solid tumors Ongoing NCT00514007 BIIB022 Phase I in advanced solid tumors Ongoing NCT00555724
CP-751,871 Phase I with sunitinib in advanced solid tumors Ongoing NCT00729833 AXL1717 Phase I in advanced solid tumors Ongoing NCT01062620 AMG479 Phase I with biologics/chemo in advanced solid tumors Ongoing NCT00974896
c-Kit
Imatinib Phase II in metastatic uveal melanoma Ongoing NCT00421317 Sunitinib Phase II with cisplatin and tamoxifen in ocular melanoma Ongoing NCT00489944 Sorafenib Phase II with carboplatin/ paclitaxel in uveal melanoma Ongoing NCT00329641 Dasatinib Phase I with bevacizumab in metastatic solid tumors Ongoing NCT00792545 Nilotinib Phase II in c-kit mutated or amplified melanoma Ongoing NCT01168050
c-Met
PF-02341066 Phase I in solid tumors other than NSCLC Not yet open NCT01121588 GSK1363089 Phase I in solid tumors Accrual completed NCT00742261
XL-184 Randomized discontinuation in advanced solid tumors Ongoing NCT00940225 ARQ 197 Phase I in refractory/advanced solid tumors Ongoing NCT00609921
EMD 1204831 Phase I in advanced solid tumors Ongoing NCT01110083 PRO143966 Phase I in advanced solid tumors Accrual completed NCT01068977
Table 2. Currently accruing clinical trials for advanced uveal melanoma. ClinicalTrials.gov
Identifier Agent Phase Sponsor/Study Lead NCT01034787 CP-675,206 II Alberta Health Services NCT00506142 Liposomal vincristine II Hana Biosciences, Inc NCT01143402 AZD6244 versus Temozolomide II Memorial Sloan-Kettering Cancer Center NCT01200342 Genasense, Carboplatin & Paclitaxel II M.D. Anderson Cancer Center NCT00738361 Paclitaxel Albumin-Stabilized Nanoparticle Formulation II Arthur G. James Cancer Hospital NCT00110123 IV versus Hepatic Arterial Infusion of Fotemustine III EORTC NCT01217398 Temozolomide & Bevacizumab II Institut Curie NCT00313508 Vaccine Therapy and Autologous Lymphocyte Infusion With or Without Fludarabine I/II H. Lee Moffitt Cancer Center NCT00471471 Multi-Epitope Peptide Vaccine I University of Pittsburgh NCT01005472 Temozolomide & Sunitinib I/II University of California, Los Angeles NCT00168870 Gemcitabine & Treosulfan versus Treosulfan II Charite University, Berlin, Germany NCT01200238 STA-9090 II Dana-Farber Cancer Institute NCT00421317 Imatinib II Centre Oscar Lambret NCT01252251 SOM230 & RAD001 II Memorial Sloan-Kettering Cancer Center
Published OnlineFirst March 28, 2011.Clin Cancer Res Mrinali Patel, Elizabeth C Smyth, Paul B Chapman, et al. Uveal MelanomaTherapeutic Implications of the Emerging Molecular Biology of
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