New developments in medulloblastoma treatment: The potential of a cyclopamine-lovastatin combination

Expert Opinion on Investigational Drugs

Volumn 17, Issue 2, 2008, Pages 185-195

  Bar, Eli E ^a   Stearns, Duncan ^b  

^a JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b DREXEL UNIVERSITY COLLEGE OF MEDICINE   (United States)

Author keywords

Apoptosis; Bcl2; Cholesterol; Hedgehog; Lovastatin; Statin

Indexed keywords

ANTINEOPLASTIC AGENT; ATORVASTATIN; CERIVASTATIN; CHOLESTEROL; CYCLOPAMINE; FLUINDOSTATIN; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; MEVINOLIN; PITAVASTATIN; PRAVASTATIN; PROTEIN BCL 2; PROTEIN PATCHED 1; ROSUVASTATIN; SIMVASTATIN; SONIC HEDGEHOG PROTEIN; TRANSCRIPTION FACTOR GLI1; UBIQUINONE; VERATRUM ALKALOID;

ANTINEOPLASTIC ACTIVITY; APOPTOSIS; BRAIN TUMOR; CANCER INHIBITION; CANCER RISK; CANCER SURVIVAL; CHEMOSENSITIVITY; CHOLESTEROL SYNTHESIS; CLINICAL TRIAL; COMBINATION CHEMOTHERAPY; DRUG SAFETY; DRUG STRUCTURE; DRUG TARGETING; DRUG TOLERABILITY; GASTROINTESTINAL CARCINOMA; HUMAN; ISOPRENYLATION; LUNG CARCINOMA; MEDULLOBLASTOMA; MUSCLE DISEASE; MUSCLE TOXICITY; NONHUMAN; PROSTATE CARCINOMA; REVIEW; RHABDOMYOLYSIS; RISK REDUCTION; TUMOR; ANIMAL; DRUG ANTAGONISM; METABOLISM;

ANIMALS; ANTINEOPLASTIC AGENTS; ANTINEOPLASTIC COMBINED CHEMOTHERAPY PROTOCOLS; CHOLESTEROL; HEDGEHOG PROTEINS; HUMANS; HYDROXYMETHYLGLUTARYL-COA REDUCTASE INHIBITORS; LOVASTATIN; MEDULLOBLASTOMA; VERATRUM ALKALOIDS;

EID: 39049149075     PISSN: 13543784     EISSN: None     Source Type: Journal    
DOI: 10.1517/13543784.17.2.185     Document Type: Review

References (116)

1. Packer RJ, Gajjar A, Vezina G, et al. Phase III study of craniospinal radiation therapy followed by adjuvant chemotherapy for newly diagnosed average-risk medulloblastoma. J Clin Oncol 2006;24:4202-8
2. Gajjar A, Chintagumpala M, Ashley D, et al. Risk-adapted craniospinal radiotherapy followed by high-dose chemotherapy and stem-cell rescue in children with newly diagnosed medulloblastoma (St Jude Medulloblastoma-96): long-term results from a prospective, multicentre trial. Lancet Oncol 2006;7:813-20
3. Geyer JR, Sposto R, Jennings M, et al. Multiagent chemotherapy and deferred radiotherapy in infants with malignant brain tumors: a report from the Children's Cancer Group. J Clin Oncol 2005;23:7621-31
4. Rood BR, MacDonald TJ, Packer RJ. Current treatment of medulloblastoma: recent advances and future challenges. Semin Oncol 2004;31:666-75
5. Thomas PR, Deutsch M, Kepner JL, et al. Low-stage medulloblastoma: final analysis of trial comparing standard-dose with reduced-dose neuraxis irradiation. J Clin Oncol 2000;18:3004-11
6. Ribi K, Relly C, Landolt MA, et al. Outcome of medulloblastoma in children: long-term complications and quality of life. Neuropediatrics 2005;36:357-65
7. Mulhern RK, Palmer SL, Merchant TE, et al. Neurocognitive consequences of risk-adapted therapy for childhood medulloblastoma. J Clin Oncol 2005;23:5511-9
8. Xu W, Janss A, Packer RJ, et al. Endocrine outcome in children with medulloblastoma treated with 18 Gy of craniospinal radiation therapy. Neuro Oncol 2004;6:113-8
9. Walter AW, Mulhern RK, Gajjar A, et al. Survival and neurodevelopmental outcome of young children with medulloblastoma at St Jude Children's Research Hospital. J Clin Oncol 1999;17:3720-8
10. Packer RJ, Goldwein J, Nicholson HS, et al. Treatment of children with medulloblastomas with reduced-dose craniospinal radiation therapy and adjuvant chemotherapy: a Children's Cancer Group Study. J Clin Oncol 1999;17:2127-36
11. Guruangan S, Dunkel IJ, Goldman S, et al. Myeloablative chemotherapy with autologous bone marrow rescue in young children with recurrent malignant brain tumors. J Clin Oncol 1998;16:2486-93
12. Ridola V, Grill J, Doz F, et al. High-dose chemotherapy with autologous stem cell rescue followed by posterior fossa irradiation for local medulloblastoma recurrence or progression after conventional chemotherapy. Cancer 2007;110:156-63
13. Rutkowski S, Bode U, Deinlein F, et al. Treatment of early childhood medulloblastoma by postoperative chemotherapy alone. N Engl J Med 2005;352:978-86
14. Di C, Liao S, Adamson DC, et al. Identification of OTX2 as a medulloblastoma oncogene whose product can be targeted by all-trans retinoic acid. Cancer Res 2005;65:919-24
15. Gajjar A, Hernan R, Kocak M, et al. Clinical, histopathologic, and molecular markers of prognosis: toward a new disease risk stratification system for medulloblastoma. J Clin Oncol 2004;22:984-93
16. Gilbertson R, Wickramasinghe C, Hernan R, et al. Clinical and molecular stratification of disease risk in medulloblastoma. Br J Cancer 2001;85:705-12
17. Gilbertson, RJ, Clifford SC. PDGFRB is overexpressed in metastatic medulloblastoma Nat Genet 2003;35:197-8
18. MacDonald TJ, Brown KM, LaFleur B, et al. Expression profiling of medulloblastoma: PDGFRA and the RAS/NWK pathway as therapeutic targets for metastatic disease. Nat Genet 2001;29:143-52
19. Webb JH. Cancer, its nature and its treatment. Lancet 1901;158:3
20. Byers T, Nestle M, McTiernan A, et al. American Cancer Society guidelines on nutrition and physical activity for cancer prevention: reducing the risk of cancer with healthy food choices and physical activity. CA Cancer J Clin 2002;52.92-119
21. Bravi F, Scotti L, Bosetti C, et al. Self-reported history of hypercholesterolaemia and gallstones and the risk of prostate cancer. Ann Oncol 2006;17:1014-7
22. Corsini A, Maggi FM, Carapano AL. Pharmacology of competitive inhibitors of HMG-CoA reductase. Pharmacol Res 1995;31:9-27
23. Farmer JA, Torre-Amione G. Comparative tolerability of the HMG-CoA reductase inhibitors. Drug Saf 2000;23:197-213
24. Hanefeld M. Clinical rationale for rosuvastatin, a potent new HMG-CoA reductase inhibitor. Int J Clin Pract 2001;55:399-405
25. Illingworth DR, Tobert JA. HMG-CoA reductase inhibitors. Adv Protein Chem 2001;56:77-114
26. Thompson GR, Naoumova RP. Novel Lipid-regulating drugs. Expert Opin Investig Drugs 2000;9:2619-28
27. Istvan ES, Deisenhofer J. Structural mechanism for statin inhibition of HMG-CoA reductase. Science 2001;292:1160-4
28. Alberts AW, MacDonald JS, Till AE, Tobert JA. Lovastatin. Cardiovasc Drug Rev 1989;7:20
29. Bottorff M, Hansten P. Long-term safety of hepatic hydroxymethyl glutaryl coenzyme A reductase inhibitors: the role of metabolism-monograph for physicians. Arch Intern Med 2000;160:2273-80
30. Hanefeld M, Deslypere JP, Ose L, et al. Efficacy and safety of 300 micrograms and 400 micrograms cerivastatin once daily in patients with primary hypercholesterolaemia: a multicentre, randomized, double-blind, placebo-controlled study. J Int Med Res 1999;27:115-29
31. Kajinami K, Mabuchi H, Saito Y. NK-104: a novel synthetic HMG-CoA reductase, inhibitor. Expert Opin Investig Drugs 2000;9:2653-61
32. Lennernas H, Fager G. Pharmacodynamics and pharmacokinetics of the HMG-CoA reductase inhibitors. Similarities and differences. Clin Pharmacokinet 1997;32:403-25
33. McTaggart F, Buckett L, Davidson R, et al. Preclinical and clinical pharmacology of rosuvastatin, a new 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor. Am J Cardiol 2001;87:28B-32B
34. Muck W. Clinical pharmacokinetics of cerivastatin. Clin Pharmacokinet 2000;39:99-116
35. Davidson MH. Safety profiles for the HMG-CoA reductase inhibitors: treatment and trust drugs 2001;61:197-206
36. Ucar M, Mjorndal T, Dahlqvist R. HMG-CoA reductase inhibitors and myotoxicity. Drug Saf 2000;22:441-57
37. Bos JL. ras oncogenes in human cancer: a review. Cancer Res 1989;49:4682-9
38. Kahn S, Yamamoto F, Almoguera C, et al. The c-K-ras gene and human cancer (review). Anticancer Res 1987;7:639-52
39. McKay IA, Paterson H, Brown R, et al. N-ras and human cancer. Anticancer Res 1986;6:483-90
40. Shih TY, Weeks MO. Oncogenes and cancer: the p21 ras genes. Cancer Invest 1984;2:109-23
41. Magee T, Marshall C. New insights into the interaction of Ras with the plasma membrane. Cell 1999;98:9-12
42. Gelb MH. Protein prenylation, et cetera: signal transduction in two dimensions. Science 1997;275:1750-1
43. Kato K, Cox AD, Hisaka MM, et al. Isoprenoid addition to Ras protein is the critical modification for its membrane association and transforming activity. Proc Natl Acad Sci USA 1992;89:6403-7
44. O'Gorman DM, Cotter TG. Molecular signals in anti-apoptotic survival pathways. Leukemia 2001;15:21-34
45. Rebollo A, Martinez AC. Ras proteins: recent advances and new functions. Blood 1999;94:2971-80
46. Reuter CW, Morgan MA, Bergmann L. Targeting the Ras signaling pathway: a rational, mechanism-based treatment for hematologic malignancies? Blood 2000;96:1655-69
47. Bouterfa HL, Sattelmeyer V, Czub S, et al. Inhibition of Ras farnesylation by lovastatin leads to downregulation of proliferation and migration in primary cultured human glioblastoma cells. Anticancer Res 2000;20:2761-71
48. Zhong WB, Wang CY, Chang TC, Lee WS. Lovastatin induces apoptosis of anaplastic thyroid cancer cells via inhibition of protein geranylgeranylation and de novo protein synthesis. Endocrinology 2003;144:3852-9
49. Sebti SM, Hamilton AD. Inhibition of Ras prenylation: a novel approach to cancer chemotherapy. Pharmacol Ther 1997;74:103-14
50. Lee MH, Cho YS, Han YM. Simvastatin suppresses self-renewal of mouse embryonic stem cells by inhibiting rhea geranylgeranylation. Stem Cells 2007;25:9654-63
51. Sagar J, Chaib B, Sales K, et al. Role of stem cells in cancer therapy and cancer stem cells: a review. Cancer Cell Int 2007;7:9
52. Al-Hajj M, Becker MW, Wicha M, et al. Therapeutic implications of cancer stem cells. Curr Opin Genet Dev 2004;14:43-7
53. Bonnet D. Cancer stem cells: lessons from leukaemia. Cell Prolif 2005;38:357-61
54. Galmozzi E, Facchetti F, La Porta CA. Cancer stem cells and therapeutic perspectives. Curr Med Chem 2006;13:603-7
55. Jones RJ, Matsui WH, Smith BD. Cancer stem cells: are we missing the target? J Natl Cancer Inst 2004;96:583-5
56. Pilkington GJ. Cancer stem cells in the mammalian central nervous system. Cell Prolif 2005;38:423-33
57. Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature 2001;414:105-11
58. Soltysova A, Altanerova V, Altaner C. Cancer stem cells. Neoplasma 2005;52:435-40
59. Liscum L, Munn NJ. Intracellular cholesterol transport. Biochim Biophys Acta 1999;1438:19-37
60. Simons K, Toomre D. Lipid rafts and signal transduction. Nat Rev Mol Cell Biol 2000;1:31-9
61. Liu Y, Sun R, Wan W, et al. The involvement of lipid rafts in epidermal growth factor-induced chemotaxis of breast cancer cells. Mol Membr Biol 2007;24:91-101
62. Poynter JN, Gruber SB, Higgins PD, et al. Statins and the risk of colorectal cancer. N Engl J Med 2005;352:2184-92
63. Coogan PF, Smith J, Rosenberg L. Statin use and risk of colorectal cancer. J Natl Cancer Inst 2007;99:32-40
64. Coogan PF, Rosenberg L, Strom BL. Statin use and the risk of 10 cancers. Epidemiology 2007;18:213-9
65. Shannon J, Tewoderos S, Garzotto M, et al. Statins and prostate cancer risk: a case-control study. Am J Epidemiol 2005;162:318-25
66. Ahmed MH, Osman MM, Alokail MS. Statins and breast cancer: a smoking gun or guilt by association? Expert Opin Drug Saf 2006;5:599-601
67. Moorman PG, Hamilton RJ. Statins and cancer risk: what do we know and where do we go from here? Epidemiology 2007;18:194-6
68. Kornblau SM, Banker DE, Stirewalt D, et al. Blockade of adaptive defensive changes in cholesterol uptake and synthesis in AML by the addition of pravastatin to idarubicin + high-dose Ara-C: a Phase 1 study. Blood 2007;109:2999-3006
69. Knox JJ, Siu LL, Chen E, et al. A Phase I trial of prolonged administration of lovastatin in patients with recurrent or metastatic squamous cell carcinoma of the head and neck or of the cervix. Eur J Cancer 2005;41:523-30
70. van der Spek E, Bloem AC, van de Donk NW, et al. Dose-finding study of high-dose simvastatin combined with standard chemotherapy in patients with relapsed or refractory myeloma or lymphoma. Haematologica 2006;91:542-5
71. Ingham PW, McMahon AP. Hedgehog signaling in animal development: paradigms and principles. Genes Dev 2001;15:3059-87
72. Osterlund T, Kogerman P. Hedgehog signaling: how to get from Smo to Ci and Gli. Trends Cell Biol 2006;16:176-80
73. Cooper MK, Wassif CA, Krakowiak PA, et al. A defective response to Hedgehog signaling in disorders of cholesterol biosynthesis. Nat Genet 2003;33:508-13
74. Hooper JE, Scott MP. Communicating with Hedgehogs. Nat Rev Mol Cell Biol 2005;6:306-17
75. Lum L, Beachy PA. The Hedgehog response network: sensors, switches, and routers. Science 2004;304:1755-9
76. Berman DM, Karhadkar SS, Hallahan AR, et al. Medulloblastoma growth inhibition by hedgehog pathway blockade. Science 2002;297:1559-61
77. Berman DM, Karhadkar SS, Maitra A, et al. Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours. Nature 2003;425:846-51
78. Karhadkar SS, Bova GS, Abdallah N, et al. Hedgehog signalling in prostate regeneration, neoplasia and metastasis. Nature 2004;431:707-12
79. Thayer SP, di Magliano MP, Heiser PW, et al. Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature 2003;425:851-6
80. Watkins DN, Berman DM, Burkholder SG, et al. Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer. Nature 2003;422:313-7
81. Bumcrot DA, Takada R, McMahon AP. Proteolytic processing yields two secreted forms of sonic hedgehog. Mol Cell Biol 1995;15:2294-303
82. Lee JJ, Ekker SC, von Kessler DP, et al. Autoproteolysis in hedgehog protein biogenesis. Science 1994;266:1528-37
83. Porter JA, Young KE, Beachy PA. Cholesterol modification of hedgehog signaling proteins in animal development. Science 1996;274:255-9
84. Burke R, Nellen D, Bellotto M, et al. Dispatched, a novel sterol-sensing domain protein dedicated to the release of cholesterol-modified hedgehog from signaling cells. Cell 1999;99:803-15
85. Porter JA, Ekker SC, Park WJ, et al. Hedgehog patterning activity: role of a lipophilic modification mediated by the carboxy-terminal autoprocessing domain. Cell 1996;86:21-34
86. Brown MS, Goldstein JL. A proteolytic pathway that controls the cholesterol content of membranes, cells, and blood. Proc Natl Acad Sci USA 1999;96:11041-8
87. Goldstein JL, Brown MS. Regulation of the mevalonate pathway. Nature 1990;343:425-30
88. Kelleher FC, Fennelly D, Rafferty M. Common critical pathways in embryogenesis and cancer. Acta Oncol 2006;45:375-88
89. Gailani MR, Bale SJ, Leffell DJ, et al. Developmental defects in Gorlin syndrome related to a putative tumor suppressor gene on chromosome 9. Cell 1992;69:111-7
90. Sasai K, Romer JT, Kimura H, et al. Medulloblastomas derived from Cxcr6 mutant mice respond to treatment with a smoothened inhibitor. Cancer Res 2007;67:3871-7
91. Bar EE, Chaudhry A, Farah MH, Eberhart CG. Hedgehog signaling promotes medulloblastoma survival via Bcl2. Am J Pathol 2007;170:347-55
92. Di Marcotullio L, Ferretti E, De Smaele E, et al. REN(KCTD11) is a suppressor of Hedgehog signaling and is deleted in human medulloblastoma. Proc Natl Acad Sci USA 2004;101:10833-8
93. Taylor MD, Liu L, Raffel C, et al. Mutations in SUFU predispose to medulloblastoma. Nat Genet 2002;31:306-10
94. Lauth M, Bergstrom A, Shimokawa T, Toftgard R. Inhibition of GLI-mediated transcription and tumor cell growth by small-molecule antagonists. Proc Natl Acad Sci USA 2007;104:8455-60
95. van de Donk NW, Kamphuis MM, Lokhorst HM, Bloem AC. The cholesterol lowering drug lovastatin induces cell death in myeloma plasma cells. Leukemia 2002;16:1362-71
96. Blanco-Colio LM, Villa A, Ortego M, et al. 3-Hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitors, atorvastatin and simvastatin, induce apoptosis of vascular smooth muscle cells by downregulation of Bcl-2 expression and Rho A prenylation. Atherosclerosis 2002;161:17-26
97. Feleszko W, Zagozdzon R, Golab J, Jakobisiak M. Potentiated antitumour effects of cisplatin and lovastatin against MmB16 melanoma in mice. Eur J Cancer 1998;34:406-11
98. Macaulay RJ, Wang W, Dimitroulakos J, Becker LE, Yeger H. Lovastatin-induced apoptosis of human medulloblastoma cell lines in vitro. J Neurooncol 1999;42:1-11
99. Wang W, Macaulay RJ. Mevalonate prevents lovastatin-induced apoptosis in medulloblastoma cell lines. Can J Neurol Sci 1999;26:305-10
100. Wang W, Macaulay RJ. Apoptosis of medulloblastoma cells in vitro follows inhibition of farnesylation using manumycin A. Int J Cancer 1999;82:430-4
101. Wang W, Macaulay RJ. Cell-cycle gene expression in lovastatin-induced medulloblastoma apoptosis. Can J Neurol Sci 2003;30:349-57
102. Corcoran RB, Scott MP. Oxysterols stimulate Sonic hedgehog signal transduction and proliferation of medulloblastoma cells. Proc Natl Acad Sci USA 2006;103:8408-13
103. Cory S. Regulation of lymphocyte survival by the bcl-2 gene family. Ann Rev Immunol 1995;13:513-43
104. Korsmeyer SJ. BCL-2 gene family and the regulation of programmed cell death. Cancer Res 1999;59:1693s-1700s
105. Oltvai ZN, Milliman CL, Korsmeyer SJ. Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell 1993;74:609-19
106. Reed JC, Miyashita T, Krajewski S, et al. Bcl-2 family proteins and the regulation of programmed cell death in leukemia and lymphoma. Cancer Treat Res 1996;84:31-72
107. Dahmane N, Ruiz i Altaba A. Sonic hedgehog regulates the growth and patterning of the cerebellum. Development 1999;126:3089-100
108. Wallace VA. Purkinje-cell-derived Sonic hedgehog regulates granule neuron precursor cell proliferation in the developing mouse cerebellum. Curr Biol 1999;9:445-8
109. Wechsler-Reya RJ, Scott MP. Control of neuronal precursor proliferation in the cerebellum by Sonic Hedgehog. Neuron 1999;22:103-14
110. Galli R, Binda F, Orfanelli U, et al. Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res 2004;64:7011-21
111. Singh SK, Hawkins C, Clarke ID, et al. Identification of human brain tumour initiating cells. Nature 2004;432:396-401
112. Bao S, Wu Q, McLendon RE, et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 2006;444:756-6
113. Clement V, Sanchez P, de Tribolet N, et al. HEDGEHOG-GLI1 signaling regulates human glioma growth, cancer stem cell self-renewal, and tumorigenicity. Curr Biol 2007;17:165-72
114. Romer J, Curran T. Targeting medulloblastoma: small-molecule inhibitors of the Sonic Hedgehog pathway as potential cancer therapeutics. Cancer Res 2005;65:4975-8
115. Myers JN, Yasumura S, Suminami Y, et al. Growth stimulation of human head and neck squamous cell carcinoma cell lines by interleukin 4. Clin Cancer Res 1996;2:127-35
116. Wiegman A, Hutten BA, de Groot E, et al. Efficacy and safety of statin therapy in children with familial hypercholesterolemia: a randomized controlled trial. JAMA 2004;292:331-7