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Molecularly Targeted Therapy for Childhood Cancer pp 231–265Cite as

Molecularly Targeted Therapies for Astrocytomas

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Abstract

Astrocytomas constitute the largest group of central nervous system (CNS) neoplasms during childhood, and incorporate tumors with diverse histological features and biological characteristics (Pollack 1994). Whereas patients with superficial low-grade gliomas are often cured with surgery alone, patients with deep-seated or malignant gliomas continue to have a suboptimal prognosis, despite recent improvements in surgery and adjuvant therapy. The prognosis remains particularly grim for patients with malignant gliomas, such as glioblastoma multiforme (GBM) and anaplastic astrocytoma, which generally lead to death within several years after diagnosis (Finlay et al. 1995). The poor response of these tumors to conventional therapies reflects a resistance of malignant glioma cells to undergo apoptosis in response to DNA damage, which may result from mutations of tumor suppressor and cell cycle control genes and aberrant activation of growth and survival signaling pathways. Although molecular pathways leading to tumorigenesis have been clearly established for adult malignant gliomas (Louis 1997), the involvement of such pathways in pediatric glial neoplasia remains inferential. For example, because in adult gliomas, platelet-derived growth factor receptor (PDGFR) and epidermal growth factor receptor (EGFR) have been observed to play important roles in tumor proliferation, and have therefore constituted logical targets for molecularly targeted therapies, such approaches have concurrently been explored in pediatric gliomas. This chapter reviews the molecular features of childhood gliomas associated with disease progression and prognosis, and discusses recent molecularly targeted therapeutic strategies.

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References

  • Abdollahi, A., Lipson, K.E., Sckell, A., et al. 2003. Combined therapy with direct and indirect angiogenesis inhibition results in enhanced antiangiogenic and antitumor effects. Cancer Res 63:8890–8898.

    PubMed  CAS  Google Scholar 

  • Albanell, J., Royo, F., Auerbach, S., et al. 2002. Pharmacokinetic studies of the epidermal growth factor receptor inhibitor ZD1839 in skin from cancer patients: histological and molecular consequences of receptor inhibition. J Clin Oncol 20:110–124.

    Article  PubMed  CAS  Google Scholar 

  • Alsina, M., Fonseca, R., Wilson, E.F., et al. 2004. Farnesyltransferase inhibitor tipifarnib is well tolerated, induces stabilization of disease, and inhibits farnesylation and oncogenic/tumor survival pathways in patients with advanced multiple myeloma. Blood 103:3271–3277.

    Article  PubMed  CAS  Google Scholar 

  • Baker, M.J., Brem, S., et al. 2002. Complete response of a recurrent, multicentric malignant glioma patient treated with phenylbutyrte. J Neurooncol 59:239–242.

    Article  PubMed  Google Scholar 

  • Barnett, F.H., Scharer-Schuksz, M., Wood, M., et al. 2004. Intra-arterial delivery of endostatin gene to in tumors prolongs survival and alters tumor vessel ultrastructure. Gene Ther.11:1283–1289.

    Article  PubMed  CAS  Google Scholar 

  • Baselga, J., Rischin, D., Ranson, M., et al. 2002. Phase I safety, pharmacokinetic, and pharmacodynamic trial of ZD1839, a selective oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with five selected solid tumor types. J Clin Oncol 20:4292–4302.

    Article  PubMed  CAS  Google Scholar 

  • Baselga, J., Pfister, D., Cooper, M.R., et al. 2000. Phase I studies of anti-epidermal growth factor receptor chimeric antibody C225 alone and in combination with cisplatin. J Clin Oncol 18:904–914.

    PubMed  CAS  Google Scholar 

  • Baumann, F., Bjeljac, M., Kollias, S.S., et al. 2004. Combined thalidomide and temozolomide treatment in patients with glioblastoma multiforme. J Neurooncol 67:191–200.

    Article  PubMed  Google Scholar 

  • Belanich, M., Pastor, M., Randall, T., et al. 1996. Retrospective study of correlation between the DNA repair protein alkyl-transferase and survival of brain tumor patients treated with carmustine. Cancer Res 56:783–788.

    PubMed  CAS  Google Scholar 

  • Bianco, R., Shin, I., Ritter, C.A., Yakes, F.M., Basso, A., Rosen, N., Tsurutani, J., Dennis, P.A., Mills, G.B., Arteaga, C.L. 2003. Loss of PTEN/MMAC1/TEP in EGF receptor-expressing tumor cells counteracts the antitumor action of EGFR tyrosine kinase inhibitors. Oncogene 22: 2812–2822.

    Article  PubMed  CAS  Google Scholar 

  • Bobo, R.H., Laske, D., Akbasak, A., et al. 1994. Convection-enhanced delivery of macromolecules in the brain. Proc Natl Acad Sci U S A 91:2076–2080.

    Article  PubMed  CAS  Google Scholar 

  • Bocangel, D.B., Finkelstein, S., Schold, S.C., et al. 2002. Multifaceted resistance of gliomas to temozolomide. Clin Cancer Res 8:2725–2734.

    PubMed  CAS  Google Scholar 

  • Bredel, M., Pollack, I.F., Freund, J.M., Hamilton, A.D., Sebti, S.M. 1998. Inhibition of Ras and related G-proteins as a therapeutic strategy for blocking malignant glioma growth. Neurosurgery 43:124–131.

    Article  PubMed  CAS  Google Scholar 

  • Bredel, M., Pollack, I.F., Freund, J.M., Rusnak, J., Lazo, J.S. 1999a. Protein kinase C inhibition by UCN-01 induces apoptosis in human glioma cells in a time-dependent fashion. J Neurooncol 41:9–20.

    Article  PubMed  CAS  Google Scholar 

  • Bredel, M., Pollack, I.F., Hamilton, R.L., James, C.D. 1999b. Epidermal growth factor receptor (EGFR) expression in high-grade non-brainstem gliomas of childhood. Clin Cancer Res 5:1786–1792.

    PubMed  CAS  Google Scholar 

  • Bruns, C.J., Harbison, M.T., Davis, D.W., et al. 2000. Epidermal growth factor receptor blockade with C225 plus gemcitabine results in regression of human pancreatic carcinoma growing orthotopically in nude mice by antiangiogenic mechanisms. Clin Cancer Res 6:1936–1948.

    PubMed  CAS  Google Scholar 

  • Buchdunger, E., Cioffi, C.L., Law, N., et al. 2000. Abl protein-tyrosine kinase inhibitor STI571 inhibits in vitro signal transduction mediated by c-kit and platelet-derived growth factor receptors. J Pharmacol Exp Ther 295:139–145.

    PubMed  CAS  Google Scholar 

  • Burris, H.A., III. 2004. Dual kinase inhibition in the treatment of breast cancer: initial experience with the EGFR/ErbB-2 inhibitor lapitinib. Oncologist 9 (Suppl 3):10–15.

    Article  PubMed  CAS  Google Scholar 

  • Cantley, L.C., Neel, B.G. 1999. New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. Proc Natl Acad Sci U S A 96:4240–4245.

    Article  PubMed  CAS  Google Scholar 

  • Cardone, M.H., Roy, N., Stennicke, H.R., et al. 1998. Regulation of cell death protease caspase-9 by phosphorylation. Science 282:1318–1321.

    Article  PubMed  CAS  Google Scholar 

  • Carducci, M.A., Musib, L., Kies, M.S., et al. 2006. Phase I dose escalation and pharmacokinetic study of enzastaurin, an oral protein kinase C beta inhibitor, in patients with advanced cancer. J Clin Oncol 24:4092–4099.

    Article  PubMed  CAS  Google Scholar 

  • Chang, S.M., Wen, P., Cloughesy, T., et al. 2005. Phase II study of CCI-779 in patients with recurrent glioblastoma multiforme. Invest New Drugs 23:357–361.

    Article  PubMed  CAS  Google Scholar 

  • Cheng, Y., Ng, H.-K., Zhang, S.-F., et al. 1999. Genetic alterations in pediatric high-grade astrocytomas. Hum Pathol 30:1284–1290.

    Article  PubMed  CAS  Google Scholar 

  • Cheng, Y., Pang, J.C., Ng, H.K., et al. 2000. Pilocytic astrocytomas do not show most of the genetic changes commonly seen in diffuse astrocytomas. Histopathology 37:437–444.

    Article  PubMed  CAS  Google Scholar 

  • Ciardiello, F., Caputo, R., Bianco, R., et al. 2001. Inhibition of growth factor production and angiogenesis in human cancer cells by ZD1839 (Iressa), a selective epidermal growth factor receptor tyrosine kinase inhibitor. Clin Cancer Res 7:1459–1465.

    PubMed  CAS  Google Scholar 

  • Ciardiello, F., Caputo, R., Bianco, R., et al. 2000. Antitumor effect and potentiation of cytotoxic drugs activity in human cancer cells by ZD-1839 (Iressa), an epidermal growth factor receptor-selective tyrosine kinase inhibitor. Clin Cancer Res 6:2053–2063.

    PubMed  CAS  Google Scholar 

  • Cloughesy, T.F., Wen, P.Y., Robins, H.I., et al. 2006.Phase II trial of tipifarnib in patients with recurrent malignant glioma either receiving or not receiving enzyme-inducing antiepileptic drugs: a North American Brain Tumor Consortium Study. J Clin Oncol 24:3651–3656

    Article  CAS  Google Scholar 

  • Collins, V.P. 1999. Progression as exemplified by human astrocytic tumors. Cancer Biol. 9:267–276.

    Article  CAS  Google Scholar 

  • Couldwell, W.T., Uhm, J.H., Antel, J.P., Yong, V.W. 1991. Enhanced protein kinase C activity correlates with the growth rate of malignant gliomas in vitro. Neurosurgery 29:880–887.

    Article  PubMed  CAS  Google Scholar 

  • Couldwell, W.T., Antel, J.P., Yong, V.W. 1992. Protein kinase C activity correlates with the growth rate of malignant gliomas: part II. Effects of glioma mitogens and modulators of protein kinase C. Neurosurgery 31:717–724.

    Article  PubMed  CAS  Google Scholar 

  • Cross, D.A., Alessi, D.R., Cohen, P., Andjelkovich, M., Hemmings, B.A. 1995. Inhibition of glycogen synthase kinase-3 by insul mediated by protein kinase B. Nature 378:785–789.

    Article  PubMed  CAS  Google Scholar 

  • Dai, C., Celestino, J.C., Okada, Y., Louis, D.N., Fuller, G.N., Holland, E.C. 2001. PDGF autocrine stimulation dedifferentiates cultured astrocytes and induces oligodendrogliomas and oligoastrocytomas from neural progenitors and astrocytes in vivo. Genes Dev 15:1913–1925.

    Article  PubMed  CAS  Google Scholar 

  • Dasgupta, B., Yi, Y., Chen, D.Y., Weber, J.D., Gutmann, D.H. 2005. Proteomic analysis reveals hyperactivation of the mammalian target of rapamycin pathway in neurofibromatosis 1-associated human and mouse brain tumors. Cancer Res 65:2755–2760.

    Article  PubMed  CAS  Google Scholar 

  • D’Atri, S., Tentori, L., Lacal, P.M., et al. 1998. Involvement of the mismatch repair system in temozolomide-induced apoptosis. Mol Pharmacol 54:334–341.

    PubMed  Google Scholar 

  • Debinski, W., Gibo, D.M., Hulet, S.W., et al. 1999. Receptor for interleukin 13 is a marker and therapeutic target for human high grade gliomas. Clin Cancer Res 5:985–990.

    PubMed  CAS  Google Scholar 

  • Debinski, W., Obiri, N.I., Pastan, I., et al. 1995. A novel chimeric protein composed of interleukin 13 and Pseudomonas exotoxin is highly cytotoxic to human carcinoma cells expressing receptors for interleukin 13 and interleukin 4. J Biol Chem 270:16775–16780.

    Article  PubMed  CAS  Google Scholar 

  • Dolan, M., Mitchell, R., Mummert, C., et al. 1991. Effect of O6-Benzylguanine analogs on sensitivity of tumor cells to the cytotoxic effects of alkylating agents. Cancer Res 51:3367–3372.

    PubMed  CAS  Google Scholar 

  • Dolan, M., Pegg, A., Moschel, R., et al. 1993. Effect ot O6-benzylguanine on the sensitivity of human colon tumor xenografts to 1,3-bis(2-chloroethyl)-1-nitrosourea. Biochem Pharmacol 46:285–290.

    Article  PubMed  CAS  Google Scholar 

  • Dresemann, G. 2005. Imatinib and hydroxyurea in pretreated progressive glioblastoma multiforme: a patient series. Ann Oncol 16:1702–1708.

    Article  PubMed  CAS  Google Scholar 

  • Druker, B.J., Talpaz, M., Resta, D.J., et al. 2001. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 344:1031–1037.

    Article  PubMed  CAS  Google Scholar 

  • End, D.W., Smets, G., Todd, A.V., et al. 2001. Characterization of the antitumor effects of the selective farnesyl protein transferase inhibitor R115777 in vivo and in vitro. Cancer Res 61:131–137.

    PubMed  CAS  Google Scholar 

  • Esteller M., Garcia-Foncillas, J., Andion, E., et al. 2000. Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. N Engl J Med 343:1350–1354.

    Article  PubMed  CAS  Google Scholar 

  • Fairbairn, L., Watson, A., Rafferty, J., et al. 1995. O6-Benzylguanine increases sensitivity of human primary bone marrow cells to the cytotoxici effects of temozolomide. Exp Hematol 23:112–116.

    PubMed  CAS  Google Scholar 

  • Feldkamp, M.M., Lau, N., Guha, A. 1999. Growth inhibition of astrocytoma cells by farnesyl transferase inhibitors is mediated by a combination of anti-proliferative, pro- apoptotic and anti-angiogenic effects. Oncogene 18:7514–7526.

    Article  PubMed  CAS  Google Scholar 

  • Ferrera, N., Hillan, K.J., Novotny, W. 2005. Bevacizumab (Avastin), a humanized anti-VEGF monoclonal antibody for cancer therapy. Biochem Biophys Res Commun 333:328–335.

    Article  CAS  Google Scholar 

  • Fields, A.P., Tyler, G., Kraft, A.S., May, W.S. 1990. Role of nuclear protein kinase C in the mitogenic response to platelet-derived growth factor. J Cell Sci 96:107–114.

    PubMed  CAS  Google Scholar 

  • Fine, H.A., Figg, W.D., Jaeckle, K., et al. 2000. Phase II trial of the antiangiogenic agent thalidomide in patients with recurrent high-grade gliomas. J Clin Oncol 18:708–715.

    PubMed  CAS  Google Scholar 

  • Fine, H.A., Kim, L., Royce, C., et al. 2005. Results from phase II trial of enzastaurin (LY317615) in patients with recurrent high grade gliomas. J Clin Oncol 23:1504a.

    Google Scholar 

  • Fine, H.A., Wen, P.Y., Maher, E.A., et al. 2003. Phase II trial of thalidomide and carmustine for patients with recurrent high-grade gliomas. J Clin Oncol 21:2299–2304.

    Article  PubMed  CAS  Google Scholar 

  • Finlay, J.L., Boyett, J.M., Yates, A.J., et al. 1995. Randomized phase III trial in childhood high-grade astrocytoma comparing vincristine, lomustine, and prednisone with the eight-drugs-in-1-day regimen. J Clin Oncol 13:112–123.

    PubMed  CAS  Google Scholar 

  • Freed, E., Symons, M., MacDonald, S.G., McCormick, F., Ruggieri, R. 1994. Binding of 14-3-3 proteins to the protein kinase Raf and effects on its activation. Science 265:1713–1716.

    Article  PubMed  CAS  Google Scholar 

  • Friedman, H.S., Johnson, S.P., Dong, Q., et al. 1997. Methylator resistance mediated by mismatch repair deficiency in a glioblastoma multiforme xenograft. Cancer Res 57:2933–2936.

    PubMed  CAS  Google Scholar 

  • Friedman, H., Kokkinakis, D., Pluda, J., et al. 1998a. Phase I Trial of O6-Benzylguanine for patients undergoing surgery for malignant glioma. J Clin Oncol 16:3570–3575.

    PubMed  CAS  Google Scholar 

  • Friedman, H.S., McLendon, R.E., Kerby, T., et al. 1998b. DNA mismatch repair and O6-alkylguanine-DNA alkyltransferase analysis and response to temodal in newly diagnosed malignant glioma. J Clin Oncol 16:3851–3857.

    PubMed  CAS  Google Scholar 

  • Fukuoka, M., Yano, S., Giaccone, G., et al. 2003. Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer. J Clin Oncol 21:2237–2246.

    Article  PubMed  CAS  Google Scholar 

  • Galanis, E., Buckner, J.C., Maurer, M.J., et al. 2005. Phase II trial of temsirolimus (CCI-779) in recurrent glioblastoma multiforme: a North Central Cancer Treatment Group study. J Clin Oncol 23:5294–5304.

    Article  PubMed  CAS  Google Scholar 

  • Gerson, S., Zborowska, E., Norton, K., et al. 1993. Synergistic efficacy of O6-benzylguanine and 1,3-bis(2-chloroethyl)-1-nitrosourea in a human colon cancer xenograft completely resistant to BCNU alone. Biochem Pharmacol 45:483–491.

    Article  PubMed  CAS  Google Scholar 

  • Gilbert, J., Baker, S.D., et al. 2001. A phase I dose escalation and bioavailability study of oral sodium phenylbutyrte in patients with refractory solid tumor malignancies. Clin Cancer Res 7:2292–2300.

    PubMed  CAS  Google Scholar 

  • Glick, R.P., Gettleman, R., Patel, K., et al. 1989. Insulin and insulin-like growth factor I in brain tumors: binding and in vitro effects. Neurosurgery 24:791–797.

    Article  PubMed  CAS  Google Scholar 

  • Goldbrunner, R.H., Bendszus, M., Wood, J., et al. 2004. PTK787/ZK222584, an inhibitor of vascular endothelial growth factor receptor tyrosine kinases, decreases glioma growth and vascularization. Neurosurgery 55:426–432.

    Article  PubMed  Google Scholar 

  • Graff, J.R., McNulty, A.M., Hanna, K.R., et al. 2005. The protein kinase Cβ-selective inhibitor, enzastaurin (LY317615.HCL), suppresses signaling through the AKT pathway, induces apoptosis, and suppresses growth of human colon cancer and glioblastoma xenografts. Cancer Res 65:7462–7469.

    Article  PubMed  CAS  Google Scholar 

  • Graner, M.W. and Bigner, D.D. 2005. Chaperone proteins and brain tumors: potential targets and possible therapeutics. Neurooncology 7:260–277.

    CAS  Google Scholar 

  • Gray, S.G., Ekstrom, T.J. 2001. The human histone deacetylase family. Exp Cell Res 262:75–83.

    Article  PubMed  CAS  Google Scholar 

  • Greenfield, L., Johnson, V.G., Youle, R.J. 1987. Mutations in diphtheria toxin separate binding from entry and amplify immunotoxin selectivity. Science 238:536–539.

    Article  PubMed  CAS  Google Scholar 

  • Griffin, C.A., Hawkins, A.L., Packer, R.J., et al. 1988. Chromosome abnormalities in pediatric brain tumors. Cancer Res 48:175–180.

    PubMed  CAS  Google Scholar 

  • Gross, J.L., Morrison, R.S., Eidsvoog, K., et al. 1990. Basic fibroblast growth factor: a potential autocrine regulator of human glioma growth. J Neurosci Res 27:689–696.

    Article  PubMed  CAS  Google Scholar 

  • Guha, A., Feldkamp, M.M., Lau, N., Boss, G., Pawson, A. 1997. Proliferation of human malignant astrocytomas is dependent on Ras activation. Oncogene 15:2755–2765.

    Article  PubMed  CAS  Google Scholar 

  • Guttmann, D. H., Donahoe, J., Brown, T., James, C.D., Perry, A. 2000. Loss of neurofibromatosis 1(NF1) gene expression in NF1-associated pilocytic astrocytomas. Neuropathol Appl Neurobiol 26:361–367.

    Article  Google Scholar 

  • Hartmann, C., Meyer, J., Balss, J., et al. 2009. Type and frequency of IDH1 and IDH2 mutations are related to astrocytic and oligodendroglial differentiation and age: a study of 1,010 diffuse gliomas. Acta Neuropathol 118:469–474.

    Article  PubMed  Google Scholar 

  • Hegi, M.E., Diserens, A.C., Gorlia, T., et al. 2005. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352:997–1003.

    Article  PubMed  CAS  Google Scholar 

  • Herbst, R.S., Giaccone, G., Schiller, J.H., et al. 2004. Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial – Intact 2. J Clin Oncol 22:785–794.

    Article  PubMed  CAS  Google Scholar 

  • Hermanson, M., Funa, K., Koopman, J., et al. 1996. Association of loss of heterozygosity on chromosome 17p with high platelet-derived growth factor α receptor expression in human malignant gliomas. Cancer Res 56:164–171.

    PubMed  CAS  Google Scholar 

  • Hidalgo, M., Siu, L.L., Nemunaitis, J., et al. 2001. Phase I and pharmacologic study of OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies. J Clin Oncol 19:3267–3279.

    PubMed  CAS  Google Scholar 

  • Hirose, Y., Berger, M.S., Pieper, R.O. 2001. Abrogation of the Chk1-mediated G(2) checkpoint pathway potentiates temozolomide-induced toxicity in a p53-independent manner in human glioblastoma cells. Cancer Res 61:5843–5849.

    PubMed  Google Scholar 

  • Hotta, T., Saito, Y., Fujita, H., et al. 1995. 06 alkylguanine-DNA Alkyltransferase activity in human malignant glioma and its clinical implications. J Neurooncol 21:135–140.

    Article  Google Scholar 

  • Howe, L.R., Leevers, S.J., Gomez, N., et al. 1992. Activation of the MAP kinase pathway by the protein kinase raf. Cell 71:335–342.

    Article  PubMed  CAS  Google Scholar 

  • Huang, S.M., Bock, J.M., Harari, P.M. 1999. Epidermal growth factor receptor blockade with C225 modulates proliferation, apoptosis, and radiosensitivity in squamous cell carcinomas of the head and neck. Cancer Res 59:1935–1940.

    PubMed  CAS  Google Scholar 

  • Huang, S-M., Li, E., Armstrong, E.A., Harari, P.M. 2002. Modulation of radiation response and tumor-induced angiogenesis after epidermal growth factor receptor inhibition by ZD1839 (Iressa). Cancer Res 62:4300–4306.

    PubMed  CAS  Google Scholar 

  • Hurwitz, H., Fehrenbache, L., Novotny, W., et al. 2004. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335–2342.

    Article  PubMed  CAS  Google Scholar 

  • Husain, S.R., Puri, R.K. 2003. Interleukin-13 receptor-directed cytotoxin for malignant glioma therapy: from bench to bedside. J Neurooncol 65:37–48.

    Article  PubMed  Google Scholar 

  • Ichimura, K., Bolin, M.B., Goike, H.M., et al. 2000. Deregulation of the p14ARF/MDM2/p53 pathway is a prerequisite for human astrocytic gliomas with G1-S transition control gene abnormalities. Cancer Res 60:417–424.

    PubMed  CAS  Google Scholar 

  • Ignoffo, R.J. 2004. Overview of bevacizumab: a new cancer therapeutic strategy targeting vascular endothelial growth factor. Am J Health Syst Pharm 61:S21–S26.

    PubMed  CAS  Google Scholar 

  • Ino, Y., Zlatescu, M.C., Sasaki, H., et al. 2000. Long survival and therapeutic responses in patients with histologically disparate high-grade gliomas demonstrating chromosome 1p loss. J Neurosurg 92:983–990.

    Article  PubMed  CAS  Google Scholar 

  • Jaeckle, K.A., Eyre, H.J., Townsend, J.J., et al: 1998. Correlation of tumor O6 methylguanine-DNA methyltransferase levels with survival of malignant astrocytoma patients treated with bis- chloroethylnitrosourea: a Southwest Oncology Group study. J Clin Oncol 16:3310–3315.

    PubMed  CAS  Google Scholar 

  • James, C.D., Carlbom, E., Nordenskjoldk M., et al. 1989. Mitotic recombination of chromosome 17 in astrocytomas. Proc Natl Acad Sci U S A 86:2858–2862.

    Article  PubMed  CAS  Google Scholar 

  • Jane, E.P., Premkumar, D.R., Pollack, I.F. 2006. Coadministration of sorafenib with rottlerin potently inhibits cell proliferation and migration in human malignant glioma cells. J Pharmacol Exp Ther 319:1070–1080.

    Article  PubMed  CAS  Google Scholar 

  • Jiang, K., Coppola, D., Crespo, N.C., et al. 2000. The phosphoinositide 3-OH kinase/AKT2 pathway as a critical target for farnesyltransferase inhibitor-induced apoptosis. Mol Cell Biol 20:139–148.

    Article  PubMed  Google Scholar 

  • Joensuu, H., Roberts, P.J., Sarlomo-Rikala, M., et al. 2001. Effect of the tyrosine kinase inhibitor STTI571 in a patient with a metastatic gastrointestinal stromal tumor. N Engl J Med 344:1052–1056.

    Article  PubMed  CAS  Google Scholar 

  • Jones, D. T., Kocialkowski, S., Liu, L., Pearson, D.M., Backlund, L. M., Ichimura K., Collins, V. P. 2008. Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. Cancer Res. 68: 8673–8677.

    Google Scholar 

  • Joshi, B.H., Plautz, G.E., Puri, R.K. 2000. Interleukin-13 Receptor a chain: a novel tumor-associated transmembrane protein in primary explants of human malignant gliomas. Cancer Res 60:1168–1172.

    PubMed  CAS  Google Scholar 

  • Katz, A., Barrios, C. H., Abramoff, R., et al. 2004. Imatinib (STI 571) is active in patients with high-grade gliomas progressing on standard therapy. Proceedings ASCO Annual Meeting 2004. J Clin Oncol 23:117 (abstract)

    Google Scholar 

  • Keyes, K.A., Mann, L., Sherman, M., et al. 2004. LY317615 decreases plasma VEGF levels in human tumor xenograft-bearing mice. Cancer Chemother Pharmacol 53:133–140.

    Article  PubMed  CAS  Google Scholar 

  • Kieran, M.W., Packer, R., Onar, A., et al. 2007. Phase I and pharmacokinetic study of the oral farnesyl-transferase inhibitor Sarasar™ (Lonafarnib–SCH66336) given twice daily to pediatric patients with advanced central nervous system tumors: A Pediatric Brain Tumor Consortium (PBTC) study. J Clin Oncol 25(21) 3137–3143.

    Article  PubMed  CAS  Google Scholar 

  • Kilic, T., Alberta, J.A., Zdunek, P.R., et al. 2000. Intracranial inhibition of platelet-derived growth factor-mediated glioblastoma cell growth by an orally active kinase inhibitor of the 2-phenylaminopyrimidine class. Cancer Res 60:143–150.

    Google Scholar 

  • Kim, E.S., Kies, M.S., Fossella, F.V., et al. 2005. Phase II study of the farnesyltransferase inhibitor lonafarnib with paclitaxel in patients with taxane-refractory/resistant nonsmall cell lung carcinoma. Cancer 104:561–569.

    Article  PubMed  CAS  Google Scholar 

  • Kleihues, P., Burger, P.C., Scheithauer, B.W. 1993. Histological typing of tumours of the central nervous system. In: Sobin, L.H. (ed.) International histological classification of tumours, Vol. 21. Geneva: Springer, pp. 11–16.

    Google Scholar 

  • Kolch, W., Heldecker, G., Kochs, G., et al. 1993. Protein kinase Cα activates Raf-1 by direct phosphorylation. Nature 364:249–252.

    Article  PubMed  CAS  Google Scholar 

  • Krishnan, S., Brown, P., Ballman, K., et al. 2005. Phase I trial of erlotinib with radiation therapy (RT) in patients with glioblastoma multiforme (GBM). J Clin Oncol 23:1513a.

    Google Scholar 

  • Kunwar, S., Prados, M.D., Chang, S.M., et al. 2007. Cintredekin Besudotox Intraparenchymal Study Group. Direct intracerebral delivery of cintredekin besudotox (IL13-PE38QQR) in recurrent malignant glioma: a report by the Cintredekin Besudotox Intraparenchymal Study Group. J Clin Oncol 25:837–844.

    Article  PubMed  CAS  Google Scholar 

  • Lang, F.F., Miller, D.C., Pisharody, S., et al. 1994. High frequency of p53 protein accumulation without p53 gene mutation in human juvenile pilocytic, low grade and anaplastic astrocytomas. Oncogene 9:949–954.

    PubMed  CAS  Google Scholar 

  • Laske, D.W., Ilercil, O., Akbasak, A., Youle, R.J., Oldfield, E.H. 1994. Efficacy of direct intratumoral therapy with targeted protein toxins for solid human gliomas in nude mice. J Neurosurg 80:520–526.

    Article  PubMed  CAS  Google Scholar 

  • Laske, D.W., Morrison, P.F., Lieberman, D.M., et al.1997a. Chronic interstitial infusion of protein to primate brain: determination of drug distribution and clearance with single-photon emission computerized tomography imaging. J Neurosurg 87:586–594.

    Article  PubMed  CAS  Google Scholar 

  • Laske, D.W., Youle, R.J., Oldfield, E.H. 1997b. Tumor regression with regional distribution of targetted toxin TF-CRM107 in patients with malignant brain tumors. Nat Med 3:1362–1368.

    Article  PubMed  CAS  Google Scholar 

  • Lassman, A.B., Rossi, M.R., Razier, J.R., et al. 2005. Molecular study of malignant gliomas treated with epidermal growth factor receptor inhibitors: tissue analysis from North American Brain Tumor Consortium Trial 01-03 and 00-01. Clin Cancer Res 11:7841–7850.

    Article  PubMed  CAS  Google Scholar 

  • Lebowitz, P.F., Prendergast, G.C. 1998. Non-Ras targets of farnesyltransferase inhibitors: focus on Rho. Oncogene 17:1439–1445.

    Article  PubMed  CAS  Google Scholar 

  • Li, D.M., Sun, H. 1998. PTEN/MMAC1/TEP1 suppressed the tumorigenicity and induces G1 cell cycle arrest in human glioblastoma cells. Proc Natl Acad Sci U S A 95:15406–15411.

    Article  PubMed  CAS  Google Scholar 

  • Libermann, T.A., Nusbaum, H.R., Razon, N., et al. 1985. Amplification, enhanced expression and possible rearrangement of EGF receptor gene in primary human brain tumors of glial origin. Nature 313:44–147.

    Article  Google Scholar 

  • Lieberman, F.S., Cloughesy, T., Fine, H., et al. 2004. NABTC phase I/II trial of ZD-1839 for recurrent malignant gliomas and unresectable meningiomas. J Clin Oncol 22:1510.

    Article  CAS  Google Scholar 

  • Liu, L., Markowitz, S., Gerson, S.L. 1996. Mismatch repair mutations override alkyltransferase in conferring resistance to temozolomide but not to 1,3-bis(2-chloroethyl)nitrosourea. Cancer Res 56:5375–5379.

    PubMed  CAS  Google Scholar 

  • Liu, L., Taverna, P., Whitacre, C.M., et al. 1999. Pharmacologic disruption of base excision repair sensitizes mismatch repair-deficient and -proficient colon cancer cells to methylating agents. Clin Cancer Res 5:2908–2917.

    PubMed  CAS  Google Scholar 

  • Lokker, N.A., Sullivan, C.M., Hollenbach, S.J.,et al. 2002. Platelet-derived growth factor (PDGF) autocrine signaling regulates survival and mitogenic pathways in glioblastoma cells: evidence that the novel PDGF-C and PDGF-D ligands may play a role in the development of brain tumors. Cancer Res 62:3729–3735.

    PubMed  CAS  Google Scholar 

  • Lorimer, I.A., Keppler-Hafkemeyer, A., Beers, R.A., et al. 1996. Recombinant immunotoxins specific for a mutant epidermal growth factor receptor: targeting with a single chain antibody variable domain isolated by phage display. Proc Natl Acad Sci U S A 93:14815–14820.

    Article  PubMed  CAS  Google Scholar 

  • Louis, D.N. 1997. A molecular genetic model of astrocytoma histopathology. Brain Pathol 7:755–764.

    Article  PubMed  CAS  Google Scholar 

  • Lynch, T.J., Bell, D.W., Sordella, R., et al. 2004. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350:2129–2139.

    Article  PubMed  CAS  Google Scholar 

  • Maity, A., Pore, N., Lee, J., Solomon, D., O’Rourke, D.M. 2000. Epidermal growth factor transcriptionally up-regulates vascular endothelial growth factor expression in human glioblastoma cells via a pathway involving phosphatidylinositol 3’-kinase and distinct from that induced by hypoxia. Cancer Res 60:5879–5886.

    PubMed  CAS  Google Scholar 

  • Marais, R., Light, Y., Mason, C., Paterson, H., Olson, M.F., Marshall, C.J. 1998. Requirement of Ras-GTP-Raf complexes for activation of Raf-1 by protein kinase C. Science 280:109–112.

    Article  PubMed  CAS  Google Scholar 

  • Marks, P.A., Richon, V.M., Rifkind, R.A. 2000. Histone deacetylase inhibitors: inducers of differentiation or apoptosis of transformed cells. J Natl Cancer Inst 92:1210–1216.

    Article  PubMed  CAS  Google Scholar 

  • Marks, P., Rifkind, R.A., Richon, V.M., et al. 2001. Histone deacetylases and cancer: causes and therapies. Nat Rev Cancer 1:194–202.

    Article  PubMed  CAS  Google Scholar 

  • McCormick, F. 1993. How receptors turn Ras on. Nature 363:15–16.

    Article  PubMed  CAS  Google Scholar 

  • Mellinghoff, I.K., Wang, M.Y., Vivanco, I., Haas-Kogan, D.A., Zhu, S., Dia, E.Q., et al. 2005. Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. N Engl J Med 353:2012–2024.

    Article  PubMed  CAS  Google Scholar 

  • Milas, L., Mason, K., Hunter, N., et al. 2000. In vivo enhancement of tumor radioresponse by C225 antiepidermal growth factor receptor antibody. Clin Cancer Res 6:323–325.

    Google Scholar 

  • Mishima, K., Johns, T.G., Luwor, R.B., et al. 2001. Growth suppression of intracranial xenografted glioblastomas overexpressing mutant epidermal growth factor receptors by systemic administration of monoclonal antibody (mAb) 806, a novel monoclonal antibody directed to the receptor. Cancer Res 61:5349–5354.

    PubMed  CAS  Google Scholar 

  • Nakamura, J.L., Karlsson, A., Arvold, N.D., et al. 2005. PKB/Akt mediates radiosensitization by the signaling inhibitor LY294002 in human malignant gliomas. J Neurooncol 71:215–222.

    Article  PubMed  CAS  Google Scholar 

  • Nishizuka, Y. 1992. Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C. Science 258:607–613.

    Article  PubMed  CAS  Google Scholar 

  • Nistér, M., Claesson-Welch, L., Eriksson, A., Heldin, C.-H., Westermark, B. 1991. Differential expression of platelet-derived growth factor receptors in human malignant glioma cell lines. J Biol Chem 266:16755–16763.

    PubMed  Google Scholar 

  • Nitta, T. and Sato, K. 1994. Specific inhibition of c-sis protein synthesis and cell proliferation with antisense oligodeoxynucleotides in human glioma cells. Neurosurgery 34:309–314.

    Article  PubMed  CAS  Google Scholar 

  • O’Brien, S.G., Guilhot, F., Larson, R.A., et al. 2003. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 348:994–1004.

    Article  PubMed  Google Scholar 

  • O’Rourke, D.M., Kao, G.D., Singh, N., Park, B.W., et al. 1998. Conversion of a radioresistant phenotype to a more sensitive one by disabling erbB receptor signaling in human cancer cells. Proc Natl Acad Sci U S A 95:10842–10847.

    Article  PubMed  Google Scholar 

  • O’Rourke, D.M., Qian, X., Zhang, H.T., et al. 1997. Trans receptor inhibition of human glioblastoma cells by erbB family ectodomains. Proc Natl Acad Sci U S A 94:3250–3255.

    Article  PubMed  Google Scholar 

  • Parsons, D.W., Jones, S., Zhang, X., et al. 2008. An integrated genomic analysis of human glioblastoma multiforme. Science 321:1807–1812.

    Article  PubMed  CAS  Google Scholar 

  • Pastan, I., FitzGerald, D. 1991. Recombinant toxins for cancer treatment. Science 254:1173.

    Article  PubMed  CAS  Google Scholar 

  • Pawson, T. 1995. Protein modules and signalling networks. Nature 373:573–580.

    Article  PubMed  CAS  Google Scholar 

  • Peddanna, N., Mendis, R., Holt, S., Verma, R.S. 1996. Genetics of colorectal cancer. Int J Oncol 9:327–335.

    PubMed  CAS  Google Scholar 

  • Peereboom, D.M., Brewer, C.J., Suh, J.H., et al. 2006. Phase II trial of erlotinib with temozolomide and concurrent radiation therapy in patients with newly diagnosed glioblastoma multiforme: final results. Neurooncology 8:448.

    Google Scholar 

  • Perez-Soler, R. 2004. The role of erlotinib (Tarceva, OSI 774) in the treatment of non-small cell lung cancer. Clin Cancer Res 10:4238s–4240s.

    Article  PubMed  CAS  Google Scholar 

  • Phuphanich S, Carson K, Grossman S et al. 2005. A phase I evaluation of the safety of escalating doses of atrasentan in adults with recurrent malignant glioma (MG). J Clin Oncol 23:1526a.

    Google Scholar 

  • Pietras, K., Ostman, A., Sjoquist, M., et al. 2001. Inhibition of platelet-derived growth factor receptors reduces interstitial hypertension and increases transcapillary transport in tumors. Cancer Res 61:2929–2934.

    PubMed  CAS  Google Scholar 

  • Pietras, K., Rubin, K, Sjoblom, T., et al. 2002. Inhibition of PDGF receptor signaling in tumor stroma enhances antitumor effect of chemotherapy. Cancer Res 62:5476–5484.

    PubMed  CAS  Google Scholar 

  • Plate, K.H., Breier, G., Weich, H.A., et al. 1992. Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo. Nature 359:845–848.

    Article  PubMed  CAS  Google Scholar 

  • Plumb, J.A., Finn, P.W., Williams, R.J., et al. 2003. Pharmacodynamic response and inhibition of growth of human tumor xenografts by the novel histone deacetylase inhibitor PXD 101. Mol Cancer Ther 2:721–728.

    PubMed  CAS  Google Scholar 

  • Pollack, I.F. 1994. Current concepts: brain tumors in children. N Engl J Med 331:1500–1507.

    Article  PubMed  CAS  Google Scholar 

  • Pollack, I.F., Bredel, M., Erff, M. 1998. The application of signal transduction inhibition as a therapeutic strategy for central nervous system tumors. Pediatr Neurosurg 29:228–244.

    Article  PubMed  CAS  Google Scholar 

  • Pollack, I.F., Erff, M., Ashkenazi, A. 2001a. Direct stimulation of apoptotic signaling by Apo2L/tumor necrosis factor-related apoptosis-inducing ligand leads to selective killing of glioma cells. Clin Cancer Res 7:1362–1369

    PubMed  CAS  Google Scholar 

  • Pollack, I.F., Finkelstein, S.D., Burnham, J., et al. 2003. The association between chromosome 1p loss and outcome in pediatric malignant gliomas: results from the CCG-945 cohort. Pediatr Neurosurg 39:114–121.

    Article  PubMed  Google Scholar 

  • Pollack, I.F., Finkelstein, S.D., Burnham, J., et al. 2001b. Age and TP53 mutation frequency in childhood gliomas. Results in a multi-institutional cohort. Cancer Res 61:7404–7407.

    PubMed  CAS  Google Scholar 

  • Pollack, I.F., Finkelstein, S.D., Woods, J., et al. 2002. Expression of p53 and prognosis in malignant gliomas in children. N Engl J Med 346:420–427.

    Article  PubMed  CAS  Google Scholar 

  • Pollack, I.F., Hamilton, R.L., James, C.D., et al. 2006a. Rarity of PTEN deletions and EGFR amplification in malignant gliomas of childhood: results from the CCG-945 cohort. J Neurosurg 105:418–424.

    Article  PubMed  Google Scholar 

  • Pollack, I.F., Hamilton, R.L., Finkelstein, S.D., et al. 1997. The relationship between TP53 mutations and overexpression of p53 and prognosis in malignant gliomas of childhood. Cancer Res 57:304–309.

    PubMed  CAS  Google Scholar 

  • Pollack, I.F., Hamilton, R.L., Sobol, R.W., et al. 2006b. O6-methylguanine-DNA methyltransferase expression strongly correlates with outcome in childhood malignant gliomas: results from the CCG-945 cohort. J Clin Oncol 24:3431–3437.

    Google Scholar 

  • Pollack, I.F., Jakacki, R.I., Blaney, S.M., et al. 2007. Phase I trial of imatinib in children with newly diagnosed brainstem and recurrent malignant gliomas: a PBTC report. Neurooncology 9:145–160.

    CAS  Google Scholar 

  • Pollack, I.F., Kawecki, S., Lazo, J.S. 1996. 7-hydroxystaurosporine (UCN-01), a selective protein kinase C inhibitor, exhibits cytotoxicity against cultured glioma cells and potentiates the antiproliferative effects of BCNU and cisplatin. J Neurosurg 84:1024–1032.

    Article  PubMed  CAS  Google Scholar 

  • Pollack, I.F., Randall, M.S., Kristofik, M.P., et al. 1991. Response of low-passage human malignant gliomas in vitro to stimulation and selective inhibition of growth factor-mediated pathways. J Neurosurg 75:284–293.

    Article  PubMed  CAS  Google Scholar 

  • Pollack, V.A., Savage, D., Baker, D., et al. 1999. Inhibition of epidermal growth factor receptor-associated tyrosine phosphorylation in human carcinomas with CP-358,774. Dynamics of receptor inhibition in situ and antitumor effects in athymic mice. J Pharmacol Exp Ther 291:739–748.

    PubMed  CAS  Google Scholar 

  • Prados, M., Lamborn, K.R., Chang, S., et al. 2006. Phase I study of erlotinib HCl alone and combined with temozolomide in patients with recurrent malignant glioma. Neurooncology 8:67–78.

    CAS  Google Scholar 

  • Prados, M.D., Lang, F.F., Sherman, J.W., et al. 2002. Convection-enhanced delivery (CED) by positive pressure infusion for intra-tumoral and peri-tumoral administration of IL13-PEQQR, a recombinant tumor-targeted cytotoxin in recurrent malignant glioma. Neurooncology 4:S78.

    Google Scholar 

  • Premkumar, D.R., Arnold, B., Pollack, I.F. 2006. Cooperative inhibitory effect of ZD1839 (Iressa) in combination with 17-AAG on glioma cell growth. Mol Carcinog 45:288–301.

    Article  PubMed  CAS  Google Scholar 

  • Prigent, S.A., Nagane, M., Lin, H., et al. 1996. Enhanced tumorigenic behavior of glioblastoma cells expressing a truncated epidermal growth factor receptor is mediated through the Ras-SHC-GRB2 pathway. J Biol Chem 271:25639–25645.

    Article  PubMed  CAS  Google Scholar 

  • Puri, R.K., Hoon, D.S., Leland, P., et al. 1996. Preclinical development of a recombinant toxin containing circularly permuted interleukin-4 and truncated Pseudomonas exotoxin for therapy of malignant astrocytoma. Cancer Res 56:5631–5637.

    PubMed  CAS  Google Scholar 

  • Quang, T.S. and Brady, L.W. 2004. Radioimmunotherapy as a novel treatment regimen: 125I-labeled monoclonal antibody 425 in the treatment of high-grade brain gliomas. Int J Radiat Oncol Biol Phys 58:972–975.

    Article  PubMed  CAS  Google Scholar 

  • Raffel, C., Frederick, L., O’Fallon, J.R., et al. 1999. Analysis of oncogene and tumor suppressor gene alterations in pediatric malignant astrocytomas reveals reduced survival for patients with PTEN mutations. Clin Cancer Res 5:4085–4090.

    PubMed  CAS  Google Scholar 

  • Rao, S., Cunningham, D., de Gramont. A., et al. 2004. Phase III double-blind placebo-controlled study of farnesyl transferase inhibitor R115777 in patients with refractory advanced colorectal cancer. J Clin Oncol 22:3950–3957.

    Article  PubMed  CAS  Google Scholar 

  • Raymond, E., Brandes, A., Van Oosterom, A., et al. 2004. Multicentre phase II study of imatinib mesylate in patients with recurrent glioblastoma: an EORTC:NDDG/BTG intergroup study. Proceedings ASCO Annual Meeting 23:107 (abstract).

    Google Scholar 

  • Reardon, D.A., Akabani, G., Coleman, R.E., et al. 2006a. Salvage radioimmunotherapy with murine iodine-131-labeled antitenascin monoclonal antibody 81C6 for patients with recurrent primary and metastatic malignant brain tumors: phase II study results. J Clin Oncol 24:115–122.

    Article  PubMed  CAS  Google Scholar 

  • Reardon, D.A., Egorin, M.J., Quinn, J.A., et al. 2005a. Phase II study of imatinib mesylate plus hydroxyurea in adults with recurrent glioblastoma multiforme. J Clin Oncol 23:9359–9368.

    Article  PubMed  CAS  Google Scholar 

  • Reardon, D.A., Quinn, J.A., Vredenburgh, J., et al. 2005b. Phase II trial of irinotecan plus celecoxib in adults with recurrent malignant glioma. Cancer 103:329–338.

    Article  PubMed  CAS  Google Scholar 

  • Reardon, D. A., Quinn, J. A., Vredenburgh, J.J., et al. 2006b. Phase 1 trial of gefitinib plus sirolimus in adults with recurrent malignant glioma. Clin Cancer Res 12:860–868.

    Article  PubMed  CAS  Google Scholar 

  • Reardon, D. and Wen, P.Y. 2006. Therapeutic advances in the treatment of glioblastoma: rationale and potential role of targeted agents. Oncologist 11:152–164.

    Article  PubMed  CAS  Google Scholar 

  • Recht, L., Torres, C.O., Smith, T.W., Raso, V., Griffin, T.W. 1990. Transferrin receptor in normal and neoplastic brain tissue. Implications for brain tumor immunotherapy. J Neurosurg 72:941–945.

    Article  PubMed  CAS  Google Scholar 

  • Rowinsky, E K., Windle, J. J., Von Hoff, D.D. 1999. Ras protein farnesyltransferase: a strategic target for anticancer therapeutic development. J Clin Oncol 17:3631–3652.

    PubMed  CAS  Google Scholar 

  • Rusnak, D.W., Affleck, K., Cockerill, S.G., et al. 2001. The characterization of novel, dual ErbB-2/EGFR, tyrosine kinase inhibitors: potential therapy for cancer. Cancer Res 61:7196–7203.

    PubMed  CAS  Google Scholar 

  • Sampson, J.H., Akabani, G., Archer, G.E., et al. 2003. Progress report of a phase I study of the intracerebral microinfusion of a recombinant chimeric protein composed of transforming growth factor (TGF)-a and a mutated form of the Pseudomonas exotoxin termed PE-38 (TP-38) for the treatment of malignant brain tumors. J Neurooncol 65:27–35.

    Article  PubMed  Google Scholar 

  • Sawa, H., Murakami, H., et al. 2004. Histone deacetylase inhibitor, FK228, induces apoptosis and suppresses cell proliferation of human glioblastoma cells in vitro and in vivo. Acta Neuropathol 107:523–531.

    Article  PubMed  CAS  Google Scholar 

  • Schlessinger, J. 2000. Cell signaling by receptor tyrosine kinases. Cell 103:211–225.

    Article  PubMed  CAS  Google Scholar 

  • Schold, S.C., Brent, T.P., Von Hofe, E., et al. 1989. 06 alkylguanine-DNA Alkyltransferase and sensitivity to procarbazine in human brain-tumor xenografts. J Neurosurg 70:573–577.

    Article  PubMed  Google Scholar 

  • Shamah, S.M., Stiles, C.D., Guha, A. 1993. Dominant-negative mutants of platelet-derived growth factor revert the transformed phenotype of human astrocytoma cells. Mol Cell Biol 13:7203–7212.

    PubMed  CAS  Google Scholar 

  • Sharma, S., Kemeny, N., Kelsen, D.P., et al. 2002. A phase II trial of farnesyl protein transferase inhibitor SCH 66336, given by twice-daily oral administration, in patients with metastatic colorectal cancer refractory to 5-fluorouracil and irinotecan. Ann Oncol 13:1067–1071.

    Article  PubMed  CAS  Google Scholar 

  • Silber, J.R., Mueller, B.A., Ewers, T.G., Berger, M.S. 1993. Comparison of O6-methylguanine-DNA methyltransferase activity in brain tumors and adjacent normal brain. Cancer Res 53:3416–3420.

    PubMed  CAS  Google Scholar 

  • Stark-Vance, V. 2005. Bevacizumab and CPT-11 in the treatment of relapsed malignant glioma. Neurooncology 7:369.

    Google Scholar 

  • Sung, T., Miller, D.C., Hayes, R.L., et al. 2000. Preferential inactivation of the p53 tumor suppressor pathway and lack of EGFR amplification distinguish de novo high grade pediatric astrocytomas from de novo adult astrocytomas. Brain Pathol 10:249–259.

    Article  PubMed  CAS  Google Scholar 

  • Taga, T., Suzuki, A., Gonzalez-Gomez, I., et al. 2002. Alpha v-Integrin antagonist EMD 121974 induces apoptosis in brain tumor cells growing on vitronectin and tenascin. Int J Cancer 98:690–697.

    Article  PubMed  CAS  Google Scholar 

  • Tentori, L., Leonetti, C., Scarsella, M., et al. 2003. Systemic administration of gpi 15427, a novel poly(adp-ribose) polymerase-1 inhibitor, increases the antitumor activity of temozolomide against intracranial melanoma, glioma, lymphoma. Clin Cancer Res 9:5370–5379.

    PubMed  CAS  Google Scholar 

  • Tentori, L., Portarena, I., Torino, F., et al. 2002. Poly(adp-ribose) polymerase inhibitor increases growth inhibition and reduces g(2)/m cell accumulation induced by temozolomide in malignant glioma cells. Glia 40:44–54.

    Article  PubMed  Google Scholar 

  • Topaly, J., Zeller, W.J., Fruehauf, S. 2001. Synergistic activity of the new ABL-specific tyrosine kinase inhibitor STI571 and chemotherapeutic drugs on the BCR-ABL-positive chronic myelogenous leukemia cells. Leukemia 15:342–347.

    Article  PubMed  CAS  Google Scholar 

  • Tuettenberg, J., Grobholz, R., Korn, T., et al. 2005. Continuous low-dose chemotherapy plus inhibition of cyclooxygenase-2 as an antiangiogenic therapy of glioblastoma multiforme. J Cancer Res Clin Oncol 131:31–40.

    Article  PubMed  CAS  Google Scholar 

  • Ullrich, A. and Schlessinger, J. 1990. Signal transduction by receptor with tyrosine kinase activity. Cell 61:203–212.

    Article  PubMed  CAS  Google Scholar 

  • Van Cutsem, E., van de, V., Karasek, P., Oettle, H., Vervenne, W.L., Szawlowski, A., et al. 2004. Phase III trial of gemcitabine plus tipifarnib compared with gemcitabine plus placebo in advanced pancreatic cancer. J Clin Oncol 22:1430–1438.

    Article  PubMed  CAS  Google Scholar 

  • von Deimling, A., Louis, D.N., Menon, A.G., et al. 1993a. Deletions on the long arm of chromosome 17 in pilocytic astrocytoma. Acta Neuropathol 86:81–85.

    Article  Google Scholar 

  • von Deimling, A., von Ammon, K., Schoenfeld, D., et al. 1993b. Subsets of glioblastoma multiforme defined by molecular genetic analysis. Brain Pathol 3:19–26.

    Article  Google Scholar 

  • Verhaak, R.G.W., Hoadley, K.A., Purdom, E., et al. 2010. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFR, IDH1, EGFR, and NF1. Cancer Cell 17:98–110.

    Article  PubMed  CAS  Google Scholar 

  • Vredenburgh, J., Desjardins, A., Herndon, J.E.II, et al. 2006. Bevacizumab and irinotecan is an effective treatment for malignant gliomas. Neurooncology 8:454.

    Google Scholar 

  • Wakeling, A.E., Guy, S.P., Woodburn, J.R., et al. 2002. ZD1839 (Iressa): An orally active inhibitor of epidermal growth factor signaling with potential for cancer therapy. Cancer Res 62:5749–5754.

    PubMed  CAS  Google Scholar 

  • Walczak, H., Miller, R.E., Ariail, K., et al. 1999. Tumoricidal activity of tumor necrosis factor-related apoptosis-inducing ligand in vivo. Nat Med 5:157–163.

    Article  PubMed  CAS  Google Scholar 

  • Wang, D., Huang, H.J., Kazlauskas, A., Cavenee, W.K. 1999. Induction of vascular endothelial growth factor expression in endothelial cells by platelet-derived growth factor through the activation of phosphatidylinositol 3-kinase. Cancer Res 59:1464–1472.

    PubMed  CAS  Google Scholar 

  • Weaver, M. and Laske, D.W. 2003. Transferrin ligand-targeted toxin conjugate (Tf-CRM107) for therapy of malignant gliomas. J Neurooncol 65:3–13.

    Article  PubMed  Google Scholar 

  • Weber, F.W., Floeth, F., Asher, A., et al. 2003. Local convection-enhanced delivery of IL4-Pseudomonas exotoxin (NBI-3001) for treatment of patients with recurrent malignant glioma. Acta Neurochir 88(Suppl):93–103.

    CAS  Google Scholar 

  • Wedge, S. and Newlands, E. 1996. O6-Benzylguanine enhances the sensitivity of a glioma xenograft with low o6-alkylguanine-DNA alkyltransferase activity to temozolomide and BCNU. Br J Cancer 73:1049–1052.

    Google Scholar 

  • Weingart, J., Grossman, S.A., Carson, K.A., et al. 2007. Phase I trial of polifeprosan 20 with carmustine implant plus continuous infusion of intravenous O6-benzylguanine in adults with recurrent malignant glioma: new approaches to brain tumor therapy CNS consortium trial. J Clin Oncol 25:399–404.

    Article  PubMed  CAS  Google Scholar 

  • Weingart J, Tatter S, Rosenfeld S, et al. 2003. Intratumoral convection-enhanced delivery of IL13-PEQQR cytotoxin for recurrent malignant glioma without planned resection: a phase I/II study. Neurooncology 5:357.

    Google Scholar 

  • Wen, P.Y., Yung, W.K., Lamborn, K.R., et al. 2006. Phase I/II study of imatinib mesylate for recurrent malignant gliomas: North American Brain Tumor Consortium Study 99-08. Clin Cancer Res 12:4899–4907.

    Article  PubMed  CAS  Google Scholar 

  • Wilhelm, S.M., Carter, C., Tang, L., et al. 2004. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 64:7099–7109.

    Article  PubMed  CAS  Google Scholar 

  • Wong, A.J., Ruppert, J.M., Bigner, S.H., et al. 1992. Structural alterations of the epidermal growth factor receptor gene in human gliomas. Proc Natl Acad Sci U S A 89:2965–2969.

    Article  PubMed  CAS  Google Scholar 

  • Wong, K.K., Chang, Y.M., Tsang, Y.T.M., et al. 2005. Expression analysis of juvenile pilocytic astrocytomas by oligonucleotide microarray reveals two potential subgroups. Cancer Res 65:76–84.

    PubMed  CAS  Google Scholar 

  • Yancopoulos, G.D., Davis, S., Gale, N.W., et al. 2000. Vascular-specific growth factors and blood vessel formation. Nature 407:242–248.

    Article  PubMed  CAS  Google Scholar 

  • Yang, J.C., Haworth, L., Sherry, R.M., et al. 2003. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 349:427–434.

    Article  PubMed  CAS  Google Scholar 

  • Yazaki, T., Ahmad, S., Chahlavi, A., et al. 1996. Treatment of glioblastoma U-87 by systemic administration of an antisense protein kinase C-α phosphorothioate oligodeoxynucleotide. Mol Pharmacol 50:236–242.

    PubMed  CAS  Google Scholar 

  • Yin, D., Zhou, H., Kumagai, T., et al. 2005. Proteasome inhibitor PS-341 causes cell growth arrest and apoptosis in human glioblastoma multiforme (GBM). Oncogene 24:344–354.

    Article  PubMed  CAS  Google Scholar 

  • Yoshida, M., Horinouchi, S., Beppu, T. 1995.Trichostatin A and trapoxin: novel chemical probes for the role of histone acetylation in chromatin structure and function. Bioessays 17:423–430.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgment

This work was supported in part by NIH grant NSP0140923.

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  1. Department of Neurosurgery, Children’s Hospital of Pittsburgh, 3705 Fifth Avenue, Pittsburgh, PA, USA

    Ian F. Pollack

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  1. Director, Center for Childhood Cancer, Nationwide Children’s Hospital, The Research Institute, 700 Children’s Drive 332, Columbus, 43205, Ohio, USA

    Peter J. Houghton

  2. Johns Hopkins The Bunting & Blaustein Ca, Medicine Kimmel Comprehensive Cancer Cen, Orleans Street 1650, Baltimore, 21231, Maryland, USA

    Robert J. Arceci

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Pollack, I.F. (2010). Molecularly Targeted Therapies for Astrocytomas. In: Houghton, P., Arceci, R. (eds) Molecularly Targeted Therapy for Childhood Cancer. Springer, New York, NY. https://doi.org/10.1007/978-0-387-69062-9_12

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