Wiener Medizinische Wochenschrift

, Volume 156, Issue 11–12, pp 351–363 | Cite as

Molecular therapies for malignant glioma

  • Markus Hutterer
  • Eberhard Gunsilius
  • Guenther Stockhammer
Themenschwerpunkt

Summary

Due to the dismal prognosis of malignant glioma with currently available therapies there is an urgent need for new treatments based on a better molecular understanding of gliomagenesis. Several concepts of molecular therapies for malignant glioma are currently being studied in preclinical and clinical settings, including small molecules targeting specific receptor-mediated signaling pathways and gene therapy. Many growth factors, growth factor receptors – usually receptor tyrosine kinasesand receptor-associated signaling pathways are critically involved in gliomagenesis. Numerous selective inhibitors, which specifically block such molecules, are currently evaluated for clinical applicability. Several gene therapy approaches have shown antitumor efficacy in experimental studies, and the first clinical trials for the treatment of malignant glioma were conducted in the 1990s. In clinical trials, retroviral herpes-simplex-thymidinkinase- (HSV-Tk-) gene therapy has been the pioneering and most commonly used approach. However, efficient gene delivery into the tumor cells still remains the crucial obstacle for successful clinical gene therapy. During the past few years a number of new gene transfer vectors based on adeno-, adeno-associated-, herpes- and lentiviruses as well as new carrier cell systems, including neural and endothelial progenitor cells, have been developed. In addition, antisense technologies have advanced in recent years and entered clinical testing utilizing intratumoral administration by convection-enhanced delivery, examplified by ongoing clinical trials of intratumoral administration of antisense TGF-β. This paper summarizes some of these recent developments in molecular therapies for malignant glioma, focusing on targeted therapies using selective small molecules and gene therapy concepts.

Keywords

Glioma Glioblastoma Molecular therapy Small molecular inhibitors Gene therapy Antisense therapy 

Molekulare Therapien bei malignen Gliomen

Zusammenfassung

Trotz den heute zur Verfügung stehenden Therapiemöglichkeiten besitzen maligne Gliome weiterhin eine schlechte Prognose. Daher besteht ein dringender Bedarf zur Evaluierung neuer Therapiekonzepte, die auf einem besseren molekularen Verständnis der Onkogenese maligner Gliome basieren. Verschiedene Ansätze molekularer Therapien bei malignen Gliomen werden in präklinischen und klinischen Studien auf ihre Wirksamkeit und Anwendbarkeit überprüft. Dazu zählen vor allem selektiv wirkende klein-molekulare Inhibitoren der Signaltransduktion und die Gen-Therapie. Viele Wachstumsfaktoren, Wachstumsfaktor-Rezeptoren – in der Regel Rezeptor-Tyrosinkinasen – und die mit dem Rezeptor assoziierten intrazellulären Signalwege sind ganz entscheidend in der Onkogenese von Gliomen beteiligt. Verschiedenste klein-molekulare Substanzen, die selektiv mit Molekülen dieser Signaltransduktionswege interferieren, werden momentan in präklinischen und klinischen Studien untersucht. Verschiedene Ansätze der Gen-Therapie zeigten in experimentellen Studien zu malignen Gliomen antitumorale Wirksamkeit. Erste klinische Studien zur Gen-Therapie dieser Tumore wurden in den 90er Jahren begonnen, in denen die retrovirale Herpes-Simplex-Thymidinkinase- (HSV-Tk-) Gen-Therapie am häufigsten angewandt wurde. Die entscheidende Hürde für eine erfolgreiche klinische Gen-Therapie ist der effiziente Gentransfer in die Tumorzelle. Aus diesem Grund wurden in den letzten Jahren neue Gentransfer-Systeme entwickelt. Diese basieren einerseits auf Adeno-, Adeno-assoziierten-, Herpes- and Lentiviren, andererseits auf Träger-Zell-Systeme, wie neurale und endotheliale Vorläuferzellen. Zusätzlich wurden in den letzten Jahren Antisense-Technologien entwickelt und bereits klinisch durch kontinuierliche intratumorale Applikation getestet (z. B. Antisense-TGF-β). Diese Arbeit beschreibt einige neue Entwicklungen molekularer Therapien für maligne Gliome, wobei der Fokus auf klein-molekularen Inhibitoren und Gentherapie-Konzepten liegt.

Schlüsselwörter

Gliom Glioblastom Molekulare Therapie Klein-molekulare Inhibitoren Gen-Therapie Antisense-Therapie 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Mahaley MS Jr, Mettlin C, Natarajan N, Laws ER Jr, Peace BB (1989) National survey of patterns of care for brain-tumor patients. J Neurosurg 71 (6): 826–836PubMedGoogle Scholar
  2. von Deimling A, Louis DN, Wiestler OD (1995) Molecular pathways in the formation of gliomas. Glia 15 (3): 328–338PubMedCrossRefGoogle Scholar
  3. Maher EA, Furnari FB, Bachoo RM, Rowitch DH, Louis DN, Cavenee WK, DePinho RA (2001) Malignant glioma: genetics and biology of a grave matter. Genes Dev 15 (11): 1311–1333PubMedCrossRefGoogle Scholar
  4. Aaronson SA (1991) Growth factors and cancer. Science 254 (5035): 1146–1153PubMedGoogle Scholar
  5. Cantley LC, Auger KR, Carpenter C, Duckworth B, Graziani A, Kapeller R, Soltoff S (1991) Oncogenes and signal transduction. Cell 64 (2): 281–302PubMedCrossRefGoogle Scholar
  6. Newton HB (2003) Molecular neuro-oncology and development of targeted therapeutic strategies for brain tumors. Part 1: Growth factor and Ras signaling pathways. Expert Rev Anticancer Ther 3 (5): 595–614PubMedCrossRefGoogle Scholar
  7. Eckhardt SG, Rizzo J, Sweeney KR, Cropp G, Baker SD, Kraynak MA, Kuhn JG et al. (1999) Phase I and pharmacologic study of the tyrosine kinase inhibitor SU101 in patients with advanced solid tumors. J Clin Oncol 17 (4): 1095–1104PubMedGoogle Scholar
  8. Newton HB (2002) Chemotherapy for the treatment of metastatic brain tumors. Expert Rev Anticancer Ther 2 (5): 495–506PubMedCrossRefGoogle Scholar
  9. Institute NC (2006) Phase III Randomized Study of Leflunomide (SU101) Versus Procarbazine for patients with Glioblastoma Multiforme in first Relapse (study has been completed, but not yet published). Available at: http://www.clinicaltrials.gov/ct/show/NCT00003293?order=1_ClinicalTrials.gov Identifier: NCT00112788
  10. Baselga J (2001) The EGFR as a target for anticancer therapy – focus on cetuximab. Eur J Cancer 37(Suppl 4): 16–22CrossRefGoogle Scholar
  11. Arteaga CL (2001) The epidermal growth factor receptor: from mutant oncogene in nonhuman cancers to therapeutic target in human neoplasia. J Clin Oncol 19 (18 Suppl): 32–40Google Scholar
  12. Mellinghoff IK, Wang MY, Vivanco I, Haas-Kogan DA, Zhu S, Dia EQ, Lu KV et al. (2005) Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. N Engl J Med 353 (19): 2012–2024PubMedCrossRefGoogle Scholar
  13. Newton HB (2004) Molecular neuro-oncology and development of targeted therapeutic strategies for brain tumors. Part 2: PI3K/Akt/PTEN, mTOR, SHH/PTCH and angiogenesis. Expert Rev Anticancer Ther 4 (1): 105–128PubMedCrossRefGoogle Scholar
  14. Feldkamp MM, Lala P, Lau N, Roncari L, Guha A (1999) Expression of activated epidermal growth factor receptors, Ras-guanosine triphosphate, and mitogen-activated protein kinase in human glioblastoma multiforme specimens. Neurosurgery 45 (6): 1442–1453PubMedCrossRefGoogle Scholar
  15. Rowinsky EK, Windle JJ, Von Hoff DD (1999) Ras protein farnesyltransferase: A strategic target for anticancer therapeutic development. J Clin Oncol 17 (11): 3631–3652PubMedGoogle Scholar
  16. Graff JR, McNulty AM, Hanna KR, Konicek BW, Lynch RL, Bailey SN, Banks C et al. (2005) The protein kinase Cbeta-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 (16): 7462–7469PubMedCrossRefGoogle Scholar
  17. Momota H, Nerio E, Holland EC (2005) Perifosine inhibits multiple signaling pathways in glial progenitors and cooperates with temozolomide to arrest cell proliferation in gliomas in vivo. Cancer Res 65 (16): 7429–7435PubMedCrossRefGoogle Scholar
  18. Faivre S, Delbaldo C, Vera K, Robert C, Lozahic S, Lassau N, Bello C et al. (2006) Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer. J Clin Oncol 24 (1): 25–35PubMedCrossRefGoogle Scholar
  19. Motzer RJ, Michaelson MD, Redman BG, Hudes GR, Wilding G, Figlin RA, Ginsberg MS et al. (2006) Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol 24 (1): 16–24PubMedCrossRefGoogle Scholar
  20. Farhadi MR, Capelle HH, Erber R, Ullrich A, Vajkoczy P (2005) Combined inhibition of vascular endothelial growth factor and platelet-derived growth factor signaling: effects on the angiogenesis, microcirculation, and growth of orthotopic malignant gliomas. J Neurosurg 102 (2): 363–370PubMedGoogle Scholar
  21. Laird AD, Vajkoczy P, Shawver LK, Thurnher A, Liang C, Mohammadi M, Schlessinger J et al. (2000) SU6668 is a potent antiangiogenic and antitumor agent that induces regression of established tumors. Cancer Res 60 (15): 4152–4160PubMedGoogle Scholar
  22. Rugo HS, Herbst RS, Liu G, Park JW, Kies MS, Steinfeldt HM, Pithavala YK et al. (2005) Phase I trial of the oral antiangiogenesis agent AG-013736 in patients with advanced solid tumors: pharmacokinetic and clinical results. J Clin Oncol 23 (24): 5474–5483PubMedCrossRefGoogle Scholar
  23. Richly H, Henning BF, Kupsch P, Passarge K, Grubert M, Hilger RA, Christensen O et al. (2006) Results of a Phase I trial of sorafenib (BAY 43-9006) in combination with doxorubicin in patients with refractory solid tumors. Ann Oncol 17 (5): 866–873PubMedCrossRefGoogle Scholar
  24. Siu LL, Awada A, Takimoto CH, Piccart M, Schwartz B, Giannaris T, Lathia C et al. (2006) Phase I trial of sorafenib and gemcitabine in advanced solid tumors with an expanded cohort in advanced pancreatic cancer. Clin Cancer Res 12 (1): 144–151PubMedCrossRefGoogle Scholar
  25. Kanzawa T, Ito H, Kondo Y, Kondo S (2003) Current and Future Gene Therapy for Malignant Gliomas. J Biomed Biotechnol 2003 (1): 25–34PubMedCrossRefGoogle Scholar
  26. King GD, Curtin JF, Candolfi M, Kroeger K, Lowenstein PR, Castro MG (2005) Gene therapy and targeted toxins for glioma. Curr Gene Ther 5 (6): 535–357PubMedCrossRefGoogle Scholar
  27. Culver KW, Ram Z, Wallbridge S, Ishii H, Oldfield EH, Blaese RM (1992) In vivo gene transfer with retroviral vector-producer cells for treatment of experimental brain tumors. Science 256 (5063): 1550–1552PubMedGoogle Scholar
  28. Stockhammer G, Brotchi J, Leblanc R, Bernstein M, Schackert G, Weber F, Ostertag C et al. (1997) Gene therapy for glioblastoma [correction of gliobestome] multiform: in vivo tumor transduction with the herpes simplex thymidine kinase gene followed by ganciclovir. J Mol Med 75 (4): 300–304PubMedCrossRefGoogle Scholar
  29. Moolten FL (1986) Tumor chemosensitivity conferred by inserted herpes thymidine kinase genes: paradigm for a prospective cancer control strategy. Cancer Res 46 (10): 5276–5281PubMedGoogle Scholar
  30. Freeman SM, Abboud CN, Whartenby KA, Packman CH, Koeplin DS, Moolten FL, Abraham GN (1993) The "bystander effect": tumor regression when a fraction of the tumor mass is genetically modified. Cancer Res 53 (21): 5274–5283PubMedGoogle Scholar
  31. Shand N, Weber F, Mariani L, Bernstein M, Gianella-Borradori A, Long Z, Sorensen AG, Barbier N (1999) A phase 1–2 clinical trial of gene therapy for recurrent glioblastoma multiforme by tumor transduction with the herpes simplex thymidine kinase gene followed by ganciclovir. GLI328 European-Canadian Study Group. Hum Gene Ther 10 (14): 2325–2335PubMedCrossRefGoogle Scholar
  32. Rainov NG (2000) A phase III clinical evaluation of herpes simplex virus type 1 thymidine kinase and ganciclovir gene therapy as an adjuvant to surgical resection and radiation in adults with previously untreated glioblastoma multiforme. Hum Gene Ther 11 (17): 2389–2401PubMedCrossRefGoogle Scholar
  33. Harrow S, Papanastassiou V, Harland J, Mabbs R, Petty R, Fraser M, Hadley D et al. (2004) HSV1716 injection into the brain adjacent to tumour following surgical resection of high-grade glioma: safety data and long-term survival. Gene Ther 11 (22): 1648–1658PubMedCrossRefGoogle Scholar
  34. Deglon N, Aebischer P (2002) Lentiviruses as vectors for CNS diseases. Curr Top Microbiol Immunol 261: 191–209PubMedGoogle Scholar
  35. Galimi F, Verma IM (2002) Opportunities for the use of lentiviral vectors in human gene therapy. Curr Top Microbiol Immunol 261: 245–254PubMedGoogle Scholar
  36. Dewey RA, Morrissey G, Cowsill CM, Stone D, Bolognani F, Dodd NJ, Southgate TD et al. (1999) Chronic brain inflammation and persistent herpes simplex virus 1 thymidine kinase expression in survivors of syngeneic glioma treated by adenovirus-mediated gene therapy: implications for clinical trials. Nat Med 5 (11): 1256–1263PubMedCrossRefGoogle Scholar
  37. Wang X, Zhang GR, Yang T, Zhang W, Geller AI (2000) Fifty-one kilobase HSV-1 plasmid vector can be packaged using a helper virus-free system and supports expression in the rat brain. Biotechniques 28 (1): 102–107PubMedGoogle Scholar
  38. Summerford C, Bartlett JS, Samulski RJ (1999) AlphaVbeta5 integrin: a co-receptor for adeno-associated virus type 2 infection. Nat Med 5 (1): 78–82PubMedCrossRefGoogle Scholar
  39. Glorioso JC, Bender MA, Goins WF, Fink DJ, DeLuca NA (1995) HSV as a gene transfer vector for the nervous system. Mol Biotechnol 4 (1): 87–99PubMedCrossRefGoogle Scholar
  40. Kofler P, Wiesenhofer B, Rehrl C, Baier G, Stockhammer G, Humpel C (1998) Liposome-mediated gene transfer into established CNS cell lines, primary glial cells, and in vivo. Cell Transplant 7 (2): 175–185PubMedCrossRefGoogle Scholar
  41. Yoshida T, Mizuno M, Taniguchi K, Nakayashiki N, Wakabayashi T, Yoshida J (2001) Rat glioma cell death induced by cationic liposome-mediated transfer of the herpes simplex virus thymidine kinase gene followed by ganciclovir treatment. J Surg Oncol 76 (1): 19–25PubMedCrossRefGoogle Scholar
  42. Ram Z, Culver KW, Walbridge S, Blaese RM, Oldfield EH (1993) In situ retroviral-mediated gene transfer for the treatment of brain tumors in rats. Cancer Res 53 (1): 83–88PubMedGoogle Scholar
  43. Aboody KS, Brown A, Rainov NG, Bower KA, Liu S, Yang W, Small JE et al. (2000) Neural stem cells display extensive tropism for pathology in adult brain: evidence from intracranial gliomas. Proc Natl Acad Sci U S A 97 (23): 12846–12851PubMedCrossRefGoogle Scholar
  44. Benedetti S, Pirola B, Pollo B, Magrassi L, Bruzzone MG, Rigamonti D, Galli R et al. (2000) Gene therapy of experimental brain tumors using neural progenitor cells. Nat Med 6 (4): 447–450PubMedCrossRefGoogle Scholar
  45. Li S, Tokuyama T, Yamamoto J, Koide M, Yokota N, Namba H (2005) Potent bystander effect in suicide gene therapy using neural stem cells transduced with herpes simplex virus thymidine kinase gene. Oncogene 69 (6): 503–508Google Scholar
  46. Gastl G, Gunsilius E, Petzer AL, Stockhammer G (2001) Endothelial cell progenitors for vascular targeting of tumors. Arch Pharmacol 364 (Suppl): R13Google Scholar
  47. Stockhammer G, Wiegele J, Puschban Z, Stefanova N, Wechselberger J, Kaehler CM, Kostron H et al. (2002) Vascular targeting of malignant glioma using endothelial progenitor cells. Neuro-Oncology 4 (Suppl 1): 94Google Scholar
  48. Stockhammer G, Obwegeser A, Kostron H, Schumacher P, Muigg A, Felber S, Maier H et al. (2000) Vascular endothelial growth factor (VEGF) is elevated in brain tumor cysts and correlates with tumor progression. Acta Neuropathol (Berl) 100 (1): 101–105CrossRefGoogle Scholar
  49. Plate KH, Breier G, Weich HA, Risau W (1992) Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo. Nature 359 (6398): 845–848PubMedCrossRefGoogle Scholar
  50. Saleh M, Stacker SA, Wilks AF (1996) Inhibition of growth of C6 glioma cells in vivo by expression of antisense vascular endothelial growth factor sequence. Cancer Res 56 (2): 393–401PubMedGoogle Scholar
  51. Machein MR, Risau W, Plate KH (1999) Antiangiogenic gene therapy in a rat glioma model using a dominant-negative vascular endothelial growth factor receptor 2. Hum Gene Ther 10 (7): 1117–1128PubMedCrossRefGoogle Scholar
  52. O'Reilly MS, Boehm T, Shing Y, Fukai N, Vasios G, Lane WS, Flynn E et al. (1997) Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 88 (2): 277–285PubMedCrossRefGoogle Scholar
  53. O'Reilly MS, Holmgren L, Shing Y, Chen C, Rosenthal RA, Moses M, Lane WS et al. (1994) Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell 79 (2): 315–328PubMedCrossRefGoogle Scholar
  54. Gale NW, Yancopoulos GD (1999) Growth factors acting via endothelial cell-specific receptor tyrosine kinases: VEGFs, angiopoietins, and ephrins in vascular development. Genes Dev 13 (9): 1055–1066PubMedGoogle Scholar
  55. Ohlfest JR, Demorest ZL, Motooka Y, Vengco I, Oh S, Chen E, Scappaticci FA et al. (2005) Combinatorial antiangiogenic gene therapy by nonviral gene transfer using the sleeping beauty transposon causes tumor regression and improves survival in mice bearing intracranial human glioblastoma. Mol Ther 12 (5): 778–788PubMedCrossRefGoogle Scholar
  56. Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T, Witzenbichler B et al. (1997) Isolation of putative progenitor endothelial cells for angiogenesis. Science 275 (5302): 964–967PubMedCrossRefGoogle Scholar
  57. Gunsilius E, Duba HC, Petzer AL, Kahler CM, Grunewald K, Stockhammer G, Gabl C et al. (2000) Evidence from a leukaemia model for maintenance of vascular endothelium by bone-marrow-derived endothelial cells. Lancet 355 (9216): 1688–1691PubMedCrossRefGoogle Scholar
  58. Lyden D, Hattori K, Dias S, Costa C, Blaikie P, Butros L, Chadburn A et al. (2001) Impaired recruitment of bonemarrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nat Med 7 (11): 1194–1201PubMedCrossRefGoogle Scholar
  59. Stockhammer G, Poewe W, Burgstaller S, Deisenhammer F, Muigg A, Kiechl S, Schmutzhard E et al. (2000) Vascular endothelial growth factor in CSF: a biological marker for carcinomatous meningitis. Neurology 54 (8): 1670–1676PubMedGoogle Scholar
  60. Roth W, Weller M (1999) Chemotherapy and immunotherapy of malignant glioma: molecular mechanisms and clinical perspectives. Cell Mol Life Sci 56 (5–6): 481–506PubMedCrossRefGoogle Scholar
  61. Jachimczak P, Hessdorfer B, Fabel-Schulte K, Wismeth C, Brysch W, Schlingensiepen KH, Bauer A et al. (1996) Transforming growth factor-beta-mediated autocrine growth regulation of gliomas as detected with phosphorothioate antisense oligonucleotides. Int J Cancer 65 (3): 332–337PubMedCrossRefGoogle Scholar
  62. Schlingensiepen KH, Schlingensiepen R, Steinbrecher A, Hau P, Bogdahn U, Fischer-Blass B, Jachimczak P (2006) Targeted tumor therapy with the TGF-beta2 antisense compound AP 12009. Cytokine Growth Factor Rev 17 (1–2): 129–139PubMedCrossRefGoogle Scholar
  63. Schlingensiepen R, Goldbrunner M, Szyrach MN, Stauder G, Jachimczak P, Bogdahn U, Schulmeyer F et al. (2005) Intracerebral and intrathecal infusion of the TGFbeta2-specific antisense phosphorothioate oligonucleotide AP 12009 in rabbits and primates: Toxicology and Safety. Oligonucleotides 15 (2): 94–104PubMedCrossRefGoogle Scholar
  64. Bobo RH, Laske DW, Akbasak A, Morrison PF, Dedrick RL, Oldfield EH (1994) Convection-enhanced delivery of macromolecules in the brain. Proc Natl Acad Sci U S A 91 (6): 2076–2080PubMedCrossRefGoogle Scholar
  65. Greenfield L, Johnson VG, Youle RJ (1987) Mutations in diphtheria toxin separate binding from entry and amplify immunotoxin selectivity. Science 238 (4826): 536–539PubMedGoogle Scholar
  66. Laske DW, Youle RJ, Oldfield EH (1997) Tumor regression with regional distribution of the targeted toxin TF-CRM107 in patients with malignant brain tumors. Nat Med 3 (12): 1323CrossRefGoogle Scholar
  67. Jacobs AH, Voges J, Kracht LW, Dittmar C, Winkeler A, Thomas A, Wienhard K et al. (2003) Imaging in gene therapy of patients with glioma. J Neurooncol 65 (3): 291–305PubMedCrossRefGoogle Scholar
  68. Tjuvajev JG, Avril N, Oku T, Sasajima T, Miyagawa T, Joshi R, Safer M et al. (1998) Imaging herpes virus thymidine kinase gene transfer and expression by positron emission tomography. Cancer Res 58 (19): 4333–4341PubMedGoogle Scholar
  69. Jacobs A, Voges J, Reszka R, Lercher M, Gossmann A, Kracht L, Kaestle C et al. (2001) Positron-emission tomography of vector-mediated gene expression in gene therapy for gliomas. Lancet 358 (9283): 727–729PubMedCrossRefGoogle Scholar
  70. Kleihues P, Ohgaki H (1999) Primary and secondary glioblastomas: from concept to clinical diagnosis. Neurooncol 1 (1): 44–51Google Scholar
  71. Waldherr C, Mellinghoff IK, Tran C, Halpern BS, Rozengurt N, Safaei A, Weber WA et al. (2005) Monitoring antiproliferative responses to kinase inhibitor therapy in mice with 3'-deoxy-3'-18F-fluorothymidine PET. J Nucl Med 46 (1): 114–120PubMedGoogle Scholar
  72. Shaul M, Abourbeh G, Jacobson O, Rozen Y, Laky D, Levitzki A, Mishani E (2004) Novel iodine-124 labeled EGFR inhibitors as potential PET agents for molecular imaging in cancer. Bioorg Med Chem 12 (13): 3421–3429PubMedCrossRefGoogle Scholar
  73. Malkin M, Mason W, Liebermann F, Hannah A (1997) Phase I study of SU101, a novel signal transduction inhibitor, in recurrent malignant glioma. Proc Am Soc Clin Oncol 16 (385a): AbstractGoogle Scholar
  74. Malkin M, Rosen L, Lopez A, Mulay M, Cloughesy T, Hannah A (1998) Phase 2 study of SU101, a PDGFR signal transduction inhibitor, in recurrent malignant glioma. Proc Am Soc Clin Oncol 17 (390a): AbstractGoogle Scholar
  75. Shapiro JR, Ashby L, Obbens E, DePaoli AC, Hannah A (1999) Phase I/II study of SU101 in combination with carmustine in the treatment of patients newly dignosed with malignant glioma. Neurooncology 1: 55Google Scholar
  76. National Cancer Institute (NCI) C (2006) Currently open Phase I, II and III studies with different targeting substances treating patients with recurrent gliomas. Available at: http://www.clinicaltrials.gov
  77. Wen PY, Yung WKH, K. (2002) Phase I study of STI571 (Gleevec) for patients with recurrent malignant gliomas and meningeomas (NABTC 99–08). Proc Am Soc Clin Oncol 21 (73a): AbstractGoogle Scholar
  78. Dresemann G (2005) Imatinib and hydroxyurea in pretreated progressive glioblastoma multiforme: a patient series. Ann Oncol 16 (10): 1702–1708PubMedCrossRefGoogle Scholar
  79. Reardon DA, Egorin MJ, Quinn JA, Rich JN Sr, Gururangan I, Vredenburgh JJ, Desjardins A et al. (2005) Phase II study of imatinib mesylate plus hydroxyurea in adults with recurrent glioblastoma multiforme. J Clin Oncol 23 (36): 9359–9368PubMedCrossRefGoogle Scholar
  80. Lieberman F, Cloughesy T, Deangelis L (2003) Phase I-II study of ZD-1839 for recurrent malignant gliomas and meningeomas progressing after radiation therapy. Proc Am Soc Clin Oncol 22 (105): AbstractGoogle Scholar
  81. Peery TS, Reardon DA, Quinn JA (2003) Phase II of ZD1839 for patients with first relapse glioblastoma. Proc Am Soc Clin Oncol 22 (99): AbstractGoogle Scholar
  82. Rich JN, Reardon DA, Peery T, Dowell JM, Quinn JA, Penne KL, Wikstrand CJ et al. (2004) Phase II trial of gefitinib in recurrent glioblastoma. J Clin Oncol 22 (1): 133–142PubMedCrossRefGoogle Scholar
  83. Prados MD, Lamborn KR, Chang S, Burton E, Butowski N, Malec M, Kapadia A et al. (2006) Phase 1 study of erlotinib HCl alone and combined with temozolomide in patients with stable or recurrent malignant glioma. Neurooncol 8 (1): 67–78Google Scholar
  84. Cloughesy TF, Kuhn J, Robins HI, Abrey L, Wen P, Fink K, Lieberman FS et al. (2005) Phase I trial of tipifarnib in patients with recurrent malignant glioma taking enzyme-inducing antiepileptic drugs: a North American Brain Tumor Consortium Study. J Clin Oncol 23 (27): 6647–6656PubMedCrossRefGoogle Scholar
  85. Cloughesy TF, Kuhn J, PY W (2002) Phase II trial of R115777 (Zarnestra) in patients with recurrent glioma not taking enzyme inducing anti-epileptic drugs (EIAED): a North American Brain Tumor Consortium (NABTC) report. Proc. Am Soc Clin Oncol 21 (80a): AbstractGoogle Scholar
  86. ClinicalTrials (2003) Phase II evaluation of temozolomide and farnesyl transferase inhibitor (SCH66336) for the treatment of recurrent and progressive glioblastoma multiforme. Available at: http://utm-notes-db2.mdacc.tmc.edu/mdacc/ClinicalTrialsWP.nsf/Index/DM01-258
  87. Chang SM, Kuhn J, Wen P, Greenberg H, Schiff D, Conrad C, Fink K et al. (2004) Phase I/pharmacokinetic study of CCI-779 in patients with recurrent malignant glioma on enzyme-inducing antiepileptic drugs. Invest New Drugs 22 (4): 427–435PubMedCrossRefGoogle Scholar
  88. Chang SM, Wen P, Cloughesy T, Greenberg H, Schiff D, Conrad C, Fink K et al. (2005) Phase II study of CCI-779 in patients with recurrent glioblastoma multiforme. Invest New Drugs 23 (4): 357–361PubMedCrossRefGoogle Scholar
  89. Galanis E, Buckner JC, Maurer MJ, Kreisberg JI, Ballman K, Boni J, Peralba JM 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 (23): 5294–5304PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Markus Hutterer
    • 1
  • Eberhard Gunsilius
    • 2
  • Guenther Stockhammer
    • 1
  1. 1.Department of Neurology, Neuro-Oncology GroupMedical University of InnsbruckInnsbruckAustria
  2. 2.Division of Hematology and OncologyMedical University of InnsbruckInnsbruckAustria

Personalised recommendations