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Molecular therapies for malignant glioma

Molekulare Therapien bei malignen Gliomen

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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.

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.

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  1. Department of Neurology, Neuro-Oncology Group, Medical University of Innsbruck, Innsbruck, Austria

    Markus Hutterer & Guenther Stockhammer

  2. Division of Hematology and Oncology, Medical University of Innsbruck, Innsbruck, Austria

    Eberhard Gunsilius

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  1. Markus Hutterer
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Correspondence to Guenther Stockhammer.

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Hutterer, M., Gunsilius, E. & Stockhammer, G. Molecular therapies for malignant glioma. Wien Med Wochenschr 156, 351–363 (2006). https://doi.org/10.1007/s10354-006-0308-3

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