Therapeutische Antagonisierung vom transforming growth factor-β (TGF-β) beim Glioblastom: Rationale und aktuelle Behandlungskonzepte

Zusammenfassung

Transforming growth factor-β (TGF-β) ist ein Zytokin, das in großen Mengen von Glioblastomzellen gebildet und wegen seiner biologischen Effekte für zahlreiche Aspekte des malignen Phänotyps der Glioblastome verantwortlich gemacht wird. TGF-β besitzt autokrine und parakrine Wirkungen auf Glioblastomzellen vermutlich vor allem in Form gesteigerter Migration und Invasion. Zudem wird ein stimulierender Effekt auf die Angiogenese postuliert. Besonderes Interesse gilt jedoch den potenten inhibitorischen Wirkungen von TGF-β sowohl auf unspezifische als auch auf spezifische Immuneffektormechanismen. Diese Beobachtungen haben zu der Hypothese geführt, dass eine Antagonisierung von TGF-β ausreichen könnte, um eine wirksame Immunantwort gegen Glioblastome zu ermöglichen. Sowohl die Hemmung der TGF-β-Synthese durch stabile Expression eines Antisenseplasmids oder Pharmaka wie N-[3,4-Dimethoxycinnamoyl]-anthranilinsäure (Tranilast) als auch die Hemmung der TGF-β-prozessierenden furinähnlichen Proteasen als auch die Expression des TGF-β-bindenden Proteins Dekorin haben in Nagermodellen des Glioblastoms therapeutische Wirkung gezeigt. Bereits in der klinischen Evaluation im Rahmen einer randomisierten Studie befindet sich die lokale Therapie mit Antisense-Oligonukleotiden gegen TGF-β₂ bei Gliomrezidiven. Zusammengefasst besteht die berechtigte Erwartung, dass TGF-β-antagonistische Therapiestrategien in absehbarer Zeit zu relevanten Fortschritten in der Glioblastomtherapie führen werden.

Abstract

Glioblastoma cells release high levels of the cytokine, transforming growth factor-β (TGF-β). The biological effects of TGF-β suggest that this molecule might play a central role in the malignant phenotype of glioblastomas. Autocrine and paracrine effects of TGF-β include the promotion of glioma cell migration and invasion. TGF-β may also stimulate angiogenesis. The potent inhibitory effects of TGF-β on unspecific and specific immune effector mechanisms have received special attention in the context of glioma biology. Altogether these observations have led to the hypothesis that antagonizing TGF-β might suffice to allow for an efficient immune response against glioblastomas. Inhibition of TGF-β synthesis by stable expression of an antisense plasmid or by drugs such as N-[3,4-dimethoxycinnamoyl]-anthranilic acid (Tranilast), or inhibition of TGF-β-processing furin-like proteases, or expression of the TGF-β-binding protein, decorin, have all shown therapeutic effects in rodent glioma models. The local application of TGF-β₂ antisense oligonucleotides is currently evaluated in a randomized clinical trial for recurrent malignant glioma. There is thus a strong rationale to expect a major progress from TGF-β-antagonistic treatment strategies for glioblastoma in the near future.

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