Apoptose-Mechanismen in der Onkogenese von Hauttumoren[*]

Zusammenfassung

Tumorerkrankungen der Haut werden zentral durch die Fähigkeit der Tumorzellen, im Rahmen von Tumorinitiation und -progression Apoptoseresistenz zu erlangen, befördert. So trägt die Apoptoseresistenz entscheidend dazu bei, dass Hauttumorerkrankungen wie das maligne Melanom und das Plattenepithelkarzinom im metastasierten Zustand therapeutisch nur schwer beeinflussbar sind und eine kurative Behandlung dieser Tumorstadien erschwert ist. Ebenso bedingt das multilokuläre Auftreten von Basalzellkarzinomen eine nicht unerhebliche Komorbidität, sodass auch diese Entität neuer Therapieformen bedarf. In den letzten Jahren mehrt sich die Evidenz, dass durch gezielte Beeinflussung zentraler Schaltstellen der apoptotischen Signaltransduktionskaskade eine bessere Behandlung dermatoonkologischer Patienten ermöglicht werden könnte. Dazu gehören p53-Reaktivatoren, Sonic-Hedgehog-Antagonisten, aber auch Bcl-2-Antagonisten, IAP-Antagonisten oder Todesrezeptor-Agonisten, die sich gegenwärtig in der präklinischen oder frühen klinischen Erprobung befinden. Der Artikel fasst den gegenwärtigen Stand zusammen und gibt einen Ausblick auf potenzielle mechanismusbasierte Therapieoptionen zur Durchbrechung der Apoptoseresistenz bei dermatoonkologischen Erkrankungen.

Abstract

The prognosis of cutaneous neoplasia such as squamous cell carcinoma (SCC), basal cell carcinoma (BCC), or malignant melanoma (MM) are severely influenced by the ability of tumor cells to develop or maintain apoptosis resistance throughout tumor progression and metastasis. Furthermore, the ability to overcome apoptosis resistance is a critical factor that determines therapeutic failure or success in metastatic SCC or MM. Moreover apoptosis resistence is a major obstacle to curative efforts in these dermatooncologic diseases. In BCC, the multitude of tumors results in a substantial comorbidity that require innovative treatment options. Over the past years, there is increasing evidence that targeted therapy aiming at the apoptotic signalling cascade in a tumor type-specific manner may result in a better success of oncological treatment. In this context, reactivators of p53, antagonists of sonic hedgehog, but also Bcl-2- or IAP antagonists as well as death receptor agonists that are currently in preclinical or early clinical development may prove to be useful in dermatooncology. The article explains the current knowledge in this rapidly moving field and summarizes potential mechanism-based therapeutic options to overcome apoptosis resistance in the different forms of skin cancer.

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1 Vortrag anlässlich des Jahressymposiums der Berliner Stiftung für Dermatologie am 31. 5. 2008.