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Molekulargenetische Untersuchungen als Basis zielgerichteter Therapien beim Basalzellkarzinom am Auge

Molecular genetic investigations as the basis for targeted treatment of basal cell carcinoma of the eye

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Zusammenfassung

Hintergrund

Basalzellkarzinome sind die häufigsten bösartigen Tumoren des Menschen überhaupt. Sie wachsen lokal destruierend und invasiv.

Fragestellung

Die Zunahme von Basalzellkarzinomen in einer alternden Gesellschaft erfordert neue, schonende Therapieansätze gerade für fortgeschrittene, schwer resezierbare, an chirurgisch herausfordernden Lokalisationen wie dem Augenlid wachsende oder metastasierte Basalzellkarzinome.

Material und Methoden

Neue Schlüsseltechnologien wie „next generation sequencing“ (NGS) ermöglichen genetische Analysen von Tumoren in Hochdurchsatzverfahren. Dadurch werden neue Erkenntnisse zur molekulargenetischen Genese von Basalzellkarzinomen erworben, die die Entwicklung neuartiger, zielgerichteter Behandlungen der betroffenen Signalwege ermöglichen.

Ergebnisse

Basalzellkarzinome besitzen entsprechend dem mehrschrittigen Photokarzinogenesemodell eine sehr hohe Last an UV-induzierten Genmutationen (75 %). Unabhängig von der Genese tragen 85 % der Basalzellkarzinome Hedgehog-signalwegaktivierende Mutationen. Mittlerweile sind 2 Hedgehog-Inhibitoren zur Behandlung des schwer resezierbaren bzw. metastasierten Basalzellkarzinoms zugelassen (Vismodegib und Sonidegib). Die Ansprechraten liegen jedoch nur bei 60 % der Patienten. Der Grund hierfür liegt in der hohen Mutationslast der Tumoren. So sind in 85 % der Basalzellkarzinome auch andere Signalwege beeinträchtigt.

Schlussfolgerungen

Molekulargenetische Untersuchungen werden die Identifizierung weiterer zielgerichteter Therapieansätze ermöglichen. Aufgrund der hohen Mutationslast sind auch Checkpoint-Inhibitoren (z. B. Cemiplimab) effektiv. UV-Schutz und Nicotinamid können die Mutationslast verringern und das Basalzellkarzinomrisiko mindern.

Abstract

Background

Basal cell carcinomas are generally the most common malignant human cancers. They grow destructively and invasively into surrounding tissue.

Objective

The rising incidence of basal cell carcinomas in an aging society demands new, less destructive treatment approaches especially for advanced and difficult to resect basal cell carcinomas at surgically demanding locations, such as those growing or metastasizing on the eyelid.

Material and methods

New key technologies, such as next generation sequencing (NGS) enable high-throughput genetic analyses of tumors. In this way new knowledge on the molecular genetic pathogenesis of basal cell carcinomas is gained, which enables the development of new targeted treatment of the affected signal pathway.

Results

In line with the multistep photocarcinogenesis theory, basal cell carcinomas possess a high load of UV-induced gene mutations (75%). Independent of the genesis 85% of basal cell carcinomas harbor activating mutations of the hedgehog signaling pathway. Accordingly, two hedgehog inhibitors for the treatment of difficult to resect or metastasized basal cell carcinomas have been licensed (vismodegib and sonidegib); however, only 60% of patients respond to this treatment. This is due to the high mutational load with 85% of the tumors harboring additional mutations in other signaling pathways.

Conclusion

Molecular genetic analyses will enable the identification of further targeted therapies for advanced basal cell carcinomas. Due to the high mutational load checkpoint inhibitors (e. g. cemiplimab) are also effective in the treatment of basal cell carcinomas. Nicotinamide and UV protection can reduce the mutational load and hence decrease the risk for tumor development.

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Funding

Förderung

Die Arbeit wurde zum Teil unterstützt durch OnkoTher-H, EU, ESF/14-BM-A55-0001/18 (S. E.); der Damp Stiftung 2017-05 (S. E.), der Dermatologischen Gesellschaft Mecklenburg-Vorpommern (L. B.) und einem Stipendium der Deutschen Stiftung Dermatologie (M.C. M.).

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Authors and Affiliations

  1. Klinik und Poliklinik für Dermatologie und Venerologie, Universitätsmedizin Rostock, Strempelstr. 13, 18057, Rostock, Deutschland

    L. Boeckmann, M. C. Martens &  S. Emmert

  2. Klinik für Augenheilkunde, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck, Deutschland

    V. Kakkassery

  3. Zentrum für Augenheilkunde, Universität zu Köln, Köln, Deutschland

    L. M. Heindl

  4. Centrum für Integrierte Onkologie (CIO) Aachen – Bonn – Cologne – Düsseldorf, Köln, Deutschland

    L. M. Heindl

Authors
  1. L. Boeckmann
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  2. M. C. Martens
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  3. V. Kakkassery
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  4. L. M. Heindl
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  5. S. Emmert
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Corresponding authors

Correspondence to L. Boeckmann or S. Emmert.

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Interessenkonflikt

L. Boeckmann, M.C. Martens, V. Kakkassery, L.M. Heindl und S. Emmert geben an, dass kein Interessenkonflikt besteht.

Für diesen Beitrag wurden von den Autoren keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien.

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Boeckmann, L., Martens, M.C., Kakkassery, V. et al. Molekulargenetische Untersuchungen als Basis zielgerichteter Therapien beim Basalzellkarzinom am Auge. Ophthalmologe 117, 106–112 (2020). https://doi.org/10.1007/s00347-019-0905-3

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  • DOI: https://doi.org/10.1007/s00347-019-0905-3

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