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Efficacy of a Triple Treatment with Irradiation, Agonistic TRAIL Receptor Antibodies and EGFR Blockade

Effektivität einer Dreifachkombinationstherapie bestehend aus Bestrahlung, TRAIL-Rezeptor-Antikörpern und EGFR-Blockade

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Strahlentherapie und Onkologie Aims and scope Submit manuscript

Background and Purpose:

Since the efficacy of a single targeted agent in combination with ionizing radiation is limited by putative treatment resistances, a rationally designed triple treatment consisting of an agonistic antibody targeting either TRAIL-R1 (mapatumumab) or TRAIL-R2 (lexatumumab), radiation and an epidermal growth factor receptor-(EGFR-)inhibiting antibody (cetuximab) was tested.

Material and Methods:

Induction of apoptosis after triple treatment was determined in Colo205, HCT116 and FaDu cells by Hoechst 33342 stain. The degree of interaction was determined by isobologram analysis. A knockout variant of HCT116 was used to examine Bax dependence of the triple treatment. The role of Akt/PKB signaling was analyzed using the phosphatidylinositol 3-kinase inhibitor LY294002. Clonogenic assays were performed to examine the effect on clonogenic survival of tumor cells.

Results:

A synergistic effect of radiation, cetuximab and agonistic TRAIL-R antibodies was demonstrated in cell lines derived from colorectal tumors or head-and-neck cancers. The efficacy of this multimodal approach was dependent on Bax and inhibition of Akt/PKB in the cell systems used. The results also show a positive impact on clonogenic cell death in several cell lines.

Conclusion:

These data suggest that rationally designed multimodal therapy approaches integrating radiation with more than one targeted agent will open new perspectives in radiation oncology.

Hintergrund und Ziel:

Die Wirkung einer Kombination von singulären molekular gezielten Substanzen mit ionisierender Strahlung kann durch Behandlungsresistenzen limitiert sein. Daher wurde geprüft, ob eine molekular gezielte Dreifachkombination, bestehend aus einem agonistischen Antikörper gegen entweder TRAIL-R1 (Mapatumumab) oder TRAIL-R2 (Lexatumumab) sowie einem Antikörper (Cetuximab) gegen den epidermalen Wachstumsfaktor-Rezeptor (EGFR), zur optimierten Tumorzellabtötung in vitro beitragen kann.

Material und Methodik:

Die Apoptoseinduktion nach Dreifachtherapie wurde in den Zelllinien Colo205, HCT116 und FaDu durch Hoechst-33342-Färbung bestimmt. Der Interaktionsgrad wurde mittels Isobologrammanalyse ermittelt. Eine Knock-out-Variante der Zelllinie HCT116 wurde verwendet, um die Bax-Abhängigkeit der Dreifachtherapie zu untersuchen. Die Rolle des Akt/PKB-Signalwegs wurde mit dem Phosphatidylinositol-3-Kinase-Inhibitor LY294002 analysiert. Koloniebildungstests wurden durchgeführt, um den Effekt auf das klonogene Überleben der Tumorzellen zu untersuchen.

Ergebnisse:

Ein synergistischer Effekt von Bestrahlung, Cetuximab und agonistischen TRAIL-R-Antikörpern ließ sich in Adeno- und Plattenepithelkarzinomzellsystemen nachweisen. Die Effektivität dieses multimodalen Ansatzes war abhängig von Bax und der Inhibierung von Akt/PKB. Parallel mit einer erhöhten Apoptoserate fand sich ein optimierte Eradikation klonogener Tumorzellen.

Schlussfolgerung:

Diese Daten deuten darauf hin, dass zielgerichtete multimodale Therapieansätze unter Einbeziehung mehrerer molekularer Zielstrukturen neue Perspektiven in der Radioonkologie eröffnen könnten.

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Authors and Affiliations

  1. Department of Radiation Oncology, CCC Tübingen, Tübingen, Germany

    Maximilian Niyazi, Patrizia Marini, Verena Jendrossek &  Claus Belka

  2. Clinical and Molecular Oncology, Charité, Campus Berlin-Buch, Humboldt University, Berlin, Germany

    Peter T. Daniel

  3. Oncology Research Department, Human Genome Sciences Inc., Rockville, MD, USA

    Robin Humphreys

  4. Department of Molecular Cell Biology, Essen, Germany

    Verena Jendrossek

  5. Department of Radiation Oncology, Ludwig Maximilian University, Munich, Germany

    Claus Belka

  6. Department of Radiation Oncology, Ludwig Maximilian University, Marchioninistraße 15, 81377, München, Germany

    Claus Belka

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  1. Maximilian Niyazi
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  2. Patrizia Marini
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  3. Peter T. Daniel
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  4. Robin Humphreys
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  5. Verena Jendrossek
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  6. Claus Belka
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Correspondence to Claus Belka.

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*Both authors contributed equally to the study.

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Niyazi, M., Marini, P., Daniel, P.T. et al. Efficacy of a Triple Treatment with Irradiation, Agonistic TRAIL Receptor Antibodies and EGFR Blockade. Strahlenther Onkol 185, 8–18 (2009). https://doi.org/10.1007/s00066-009-1856-4

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  • DOI: https://doi.org/10.1007/s00066-009-1856-4

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