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Journal of Cancer Research and Clinical Oncology

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Open Access 01-07-2020 | Original Article – Cancer Research

Olaparib and temozolomide in desmoplastic small round cell tumors: a promising combination in vitro and in vivo

Authors: Anke E. M. van Erp, Laurens van Houdt, Melissa H. S. Hillebrandt-Roeffen, Niek F. H. N. van Bree, Uta E. Flucke, Thomas Mentzel, Janet Shipley, Ingrid M. E. Desar, Emmy D. G. Fleuren, Yvonne M. H. Versleijen-Jonkers, Winette T. A. van der Graaf

Published in: Journal of Cancer Research and Clinical Oncology | Issue 7/2020

Abstract

Purpose

Desmoplastic small round cell tumors (DSRCTs) are highly malignant and very rare soft tissue sarcomas with a high unmet need for new therapeutic options. Therefore, we examined poly(ADP-ribose) polymerase 1 (PARP1) and Schlafen-11 (SLFN11) expression in DSRCT tumor tissue and the combination of PARP inhibitor olaparib with the alkylating agent temozolomide (TMZ) in a preclinical DSRCT model.

Methods

PARP1 and SLFN11 have been described as predictive biomarkers for response to PARP inhibition. Expression of PARP1 and SLFN11 was assessed in 16 and 12 DSRCT tumor tissue samples, respectively. Effects of single-agent olaparib, and olaparib and TMZ combination treatment were examined using the preclinical JN-DSRCT-1 model. In vitro, single-agent and combination treatment effects on cell viability, the cell cycle, DNA damage and apoptosis were examined. Olaparib and TMZ combination treatment was also assessed in vivo.

Results

PARP1 and SLFN11 expression was observed in 100% and 92% of DSRCT tumor tissues, respectively. Olaparib treatment reduced cell viability and cell migration in a dose-dependent manner in vitro. Drug synergy between olaparib and TMZ was observed in vitro and in vivo. Combination treatment led to a cell-cycle arrest and induction of DNA damage and apoptosis, even when combined at low dosages.

Conclusion

We show high PARP1 and SLFN11 expression in DSRCT tumor material and antitumor effects following olaparib and TMZ combination treatment in a preclinical DSRCT model. This suggests that olaparib and TMZ combination treatment could be a potential treatment option for DSRCTs.

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Title: Olaparib and temozolomide in desmoplastic small round cell tumors: a promising combination in vitro and in vivo
Authors: Anke E. M. van Erp
Laurens van Houdt
Melissa H. S. Hillebrandt-Roeffen
Niek F. H. N. van Bree
Uta E. Flucke
Thomas Mentzel
Janet Shipley
Ingrid M. E. Desar
Emmy D. G. Fleuren
Yvonne M. H. Versleijen-Jonkers
Winette T. A. van der Graaf
Publication date: 01-07-2020
Publisher: Springer Berlin Heidelberg
Published in: Journal of Cancer Research and Clinical Oncology / Issue 7/2020
Print ISSN: 0171-5216
Electronic ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-020-03211-z

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Conclusion

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