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

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ICR Authors

Shipley, Janet

Authors

van Erp, AEM
van Houdt, L
Hillebrandt-Roeffen, MHS
van Bree, NFHN
Flucke, UE
Mentzel, T
Shipley, J
Desar, IME
Fleuren, EDG
Versleijen-Jonkers, YMH
van der Graaf, WTA

Document Type

Journal Article

Date

2020-07-01

Date Accepted

2020-04-03

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.

Citation

Journal of cancer research and clinical oncology, 2020, 146 (7), pp. 1659 - 1670

DOI

10.1007/s00432-020-03211-z

URI

https://repository.icr.ac.uk/handle/internal/4351

Rights

https://creativecommons.org/licenses/by/4.0

Source Title

Publisher

SPRINGER

ISSN

0171-5216

eISSN

1432-1335

Collections

Cancer Therapeutics
Molecular Pathology

Research Team

Sarcoma Molecular Pathology
Sarcoma Molecular Pathology

Notes