Olaparib and temozolomide in desmoplastic small round cell tumors: a promising combination in vitro and in vivo.
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Date
2020-07-01ICR Author
Author
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
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
Cell Line, Tumor
Animals
Humans
Mice
Disease Models, Animal
Piperazines
Phthalazines
Nuclear Proteins
Antineoplastic Agents
Xenograft Model Antitumor Assays
Apoptosis
Cell Survival
Gene Expression
Drug Synergism
Adolescent
Adult
Child
Female
Male
Young Adult
Desmoplastic Small Round Cell Tumor
Poly(ADP-ribose) Polymerase Inhibitors
Poly (ADP-Ribose) Polymerase-1
Temozolomide
Research team
Sarcoma Molecular Pathology
Sarcoma Molecular Pathology
Language
eng
Date accepted
2020-04-03
Citation
Journal of cancer research and clinical oncology, 2020, 146 (7), pp. 1659 - 1670
Publisher
SPRINGER