Abstract
PurposeDesmoplastic 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.MethodsPARP1 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.ResultsPARP1 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.ConclusionWe 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.
Highlights
Desmoplastic small round cell tumors (DSRCTs) are very rare soft tissue sarcomas (STS) with an incidence rate of 0.2–0.5/million
Since previous research showed that single-agent PARPtargeted treatment did not elicit high responses in ES patients (Choy et al 2014; Vormoor and Curtin 2014) and combination treatment using the alkylating agent temozolomide (TMZ) led to a synergistic effect in ES in vitro, a complete tumor regression and reduction of lung metastases in ES in vivo, and a clinical trial is currently examining the combination (NCT01858168), we examined the combined effect of Poly(ADP-ribose) polymerase (PARP) inhibitor olaparib and TMZ in DSRCTs (Brenner et al 2012; Engert et al 2015; Gill et al 2015; Ordonez et al 2015; Smith et al 2015; Stewart et al 2014)
To examine the presence of poly(ADP-ribose) polymerase 1 (PARP1) in DSRCT tumor tissue, PARP1 expression was assessed by immunohistochemistry
Summary
Desmoplastic small round cell tumors (DSRCTs) are very rare soft tissue sarcomas (STS) with an incidence rate of 0.2–0.5/million. The treatment of DSRCTs consists of intensive combination chemotherapy, when possible, surgery—sometimes combined with hyperthermic intraperitoneal chemotherapy (HIPEC)—and on indication radiotherapy, including whole abdominal irradiation. These treatments can be toxic and despite the fact that a small subset of patients shows a good response to treatment, this response is relatively short lasting (HayesJordan et al 2016). Second-line treatment for patients with recurrent disease that have been used are vascular endothelial growth factor (receptor) (VEGF(R))-, mammalian target of rapamycin (mTOR)-, and platelet-derived growth factor receptor (PDGFR)-based targeted therapy These treatments can again induce favorable, short-lived, responses (Chen and Feng 2019; Italiano et al 2013; Menegaz et al 2018; Tarek et al 2018; Thijs et al 2010). Treatment results in a 5-year overall survival (OS) rate of 15–25%, which shows the high unmet need for novel treatments in DSRCTs (Bent et al 2016; Subbiah et al 2018)
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