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- W4361951731 abstract "<div>Abstract<p><b>Purpose:</b> Inhibitors of PARP, an enzyme involved in base excision repair, have demonstrated single-agent activity against tumors deficient in homologous repair processes. Ewing sarcoma cells are also sensitive to PARP inhibitors, although the mechanism is not understood. Here, we evaluated the stereo-selective PARP inhibitor, talazoparib (BMN 673), combined with temozolomide or topotecan.</p><p><b>Experimental Design:</b> Talazoparib was tested in vitro in combination with temozolomide (0.3–1,000 μmol/L) or topotecan (0.03–100 nmol/L) and <i>in vivo</i> at a dose of 0.1 mg/kg administered twice daily for 5 days combined with temozolomide (30 mg/kg/daily x 5; combination A) or 0.25 mg/kg administered twice daily for 5 days combined with temozolomide (12 mg/kg/daily x 5; combination B). Pharmacodynamic studies were undertaken after 1 or 5 days of treatment.</p><p><b>Results:</b> <i>In vitro</i> talazoparib potentiated the toxicity of temozolomide up to 85-fold, with marked potentiation in Ewing sarcoma and leukemia lines (30–50-fold). There was less potentiation for topotecan. <i>In vivo</i>, talazoparib potentiated the toxicity of temozolomide, and combination A and combination B represent the MTDs when combined with low-dose or high-dose talazoparib, respectively. Both combinations demonstrated significant synergism against 5 of 10 Ewing sarcoma xenografts. The combination demonstrated modest activity against most other xenograft models. Pharmacodynamic studies showed a treatment-induced complete loss of PARP only in tumor models sensitive to either talazoparib alone or talazoparib plus temozolomide.</p><p><b>Conclusions:</b> The high level of activity observed for talazoparib plus temozolomide in Ewing sarcoma xenografts makes this an interesting combination to consider for pediatric evaluation. <i>Clin Cancer Res; 21(4); 819–32. ©2014 AACR</i>.</p></div>" @default.
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- W4361951731 date "2023-03-31" @default.
- W4361951731 modified "2023-09-26" @default.
- W4361951731 title "Data from Synergistic Activity of PARP Inhibition by Talazoparib (BMN 673) with Temozolomide in Pediatric Cancer Models in the Pediatric Preclinical Testing Program" @default.
- W4361951731 doi "https://doi.org/10.1158/1078-0432.c.6524004.v1" @default.
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