TY - JOUR
T1 - Synergistic activity of PARP inhibition by talazoparib (BMN 673) with temozolomide in pediatric Cancer Models in the Pediatric Preclinical Testing Program
AU - Smith, Malcolm A.
AU - Reynolds, C. Patrick
AU - Kang, Min H.
AU - Kolb, E. Anders
AU - Gorlick, Richard
AU - Carol, Hernan
AU - Lock, Richard B.
AU - Keir, Stephen T.
AU - Maris, John M.
AU - Billups, Catherine A.
AU - Lyalin, Dmitry
AU - Kurmasheva, Raushan T.
AU - Houghton, Peter J.
N1 - Publisher Copyright:
© 2014 American Association for Cancer Research.
PY - 2015/2/15
Y1 - 2015/2/15
N2 - Purpose: 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 stereoselective PARP inhibitor, talazoparib (BMN 673), combined with temozolomide or topotecan. Experimental Design: Talazoparib was tested in vitro in combination with temozolomide (0.3-1,000 μmol/L) or topotecan (0.03-100 nmol/L) and in vivo at a dose of 0.1 mg/kg administered twice daily for 5 days combined with temozolomide (30 mg/kg/daily × 5; combination A) or 0.25 mg/kg administered twice daily for 5 days combined with temozolomide (12 mg/kg/daily × 5; combination B). Pharmacodynamic studies were undertaken after 1 or 5 days of treatment. Results: In vitro talazoparib potentiated the toxicity of temo-zolomide up to 85-fold, with marked potentiation in Ewing sarcoma and leukemia lines (30-50-fold). There was less potentiation for topotecan. In vivo, 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. Conclusions: The high level of activity observed for talazoparib plus temozolomide in Ewing sarcoma xenografts makes this an interesting combination to consider for pediatric evaluation.
AB - Purpose: 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 stereoselective PARP inhibitor, talazoparib (BMN 673), combined with temozolomide or topotecan. Experimental Design: Talazoparib was tested in vitro in combination with temozolomide (0.3-1,000 μmol/L) or topotecan (0.03-100 nmol/L) and in vivo at a dose of 0.1 mg/kg administered twice daily for 5 days combined with temozolomide (30 mg/kg/daily × 5; combination A) or 0.25 mg/kg administered twice daily for 5 days combined with temozolomide (12 mg/kg/daily × 5; combination B). Pharmacodynamic studies were undertaken after 1 or 5 days of treatment. Results: In vitro talazoparib potentiated the toxicity of temo-zolomide up to 85-fold, with marked potentiation in Ewing sarcoma and leukemia lines (30-50-fold). There was less potentiation for topotecan. In vivo, 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. Conclusions: The high level of activity observed for talazoparib plus temozolomide in Ewing sarcoma xenografts makes this an interesting combination to consider for pediatric evaluation.
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U2 - 10.1158/1078-0432.CCR-14-2572
DO - 10.1158/1078-0432.CCR-14-2572
M3 - Article
C2 - 25500058
AN - SCOPUS:84923164096
SN - 1078-0432
VL - 21
SP - 819
EP - 832
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 4
ER -