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Clin Cancer Res. 2015 Feb 15;21(4):819-32. doi: 10.1158/1078-0432.CCR-14-2572. Epub 2014 Dec 10.

Synergistic activity of PARP inhibition by talazoparib (BMN 673) with temozolomide in pediatric cancer models in the pediatric preclinical testing program.

Author information

1
Cancer Therapy Evaluation Program, NCI, Bethesda, Maryland. Malcolm.Smith@nih.gov.
2
Texas Tech University Health Sciences Center, Lubbock, Texas.
3
A.I. duPont Hospital for Children, Wilmington, Delaware.
4
The Children's Hospital at Montefiore, Bronx, New York.
5
Children's Cancer Institute Australia for Medical Research, Randwick, New South Wales, Australia.
6
Duke University Medical Center, Durham, North Carolina.
7
Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine and Abramson Family Cancer Research Institute, Philadelphia, Pennsylvania.
8
St. Jude Children's Research Hospital, Memphis, Tennessee.
9
Nationwide Children's Hospital, Columbus, Ohio.

Abstract

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 stereo-selective 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 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.

RESULTS:

In vitro 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. 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.

PMID:
25500058
PMCID:
PMC4587665
DOI:
10.1158/1078-0432.CCR-14-2572
[Indexed for MEDLINE]
Free PMC Article

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