Synergistic activity of PARP inhibition by talazoparib (BMN 673) with temozolomide in pediatric Cancer Models in the Pediatric Preclinical Testing Program

Malcolm A. Smith, C. Patrick Reynolds, Min H. Kang, E. Anders Kolb, Richard Gorlick, Hernan Carol, Richard B. Lock, Stephen T. Keir, John M. Maris, Catherine A. Billups, Dmitry Lyalin, Raushan T. Kurmasheva, Peter J. Houghton

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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 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.

Original languageEnglish (US)
Pages (from-to)819-832
Number of pages14
JournalClinical Cancer Research
Volume21
Issue number4
DOIs
StatePublished - Feb 15 2015

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temozolomide
Pediatrics
Ewing's Sarcoma
Topotecan
Neoplasms
Heterografts
talazoparib
Enzyme Inhibitors

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Synergistic activity of PARP inhibition by talazoparib (BMN 673) with temozolomide in pediatric Cancer Models in the Pediatric Preclinical Testing Program. / Smith, Malcolm A.; Reynolds, C. Patrick; Kang, Min H.; Kolb, E. Anders; Gorlick, Richard; Carol, Hernan; Lock, Richard B.; Keir, Stephen T.; Maris, John M.; Billups, Catherine A.; Lyalin, Dmitry; Kurmasheva, Raushan T.; Houghton, Peter J.

In: Clinical Cancer Research, Vol. 21, No. 4, 15.02.2015, p. 819-832.

Research output: Contribution to journalArticle

Smith, MA, Reynolds, CP, Kang, MH, Kolb, EA, Gorlick, R, Carol, H, Lock, RB, Keir, ST, Maris, JM, Billups, CA, Lyalin, D, Kurmasheva, RT & Houghton, PJ 2015, 'Synergistic activity of PARP inhibition by talazoparib (BMN 673) with temozolomide in pediatric Cancer Models in the Pediatric Preclinical Testing Program', Clinical Cancer Research, vol. 21, no. 4, pp. 819-832. https://doi.org/10.1158/1078-0432.CCR-14-2572
Smith, Malcolm A. ; Reynolds, C. Patrick ; Kang, Min H. ; Kolb, E. Anders ; Gorlick, Richard ; Carol, Hernan ; Lock, Richard B. ; Keir, Stephen T. ; Maris, John M. ; Billups, Catherine A. ; Lyalin, Dmitry ; Kurmasheva, Raushan T. ; Houghton, Peter J. / Synergistic activity of PARP inhibition by talazoparib (BMN 673) with temozolomide in pediatric Cancer Models in the Pediatric Preclinical Testing Program. In: Clinical Cancer Research. 2015 ; Vol. 21, No. 4. pp. 819-832.
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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 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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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.

PY - 2015/2/15

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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.

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