Initial testing (stage 1) of the PARP inhibitor BMN 673 by the pediatric preclinical testing program: PALB2 mutation predicts exceptional in vivo response to BMN 673

Malcolm A. Smith, Oliver A. Hampton, C. Patrick Reynolds, Min H. Kang, John M. Maris, Richard Gorlick, E. Anders Kolb, Richard Lock, Hernan Carol, Stephen T. Keir, Jianrong Wu, Raushan T. Kurmasheva, David A. Wheeler, Peter J. Houghton

Research output: Contribution to journalArticle

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Abstract

Background: BMN 673 is a potent inhibitor of poly-ADP ribose polymerase (PARP) that is in clinical testing with a primary focus on BRCA-mutated cancers. BMN 673 is active both through inhibiting PARP catalytic activity and by tightly trapping PARP to DNA at sites of single strand breaks. Procedure: BMN 673 was tested in vitro at concentrations ranging from 0.1nM to 1μM and in vivo at a daily dose of 0.33mg/kg administered orally twice daily (Mon-Fri) and once daily on weekends (solid tumors) for 28 days. Results: The median relative IC50 (rIC50) concentration against the PPTP cell lines was 25.8nM. The median rIC50 for the Ewing cell lines was lower than for the remaining cell lines (6.4 vs. 31.1nM, respectively). In vivo BMN 673 induced statistically significant differences in EFS distribution in 17/43 (39.5%) xenograft models. Three objective regressions were observed: a complete response (CR) in a medulloblastoma line (BT-45), a maintained CR in a Wilms tumor line (KT-10), and a maintained CR in an ependymoma line (BT-41). BMN 673 maintained its high level of activity against KT-10 with a threefold reduction in dose. KT-10 possesses a truncating mutation in PALB2 analogous to PALB2 mutations associated with hereditary breast and ovarian cancer that abrogate homologous recombination (HR) repair. Conclusions: The PPTP results suggest that single agent BMN 673 may have limited clinical activity against pediatric cancers. Single agent activity is more likely for patients whose tumors have defects in HR repair.

Original languageEnglish (US)
Pages (from-to)91-98
Number of pages8
JournalPediatric Blood and Cancer
Volume62
Issue number1
DOIs
StatePublished - Jan 1 2015

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Pediatrics
Mutation
Recombinational DNA Repair
Poly(ADP-ribose) Polymerases
Cell Line
Inhibitory Concentration 50
Neoplasms
Ependymoma
Medulloblastoma
Wilms Tumor
Heterografts
Ovarian Neoplasms
talazoparib
Poly(ADP-ribose) Polymerase Inhibitors
Breast Neoplasms
DNA
N-propyl-4-phenyl-1,2,3,6-tetrahydropyridine

Keywords

  • Developmental therapeutics
  • PALB2
  • PARP inhibitor
  • Preclinical testing

ASJC Scopus subject areas

  • Oncology
  • Pediatrics, Perinatology, and Child Health
  • Hematology
  • Medicine(all)

Cite this

Initial testing (stage 1) of the PARP inhibitor BMN 673 by the pediatric preclinical testing program : PALB2 mutation predicts exceptional in vivo response to BMN 673. / Smith, Malcolm A.; Hampton, Oliver A.; Reynolds, C. Patrick; Kang, Min H.; Maris, John M.; Gorlick, Richard; Kolb, E. Anders; Lock, Richard; Carol, Hernan; Keir, Stephen T.; Wu, Jianrong; Kurmasheva, Raushan T.; Wheeler, David A.; Houghton, Peter J.

In: Pediatric Blood and Cancer, Vol. 62, No. 1, 01.01.2015, p. 91-98.

Research output: Contribution to journalArticle

Smith, MA, Hampton, OA, Reynolds, CP, Kang, MH, Maris, JM, Gorlick, R, Kolb, EA, Lock, R, Carol, H, Keir, ST, Wu, J, Kurmasheva, RT, Wheeler, DA & Houghton, PJ 2015, 'Initial testing (stage 1) of the PARP inhibitor BMN 673 by the pediatric preclinical testing program: PALB2 mutation predicts exceptional in vivo response to BMN 673', Pediatric Blood and Cancer, vol. 62, no. 1, pp. 91-98. https://doi.org/10.1002/pbc.25201
Smith, Malcolm A. ; Hampton, Oliver A. ; Reynolds, C. Patrick ; Kang, Min H. ; Maris, John M. ; Gorlick, Richard ; Kolb, E. Anders ; Lock, Richard ; Carol, Hernan ; Keir, Stephen T. ; Wu, Jianrong ; Kurmasheva, Raushan T. ; Wheeler, David A. ; Houghton, Peter J. / Initial testing (stage 1) of the PARP inhibitor BMN 673 by the pediatric preclinical testing program : PALB2 mutation predicts exceptional in vivo response to BMN 673. In: Pediatric Blood and Cancer. 2015 ; Vol. 62, No. 1. pp. 91-98.
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abstract = "Background: BMN 673 is a potent inhibitor of poly-ADP ribose polymerase (PARP) that is in clinical testing with a primary focus on BRCA-mutated cancers. BMN 673 is active both through inhibiting PARP catalytic activity and by tightly trapping PARP to DNA at sites of single strand breaks. Procedure: BMN 673 was tested in vitro at concentrations ranging from 0.1nM to 1μM and in vivo at a daily dose of 0.33mg/kg administered orally twice daily (Mon-Fri) and once daily on weekends (solid tumors) for 28 days. Results: The median relative IC50 (rIC50) concentration against the PPTP cell lines was 25.8nM. The median rIC50 for the Ewing cell lines was lower than for the remaining cell lines (6.4 vs. 31.1nM, respectively). In vivo BMN 673 induced statistically significant differences in EFS distribution in 17/43 (39.5{\%}) xenograft models. Three objective regressions were observed: a complete response (CR) in a medulloblastoma line (BT-45), a maintained CR in a Wilms tumor line (KT-10), and a maintained CR in an ependymoma line (BT-41). BMN 673 maintained its high level of activity against KT-10 with a threefold reduction in dose. KT-10 possesses a truncating mutation in PALB2 analogous to PALB2 mutations associated with hereditary breast and ovarian cancer that abrogate homologous recombination (HR) repair. Conclusions: The PPTP results suggest that single agent BMN 673 may have limited clinical activity against pediatric cancers. Single agent activity is more likely for patients whose tumors have defects in HR repair.",
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AU - Hampton, Oliver A.

AU - Reynolds, C. Patrick

AU - Kang, Min H.

AU - Maris, John M.

AU - Gorlick, Richard

AU - Kolb, E. Anders

AU - Lock, Richard

AU - Carol, Hernan

AU - Keir, Stephen T.

AU - Wu, Jianrong

AU - Kurmasheva, Raushan T.

AU - Wheeler, David A.

AU - Houghton, Peter J.

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N2 - Background: BMN 673 is a potent inhibitor of poly-ADP ribose polymerase (PARP) that is in clinical testing with a primary focus on BRCA-mutated cancers. BMN 673 is active both through inhibiting PARP catalytic activity and by tightly trapping PARP to DNA at sites of single strand breaks. Procedure: BMN 673 was tested in vitro at concentrations ranging from 0.1nM to 1μM and in vivo at a daily dose of 0.33mg/kg administered orally twice daily (Mon-Fri) and once daily on weekends (solid tumors) for 28 days. Results: The median relative IC50 (rIC50) concentration against the PPTP cell lines was 25.8nM. The median rIC50 for the Ewing cell lines was lower than for the remaining cell lines (6.4 vs. 31.1nM, respectively). In vivo BMN 673 induced statistically significant differences in EFS distribution in 17/43 (39.5%) xenograft models. Three objective regressions were observed: a complete response (CR) in a medulloblastoma line (BT-45), a maintained CR in a Wilms tumor line (KT-10), and a maintained CR in an ependymoma line (BT-41). BMN 673 maintained its high level of activity against KT-10 with a threefold reduction in dose. KT-10 possesses a truncating mutation in PALB2 analogous to PALB2 mutations associated with hereditary breast and ovarian cancer that abrogate homologous recombination (HR) repair. Conclusions: The PPTP results suggest that single agent BMN 673 may have limited clinical activity against pediatric cancers. Single agent activity is more likely for patients whose tumors have defects in HR repair.

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