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

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 0.1 nM to 1 μM and in vivo at a daily dose of 0.33 mg/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 25.8 nM. The median rIC50 for the Ewing cell lines was lower than for the remaining cell lines (6.4 vs. 31.1 nM, 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.

Keywords: PALB2; PARP inhibitor; developmental therapeutics; preclinical testing.

Figure 1

(A) Correlation between SLFN11 expression values (x-axis) and Relative I/O values expressed numerically rather than as percents (ranging from -1.0 as complete cytotoxicity to +1.0 as no treatment effect, with 0 as cytostasis). (B) Median Relative I/O values for PPTP cell lines for lines with low SLFN11 expression (median).

Figure 2

Left: The colored heat map depicts group response scores. A high level of activity is indicated by a score of 6 or more, intermediate activity by a score of ≥2 but <6, and low activity by a score of <2. Right: representation of tumor sensitivity based on the difference of individual tumor lines from the midpoint response (stable disease). Bars to the right of the median represent lines that are more sensitive, and to the left are tumor models that are less sensitive. Red bars indicate lines with a significant difference in EFS distribution between treatment and control groups, while blue bars indicate lines for which the EFS distributions were not significantly different.

Figure 3

Sensitivity of KT-10 xenografts to BMN 673. A, Control; B, 0.1625 mg/kg BID (M-F) and 0.33 mg/g SID at weekends; C, 0.1 mg/kg BID and 0.2 SID; D, 0.05 mg/kg BID and 0.1 mg/kg SID on weekends. Mice were treated for 28 days.

Figure 4

Disease-associated mutations in PALB2, including the c.3323delA (p.Y1108fs) mutation observed for KT-10. Frame shift and nonsense mutations are depicted above the PALB2 protein schematic, while missense mutations are shown below. Breast-cancer associated mutations are shown in purple font, Fanconi anemia mutations in red font, pancreatic cancer mutations in green font, and ovarian cancer mutations in blue font. A listing of mutations and references is provided in Supplemental Table IV.