Introduction: BMN 673 is a potent and selective inhibitor of PARP1/2. Inhibitors of PARP such as BMN 673 show clinical activity against cancers lacking homologous repair through mutations in BRCA1 and 2. For Ewing sarcoma (ES), the EWS/FLI1 chimeric transcription factor increases PARP expression, and PARP appears to facilitate EWS/FLI1 function. Two reports have indicated that ES cell lines are more sensitive to PARP inhibitors than most other cell lines.
Methods: BMN 673 was evaluated as a single agent and in combination with TMZ against the 23 cell lines of the PPTP in vitro panel using 96 hour exposure. In single-agent studies, daily oral BMN 673 administration was tested against the PPTP solid tumor xenografts (SCID mice) and acute lymphoblastic leukemia (ALL; NOD-SCID mice) panels using a dose of 0.16 mg/kg BID x 5 and 0.33 mg/kg QD on weekends for up to 28 days. In combination studies, two dose levels of BMN 673 (0.25 & 0.1 mg/kg BID x 5 days) given with TMZ (12 & 30 mg/kg/day x 5 days, respectively) were evaluated against ES xenografts. Standard PPTP measures of in vivo antitumor activity were employed to assess response.
Results: The median relative IC50 (rIC50) for BMN 673 against the PPTP cell lines was 28 nM, with a range from 4 nM to >1000 nM. There was a trend for lower rIC50 values for the ES cell line panel. In combination with a fixed concentration of BMN 673 (10 nM), the TMZ rIC50 was markedly reduced for some PPTP cell lines, with ES cell lines showing up to a 60-fold reduction. In vivo, BMN 673 was well tolerated with only a 1.9% toxicity rate in the treated groups. BMN 673 induced significant improvements in event-free survival (EFS) distribution compared to control in 18 of 35 (51%) of the evaluable solid tumor xenografts, but in 0 of 8 ALL models. Only 2 of 34 (6%) evaluable solid tumor xenografts and no ALL models showed EFS T/C values > 2. Complete responses (CR) were observed for a Wilms tumor and a medulloblastoma model.
BMN 673 in combination with TMZ induced CRs that were maintained through week 12 for 2 of 4 ES xenografts (TMZ dosed at either 12 or 30 mg/kg/day). Among an additional 6 ES xenografts that have recently initiated testing, 3 have ongoing CRs to the combination at Weeks 4 to 5. None of the ES xenografts responded to 5 days of treatment with single agent TMZ (30 mg/kg) or BMN 673 (0.5 mg/kg/day).
Conclusions: Single agent BMN 673 shows limited activity against the PPTP solid tumor and ALL models, with no single agent activity against ES xenografts in vivo, despite ES cell lines demonstrating differential sensitivity in vitro. BMN 673 as a single agent induced CRs in 2 of 43 models, both of which are also highly responsive to cisplatin. Dramatic activity for the BMN 673 plus TMZ combination was observed for 5 of 10 ES models, with maintained CRs noted in vivo at TMZ doses as low as 12 mg/kg. Based on these results a pediatric phase 1 trial of BMN 673 plus TMZ is planned. (Supported by NO1-CM-42216)
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C206.
Citation Format: Malcolm Smith, Min Kang, Patrick Reynolds, Richard Gorlick, Anders Kolb, John Maris, Richard Lock, Hernan Carol, Stephen Keir, Catherine Billups, Raushan Kurmasheva, Peter Houghton. Pediatric Preclinical Testing Program (PPTP) evaluation of BMN 673, an inhibitor of Poly-ADP Ribose Polymerase (PARP), alone and with Temozolomide (TMZ). [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C206.