Abstract B62: Potent single agent in vivo activity of the PARP inhibitor veliparib (ABT-888) in BRCA-deficient xenografts (MX-1 and Capan-1).

Abstract

Abstract PARP's role in DNA damage recognition/repair makes PARP inhibition an attractive cancer therapeutic target. Veliparib (ABT-888) is a potent PARP inhibitor with excellent oral bioavailability that readily crosses the blood-brain barrier and is currently in Phase 2 clinical trials. Veliparib has shown significant ability to potentiate multiple DNA damaging agents (cisplatin, carboplatin, cyclophosphamide, irinotecan, radiation and temozolomide) in a spectrum of tumors from multiple histological types. In studies using cytotoxic combinations with veliparib (cisplatin, cyclophosphamide, TMZ) there was a marked increase in efficacy over cytotoxic monotherapies, especially in the MX-1 breast model. Since DNA repair deficiencies (e.g. HR-defective) are known to render cells very sensitive to PARP inhibition, we genotyped the MX-1 breast line and found it to be HR-deficient. Subsequent studies with both the MX-1 (BRCA1-deleted and BRCA2-mutated breast line) and the Capan-1 (BRCA2-deficient pancreatic cancer cell line), showed that veliparib (25 mg/kg/day, p.o., b.i.d.×5) demonstrated enhancement of TMZ (50 mg/kg/day, p.o., q.d.×5) activity, with regressions compared to TMZ alone (81–97% TGI, tumor growth inhibition). Continuous dosing at 4×-8× higher doses (100 and 200 mg/kg/day, p.o., b.i.d.×21) demonstrated a significant single agent, dose-responsive activity (26–87% TGI). Similar results were observed with single agent veliparib treatment of BRCA isogenic cell lines in vitro. Further, the combination treatment of veliparib (100 and 200 mg/kg/day, p.o., b.i.d.×21) with carboplatin, carbotaxol, radiation, gemcar, cyclophosphamide, topotecan and TMZ also demonstrated a measurable advantage over either veliparib or cytotoxic agent alone. Both high dose single agent veliparib and the cytotoxic combination therapy were well tolerated and there were no observable animal health concerns; this indicated the feasibility of using the single agent and cytotoxic combination regimen in the clinic. Analysis of tumors for the reduction of PAR after veliparib treatment demonstrated a correlative and significant reduction by western blot indicating the ability of veliparib to inhibit PARP activity in vivo. Altogether, our studies show the strong activity of veliparib as a single agent in BRCA-deficient xenografts as well as the enhanced activity and tolerability of veliparib in combination with various cytotoxic agents. These results warrant investigation of single agent therapy and cytotoxic combination regimens in BRCA-deficient patients to further the clinical development of veliparib. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B62.