Abstract 592: Preclinical evaluation of the PARP inhibitor veliparib (ABT-888) in combination with cytotoxic chemotherapy in acute myeloid leukemia.

Abstract

Abstract Genomic instability and impaired DNA repair are features of acute myeloid leukemia (AML). DNA damaging agents such as cyclophosphamide and anthracyclines exert their antileukemic activity by generating widespread genomic damage, coupled with inefficient DNA repair, and ultimately apoptosis. Poly(ADP-ribose) polymerase (PARP) enzymes are important in recognizing and catalyzing DNA repair, particularly in cells with impaired double stranded DNA (ds-DNA) repair. Veliparib (ABT-888) is a potent, orally bioavailable small molecule inhibitor of PARP-1 and PARP-2. We hypothesized that the ABT-888 would exploit DNA repair defects in AML cell lines and enhance cytotoxicity when combined with cyclophosphamide and idarubicin. Leukemic cell lines were exposed to escalating doses of ABT-888 (50 - 5000 nM) alone and in combination with idarubicin hydrochloride (ida)(1 - 30 nM), or 4-hydroperoxycyclophosphamide (4-HC)(1 - 6 micromolar) at various time points (24, 48 & 72 hrs) and sequences. Cell viability was measured by XTT cell proliferation assay and trypan blue exclusion. Apoptosis was measured by Annexin V flow cytometry. Cell cycle analysis was measured via propium iodide flow cytometry. Measurement PAR polymerization was performed with a standard ELISA assay. ABT-888 potently inhibited PAR polymerization (<10% of control) in HL60 cells at achievable serum concentration (200 nM) at 24, 48, & 72 hrs, both alone and in combination with chemotherapy. Single-agent ABT-888 had modest activity in inhibiting HL60 viability and inducing apoptosis, with an IC50 in the high micromolar range. Exposure of HL60 cell lines to increasing doses of ida or 4-HC led to dose dependent decrease in viability, increased apoptosis, and cell cycle perturbation. Simultaneous treatment with increasing doses of ABT-888 (40-500 nM) did not significantly increase cytotoxicity or apoptosis and had no effect on cell cycle beyond chemotherapy alone. Additional leukemia cell lines tested (OCI-AML3, K562, NB4) yielded similar results. The sequence of administration was then investigated. When ABT-888 (200 nM) was introduced prior to the cytotoxic drug, there appeared to be antagonism, with reduced cytotoxicity at each dose level for the combination, compared to chemotherapy alone. When the ABT-888 followed the cytotoxic drug, results were similar to simultaneous administration. The interaction between PARP inhibitors and cytotoxic chemotherapy in AML cell lines appears to be schedule dependent. Further studies to define the optimal schedule, drug combination, and susceptible cell types, including those with defective ds-DNA repair are needed. Citation Format: Tapan Kadia, Sara McCay, Hui Yang, Irene Ganan-Gomez, Yue Wei, Guillermo Garcia-Manero. Preclinical evaluation of the PARP inhibitor veliparib (ABT-888) in combination with cytotoxic chemotherapy in acute myeloid leukemia. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 592. doi:10.1158/1538-7445.AM2013-592