Abstract 3777: Combining VELIPARIB (ABT-888) with temozolomide shows strong synergy when treating temozolomide-resistant and recurrent GBM cell lines

Introduction: The survival trends for glioblastoma (GBM) patients have remained largely static, reflecting lack of improvement in the therapeutic options for patients. Less than 5% of newly diagnosed GBM survive more than 5 years. Standard treatment for GBM comprises of radiotherapy and temozolomide (TMZ) chemotherapy (chemoradiotherapy). Methylation of the promoter region of MGMT has been shown to be predictive of response to chemoradiotherapy. Approximately 30% of GBM are MGMT methylated. ABT-888 (Veliparib; Abbvie) is a Poly (ADP-ribose) polymerase (PARP) inhibitor that has been shown to enhance response of GBM to chemoradiotherapy in MGMT methylated patients. However, despite response (and lack of response in the case of MGMT unmethylated patients), recurrent GBM is refractory to treatment, occurring 2-3cm from the original resection and patient die within few months after recurrence. Herein we demonstrate the use of ABT-888 might be effective in patients who have recurrent GBM.Methods: We tested ABT-888 alone and in combination with TMZ on low passage patient derived cell lines cultured from patients with recurrent GBM. We have used low passage patient derived cells including BAH and HW that are MGMT methylated. We also used U87, U251 and LN229 that are immortalized cells that are MGMT methylated. Of these lines, only U251 harbors a mutation in the binding domain of TP53. We also tested MGMT methylated low passage patient derived cell lines where TMZ resistance was selected for through continuous TMZ treatment of the cell line.Results: Consistent with previous studies, monotherapy with ABT-888 was largely ineffective on all of the cell lines. We combined a low dose of ABT-888 (5μM) with a range of TMZ concentrations. Combination treatment was highly efficacious with sensitivity to TMZ improved by 30-70% when tested in 5 recurrent cell lines. All cell lines were MGMT unmethylated. We continuously treated 3 cell lines (2 MGMT methylated and 1 MGMT unmethylated) with TMZ until resistance was achieved. We found a response to the ABT-888/ TMZ combination was dramatic. Cells were 75% more sensitive to ABT-888/TMZ compared to retreatment with TMZ.Conclusion: This novel strategy of combining ABT-888 with TMZ demonstrated synergistic antitumor activity for the treatment of relapsed and/or “chemo-resistant” GBM cell lines. Further investigation of this synergy has potential for rapid translation into clinical studies.Citation Format: Kerrie McDonald, Kyoko Nozue-Okada, Mustafa Khasraw. Combining VELIPARIB (ABT-888) with temozolomide shows strong synergy when treating temozolomide-resistant and recurrent GBM cell lines. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3777. doi:10.1158/1538-7445.AM2014-3777

Duke Scholars

Author Mustafa Khasraw Neurosurgery