Abstract A12: Genomically unstable glioblastoma are sensitive to Parp inhibition
McDonald, KL; Khasraw, M; Jue, TR; Joshi, S; Yin, J
Published in: Cancer Research
Background: The development of effective targeted drugs for the treatment of glioblastoma (GBM) represents a major unmet need. Veliparib (ABT-888; Abbvie) inhibits both PARP1 and PARP2 (poly[ADP-ribose] polymerase). The successful clinical application of veliparib and other PARP inhibitors (PARPi) will be assisted by the identification of predictive biomarkers.Materials and Methods: We performed whole genome sequencing (WGS) on ten GBM specimens with matched normal DNA. Mutations were detected using qSNP and GATK and indels called with Pindel and GATK. Somatic structural variants were identified using the qSV package. For all ten specimens we developed patient derived cell lines (PDCLs). We tested the efficacy of the combination of veliparib and temozolomide (TMZ) on all of the PDCLs.Results: Strikingly, in 2 patient samples denoted as G89 and G54, the mutation rate was at least 16-fold higher compared to the other 8 participants. G89 and G54 exhibited a large number of single nucleotide variants (SNVs), insertions, deletions and structural variant (SV) events (>2 million) when compared to the other 8 patient samples. The scale of genomic instability suggested defects in DNA maintenance, which could potentially define sensitivity to DNA damaging agents. Upon closer examination of the mutational profile of G89 and G54, mutations were found in at least one of the mismatch repair (MMR) genes: MLH1, MSH2, MSH6 and PMS2. We also detected mutations in other genes involved in DNA maintenance such as XRCC4, FANCA, FANCD2, ATR, RPA1, REV3L and PARP1. We designated these patients' GBM as U-GBM class. We found the U-GBM class of tumors, G89 and G54 to be hypersensitive to the combination of TMZ/veliparib.Conclusion: Mutations in DNA maintenance pathways may be a method for selecting patients for therapies involving the combination of DNA damaging agents such as radiotherapy, and PARP inhibitors. Additionally, the signature associated with genomically unstable GBM may be a method of identifying potential responders to PARP inhibitor therapy.Citation Format: Kerrie L. McDonald, Mustafa Khasraw, Toni Rose Jue, Swapna Joshi, Julia Yin. Genomically unstable glioblastoma are sensitive to Parp inhibition. [abstract]. In: Proceedings of the AACR Special Conference: Advances in Brain Cancer Research; May 27-30, 2015; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2015;75(23 Suppl):Abstract nr A12.
