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Identification of glioblastoma patients who stand to benefit from PARP inhibitor therapy.

Year: 2015
Type: conference-abstract
Abstract: 2071 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. Methods: Efficacy of veliparib in combination with radiotherapy (RT) was tested on a panel of primary and recurrent GBM patient-derived cell lines (PDCLs). In order to screen for potential biomarkers for PARPi we performed whole genome sequencing (WGS) on sensitive and resistant PDCLs and also measured the expression of 96 candidate DNA repair pathway genes using the RT2 Profiler PCR Array (Human DNA Repair; Qiagen) Results: Differential sensitivity to veliparib and RT were observed amongst the panel of PDCLs. Three out of sixteen PDCLs showed hypersensitivity to veliparib/RT. PDCLs sensitive to treatment exhibited a large number of structural variation (SV) events ( > 200). The average SV events identified in the resistant PDCLs were < 50. We detected mutations in genes involved in mismatch repair (MMR): 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 only in the sensitive PDCLs. Conclusions: 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.
DOI: 10.1200/jco.2015.33.15_suppl.2071
Language: English
Subfield: Oncology
Field: Medicine
Open Access status: green
OpenAlex ID: W2601993771
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