Abstract 3218: Molecular function of PARP inhibition in glioblastoma

Abstract

Abstract Glioblastoma (GBM) is the most common primary malignant brain tumor, whose major biomarkers are the DNA methylation status of the promoter for O6-methylguanine-DNA-methyltransferase (MGMT) and the loss/mutation of the tumor suppressor phosphatase and tensin homolog (PTEN). Despite treatment combining surgery, radiotherapy and chemotherapy with the alkylating agent temozolomide (TMZ), patient survival remains poor and recurrence is virtually inevitable, due to TMZ resistance. Poly(ADP-ribose)polymerase-1 (PARP-1) is a nuclear protein involved in multiple facets of DNA repair and transcriptional regulation. This enzyme catalyses the transfer and polymerization of ADP ribose units from NAD+ to form branched polymers of ADP-ribose, called poly(ADP-ribose) (PAR), covalently attached to heterologous acceptor proteins or PARP-1 itself. There is a growing interest in PARP inhibitors (PARPi) for their clinical potential in cancer treatment. Because of the importance of PARP-1 activity in the maintenance of genomic integrity and DNA repair, treatment with PARPi as adjuvant to TMZ chemotherapy can be beneficial in GBM. PARPi are currently in clinical trials for patients with GBM (NCT02152982, NCT01390571, NCT01514201), and one of them is a phase II/III study of the PARPi veliparib for patients with newly-diagnosed GBM (NCT02152982). However, the molecular role of PARP-1 and its activity in GBM remains elusive. Using cellular and molecular approach, we are assessing the effectiveness of the PARPi veliparib compared to standard treatment with TMZ in PTEN-mutated GBM and TMZ-resistant GBM cell lines. By understanding the biology of PARP inhibition in GBM, we will establish a specific molecular signature that predicts the efficacy of PARPi treatment in patients diagnosed with GBM. Citation Format: Christopher Aldrighetti, Barbara Huebert, Delphine Quenet. Molecular function of PARP inhibition in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3218. doi:10.1158/1538-7445.AM2017-3218