Inhibition of PARP results in highly effective radiosensitization of Gr. 3 medulloblastomas

Medulloblastoma (MB) is the most frequent high-grade brain tumor of childhood and adolescence. Multimodal therapy of MB consists of combined surgery, chemotherapy and radiotherapy. Biologically, MB is a heterogeneous disease with at least four different sub-groups: WNT, SHH-TP53 mutant, SHH-TP53 wildtype and non-WNT/non-SHH (Gr. 3/4), with significant implications for prognosis. Despite the high importance of RT for disease control in MB, mechanisms underlying response and resistance to RT are incompletely understood. Furthermore, the development of new treatment approaches to increase radiosensitivity is highly important.

For the analysis of cellular radiosensitivity and DNA repair MB cell lines and ex vivo slice cultures of patient samples, patient-derived xenograft (PDX) and genetically engineered mouse models (GEMM) were used. The SHH medulloblastoma-derived cell lines were the most radioresistant strains, whereas the Gr. 3/4 cell lines demonstrated profoundly higher cellular radiosensitivity. Analysis of residual DSBs demonstrated a significant correlation between DSB repair capacity and cellular survival in vitro. In line with this, ex vivo analysis revealed elevated numbers of residual irradiation-induced DSBs in Gr. 3 samples as compared to those from SHH subgroup.

In first radiosensitizing approaches we treated the Gr. 3 MB cells and tumor slice cultures with the PARP inhibitors olaparib and pamiparib before irradiation. Twenty-four hours after treatment cell lines and tumor slice cultures displayed elevated residual DSB indicating compromised DNA repair. Moreover, Gr. 3 MB cell lines showed increased cellular radiosensitivity, when they were treated with PARP inhibitors before irradiation, demonstrating that PARP inhibition is an effective strategy to radiosensitize Gr. 3 MB cells.

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Artikel online veröffentlicht:
09. November 2023