Abstract
Medulloblastoma is the most common malignant childhood brain tumor, and 5-year overall survival rates are as low as 40% depending on molecular subtype, with new therapies critically important. As radiotherapy and chemotherapy act through the induction of DNA damage, the sensitization of cancer cells through the inhibition of DNA damage repair pathways is a potential therapeutic strategy. The poly-(ADP-ribose) polymerase (PARP) inhibitor veliparib was assessed for its ability to augment the cellular response to radiation-induced DNA damage in human medulloblastoma cells. DNA repair following irradiation was assessed using the alkaline comet assay, with veliparib inhibiting the rate of DNA repair. Veliparib treatment also increased the number of γH2AX foci in cells treated with radiation, and analysis of downstream pathways indicated persistent activation of the DNA damage response pathway. Clonogenicity assays demonstrated that veliparib effectively inhibited the colony-forming capacity of medulloblastoma cells, both as a single agent and in combination with irradiation. These data were then validated in vivo using an orthotopic implant model of medulloblastoma. Mice harboring intracranial D425 medulloblastoma xenografts were treated with vehicle, veliparib, 18 Gy multifractionated craniospinal irradiation (CSI), or veliparib combined with 18 Gy CSI. Animals treated with combination therapy exhibited reduced tumor growth rates concomitant with increased intra-tumoral apoptosis observed by immunohistochemistry. Kaplan–Meier analyses revealed a statistically significant increase in survival with combination therapy compared to CSI alone. In summary, PARP inhibition enhanced radiation-induced cytotoxicity of medulloblastoma cells; thus, veliparib or other brain-penetrant PARP inhibitors are potential radiosensitizing agents for the treatment of medulloblastoma.
Highlights
Brain tumors represent one of the leading causes of mortality in children, with medulloblastoma the most common childhood brain cancer (Millard and De Braganca, 2016)
These results indicate that poly-(ADPribose) polymerase (PARP) inhibition reduces the repair rate of radiation-induced DNA damage in human medulloblastoma cells
Due to its effect on DNA damage repair, we investigated if there was a synergistic effect of combining veliparib and radiotherapy in vitro using three different mathematical models of measuring drug-radiation interactions (Bliss, 1939; Loewe, 1953; Tan et al, 2012): the Loewe Additivity method (Figures 2A,B), Bliss Independence model, and the highest single agent (HSA) model
Summary
Brain tumors represent one of the leading causes of mortality in children, with medulloblastoma the most common childhood brain cancer (Millard and De Braganca, 2016). Medulloblastoma is a heterogeneous group of cancers that can been divided into four core molecular subgroups: SHH, WNT, Group 3, and Group 4 (Thompson et al, 2006; Louis et al, 2016) These subgroups can be further classified into 13 subtypes based on genomic, epigenomic, proteomic, and clinical features (Hovestadt et al, 2020). We recently performed a drug screen that identified kinase inhibitors of the DNA damage response (DDR) pathway and cell cycle machinery as potent agents against MYC-amplified Group 3 medulloblastoma in combination with chemotherapy (Endersby et al, 2021). A number of PARP inhibitors have been developed and may be used clinically to treat cancers with homologous recombination (HR) deficiency, such as those with mutations in BRCA1, BRCA2, and PALB2. PARP inhibitors have recently been investigated for their ability to sensitize brain cancer cells to chemotherapy and radiotherapy (Van Vuurden et al, 2011; Chornenkyy et al, 2015; Jue et al, 2017) and it is this approach that we sought to test in medulloblastoma
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