Veliparib Is an Effective Radiosensitizing Agent in a Preclinical Model of Medulloblastoma

Jessica Buck; Patrick J C Dyer; Hilary Hii; Brooke Carline; Mani Kuchibhotla; Jacob Byrne; Meegan Howlett; Jacqueline Whitehouse; Martin A Ebert; Kerrie L McDonald; Nicholas G Gottardo; Raelene Endersby

doi:10.3389/fmolb.2021.633344

Veliparib Is an Effective Radiosensitizing Agent in a Preclinical Model of Medulloblastoma

Front Mol Biosci. 2021 Apr 29:8:633344. doi: 10.3389/fmolb.2021.633344. eCollection 2021.

Authors

Jessica Buck^{1

2}, Patrick J C Dyer¹, Hilary Hii¹, Brooke Carline¹, Mani Kuchibhotla¹, Jacob Byrne¹, Meegan Howlett^{1

2}, Jacqueline Whitehouse^{1

2}, Martin A Ebert^{3

4}, Kerrie L McDonald⁵, Nicholas G Gottardo^{1

6}, Raelene Endersby^{1

2}

Affiliations

¹ Brain Tumour Research Program, Telethon Kids Cancer Centre, Telethon Kids Institute, Perth, WA, Australia.
² Centre for Child Health Research, University of Western Australia, Perth, WA, Australia.
³ School of Physics, Mathematics and Computing, University of Western Australia, Perth, WA, Australia.
⁴ Radiation Oncology, Sir Charles Gairdner Hospital, Perth, WA, Australia.
⁵ Brain Cancer Consultancy, Sydney, NSW, Australia.
⁶ Department of Paediatric Oncology and Haematology, Perth Children's Hospital, Perth, WA, Australia.

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.

Keywords: DNA repair; Medulloblastoma; poly(ADP-ribose) polymerase; radiotherapy; veliparib.