Poster Presentation 36th Lorne Cancer Conference 2024

Radiosensitising paediatric medulloblastoma cells by exploiting the dna damage response pathway (#217)

Jacob Byrne 1 , Hilary Hii 1 , Jessica Buck 1 2 , Mani Kuchibohtla 1 , Meegan Howlett 1 2 , Jacqueline Whitehouse 1 2 , Hetal Dholaria 1 2 3 , Nick Gottardo 1 2 3 , Brooke Carline 1 , Jessica Lawler 1 , Martin Ebert 4 , Terry Johns 1 2 , Raelene Endersby 1 2
  1. Telethon Kids Institute, Nedlands, WA, Australia
  2. Centre for Child Health Research, University of Western Australia, Nedlands, WA, Australia
  3. Department of Paediatric Oncology and Haemotology, Perth Children's Hospital, Nedlands, WA, Australia
  4. School of Physics, Computing and Math, University of Western Australia, Nedlands, WA, Australia

 

Brain cancer is one of the deadliest human cancers and causes more childhood deaths than any other disease. Survival rates for children with high-risk forms of MYC-amplified Group 3 medulloblastoma (Group 3 subtype 2, or MB-G3-2) are less than 40% after 5 years. While the survival benefit of craniospinal irradiation (CSI) is well-established, and essential to cure children, its use is associated with debilitating toxicity and developmental complications that persist into adult life. In this context, there is an urgent need to identify novel radiosensitising agents, which may offer clinical benefit with reduced toxicity.  

 Radiation is a potent inducer of DNA damage. ATR, CHK1/2 and WEE1 kinases are key components of the DNA damage response (DDR) and essential to facilitate activation of DNA repair pathways. Inhibitors (i) of these kinases, ceralasertib (ATRi), prexasertib (CHKi) and adavosertib (WEE1i), have shown promise for their potential to radiosensitise adult cancer cells and abrogate DNA damage repair, however this has not yet been investigated in paediatric brain cancer.

 Here, we utilise multiple patient-derived orthotopic xenograft (PDOX) mouse models of MB-G3-2, and CSI delivered in a precise manner that mimics clinical dosing. When used concurrently with CSI, ATRi and CHKi significantly prolonged survival compared to CSI alone across three MB-G3-2 models. The most effective response was observed when CHKi was administered concurrently with CSI followed by an additional six weeks of CHKi monotherapy, which remarkably led to long-term survival in >90% of mice harbouring aggressive D425 MB-G3-2 tumours. Using flow cytometry and immunoblotting, we demonstrate that these inhibitors function by prevention of cell cycle arrest, leading to impaired DNA repair and accumulation of DNA damage, followed by subsequent apoptosis. These mechanistic insights provide a basis for the optimisation of when these drugs should be integrated into existing clinical radiation protocols. In sum, this study demonstrates the radio-sensitising effects of drugs targeting the DNA damage response in high-risk medulloblastoma and highlights them as strong candidates for incorporation into existing radiation protocols.