Poster Presentation 32nd Lorne Cancer 2020

CHK1/2 inhibition synergises with radiotherapy in preclinical models of medulloblastoma enabling a reduction in radiation dosage without compromising survival (#128)

Jessica Buck 1 2 , Hilary Hii 2 , Brooke Strowger 2 , Mani Kuchibhotla 2 , Elissa Tolson 3 , Martin Ebert 4 , Nick Gottardo 2 5 , Raelene Endersby 1 2
  1. Centre for Child Health Research, University of Western Australia, Crawley, WA, Australia
  2. Brain Tumour Research, Telethon Kids Institute, Nedlands, WA, Australia
  3. Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia
  4. School of Physics, Mathematics and Computing, University of Western Australia, Crawley, WA, Australia
  5. Department of Paediatric and Adolescent Oncology/Haematology, Perth Children's Hospital, Nedlands, WA, Australia

Introduction

Children with medulloblastoma are treated with radiotherapy to the whole brain (WBIR) and spine. Radiotherapy to the developing brain causes severe long-term side-effects, including cognitive deficits and secondary cancers, and therefore mechanisms to reduce radiation dosage are being investigated. Prexasertib is a CHK1/2 inhibitor we identified as a highly effective agent against medulloblastoma that also synergises with radiotherapy. The purpose of this study was to determine whether combining prexasertib with radiotherapy could enable a reduction of the radiation dose while maintaining or improving survival rates.

Methods

Immunodeficient mice were implanted with D425 or D283 human medulloblastoma cells. At day 7, mice were treated with 18Gy WBIR (full dose, 10x1.8Gy fractions), 9Gy WBIR (reduced dose, 5x1.8Gy fractions), 9Gy + prexasertib (20mg/kg daily), 18Gy + prexasertib, or a control sham-treated group. Tumour growth was measured weekly using bioluminescence, and overall survival recorded.

Results

In the D425 model, median survival for control mice was 15.5 days, and mice receiving 9Gy WBIR had inferior survival compared to mice treated with 18Gy WBIR (22 and 34 days, respectively [p<0.01]). Importantly, the addition of prexasertib to 9Gy WBIR increased survival such that it was not significantly different to 18Gy WBIR (39 days). The addition of prexasertib to 18Gy WBIR resulted in further extended survival (106 days, p<0.01).

In the D283 model, median survival for control mice was 25.5 days (n=6) and similar to above, mice receiving 9Gy WBIR survived less than mice treated with 18Gy WBIR was (58 and 120 days, respectively [p<0.05]). Studies to assess the impact of prexasertib in this model are ongoing.

Conclusion

Prexasertib has potent radiosensitising activity in medulloblastoma. We show that halving radiotherapy dosage negatively impacts survival, however the addition of prexasertib to 9Gy WBIR results in equivalent survival to mice receiving 18Gy. These data indicate that prexasertib may enable reductions in the intensity of radiotherapy without compromising survival and this may alleviate some treatment-related side effects  for medulloblastoma survivors.