• Howlett, Meegan
• Dholaria, Hetal
• Kuchibhotla, Mani
• Whitehouse, Jacqueline P.
• Endersby, Raelene
• Hii, Hilary
• Carline, Brooke
• Buck, Jessica
• Palanisamy, Ranjith
• Larder, Sally
• Gottardo, Nicholas G.
• Ebert, Martin A.

Abstract

<jats:title>Abstract</jats:title><jats:sec><jats:title>BACKGROUND</jats:title><jats:p>Despite treatment intensification, survival for high-risk subgroups of medulloblastoma (MB) such as MYC-amplified Group 3 (Gr3-II) and p53-mutant SHH (SHH-3p53mut) have remained dismal with overall survival around 40% and 20% respectively. Our previous studies have shown that the DNA-damage response inhibitors (DDRis) prexasertib and ceralasertib enhance the effects of CSI using medulloblastoma cell line-derived orthotopic mouse models. However, patient-derived orthotopic xenografts (PDOXs) are considered superior models for preclinical testing compared to immortalised cell lines. Here, we developed a CSI protocol for multiple PDOX models of high-risk medulloblastoma and tested the optimal protocol with concurrent DDRis.</jats:p></jats:sec><jats:sec><jats:title>METHOD</jats:title><jats:p>For our CSI optimisation studies, MED211FH (Gr3-II) or MED813FH (SHH-3p53mut) tumour-bearing mice were monitored for clinical symptoms of tumour before commencing treatment. Multiple, fractionated CSI dosing schedules using a 5-days-on, 2-days-off treatment cycle were trialled based on our lab’s previously established CSI protocols before a schedule of 10 x 0.5 Gy fractions (5.0 Gy total) proved optimal. This schedule was then used in both PDOX models plus an additional SHH-3p53mut model (MED314mCLFH), either alone or in combination with concurrent prexasertib or ceralasertib.</jats:p></jats:sec><jats:sec><jats:title>RESULTS</jats:title><jats:p>MED211FH and MED813FH mice treated with 5.0 Gy CSI alone resulted in significantly improved median survival compared to control mice (p&amp;lt;0.0001 and p&amp;lt;0.005 respectively) While 5.0 Gy CSI plus concurrent prexasertib or ceralasertib showed significantly improved survival when compared to CSI alone for each model used. MED211FH: p&amp;lt;0.01 and p&amp;lt;0.001 respectively, MED813FH: p&amp;lt;0.05 and p&amp;lt;0.01 respectively and MED314mCLFH: p&amp;lt;0.05 for both DDRi combination groups.</jats:p></jats:sec><jats:sec><jats:title>CONCLUSION</jats:title><jats:p>Remarkably, concurrent use of prexasertib or ceralasertib with CSI significantly improved survival in fatal Gr3-II and SHH-3p53mut models. With these results, we provide robust preclinical evidence for radiosensitising use of DDRi in paediatric high-risk MB and recommend swift clinical translation.</jats:p></jats:sec>

Topics

• size-exclusion chromatography