Abstract TP53 pathway alterations are well-described events in medulloblastoma (MB) and are predictive of poor clinical outcome. Alterations are rare at diagnosis in Group3 (Gr3) and Group4, but enriched in Sonic Hedgehog and WNT subgroups. However, TP53 mutations are observed in all subgroups at relapse. Radiation therapy, along with surgery and chemotherapy, represents the standard of care treatment for MB. Loss of p53 function correlates with increased resistance to radiation in several cancers conferring poor survival for patients. In this study, we exposed the MYCN-driven/Trp53kiki (with tamoxifen-inducible p53 activation) Gr3 MB GEMM to a clinically relevant fractionated radiation therapy (RT) regime, to assess the role of p53 in Gr3 radio-resistance and relapse. Mice exhibiting tumour progression (bioluminescence (BLI) signal >109 photons/second) were randomized to treatment groups. A small animal radiation research platform was used to deliver CT-guided cranio-spinal irradiation (CSI) and a cranial boost (CB). Mice were followed for survival and tumour burden tracked using BLI. Bodyweight was monitored to evaluate treatment tolerability. Full dose radiation therapy (54Gy CB, 36Gy CSI, α/β=10) or dose modulation (12Gy CB, 8Gy CSI) was performed. The results showed comparable primary tumour regression in response to RT in p53 inactive and active backgrounds, followed by imminent relapse or prolonged remission respectively. No significant acute toxicity was observed. Temporary activation of p53 during RT improved tumour-free survival and decreased the incidence of relapse. In conclusion, we developed a new model which will help improve understanding of the radiobiology of high-risk MB and future preclinical trials.
Background: Overexpression of EGFR is a negative prognostic factor in head and neck squamous cell carcinoma (HNSCC). Patients with HNSCC who respond to EGFR-targeted tyrosine kinase inhibitors (TKIs) eventually develop acquired resistance. Strategies to identify HNSCC patients likely to benefit from EGFR-targeted therapies, together with biomarkers of treatment response, would have clinical value. Methods: Functional MRI and 18F-FDG PET were used to visualise and quantify imaging biomarkers associated with drug response within size-matched EGFR TKI-resistant CAL 27 (CALR) and sensitive (CALS) HNSCC xenografts in vivo, and pathological correlates sought. Results: Intrinsic susceptibility, oxygen-enhanced and dynamic contrast-enhanced MRI revealed significantly slower baseline R2*, lower hyperoxia-induced ΔR2* and volume transfer constant Ktrans in the CALR tumours which were associated with significantly lower Hoechst 33342 uptake and greater pimonidazole-adduct formation. There was no difference in oxygen-induced ΔR1 or water diffusivity between the CALR and CALS xenografts. PET revealed significantly higher relative uptake of 18F-FDG in the CALR cohort which was associated with significantly greater Glut-1 expression. Conclusion: CALR xenografts established from HNSCC cells resistant to EGFR TKIs are more hypoxic, poorly perfused and glycolytic than sensitive CALS tumours. MRI combined with PET can be used to non-invasively assess HNSCC response/resistance to EGFR inhibition.
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