Background: Craniospinal irradiation (CSI) is a crucial component of treatment for medulloblastoma (MB), a brain tumor clinically stratified into prognostically distinct molecular subgroups. Preclinical models of clinically-relevant CSI offer the potential to study radiation dose and volume effects in these subgroups and identify subgroup-specific combination adjuvant therapies, particularly for very-high-risk MB in which treatments are often unsuccessful. Methods: The commercially available Small Animal Radiation Research Platform equipped with a motorized variable collimator was used for image-guided CSI. Mice were implanted in brain cortices with patient-derived orthotopic xenografts (PDOXs) of very-high-risk Group 3 (G3) or Sonic Hedgehog (SHH) MB and were treated with fully-fractionated CSI at 2 Gy/fraction to a cumulative 36 Gy. Radiation therapy dose response effects on tumor burden and overall survival were assessed. The pattern of treatment failure was determined by bioluminescence and confirmed histologically. Acute toxicity was appraised by body weight measurements and blood work. Results: We established an accurate, efficient preclinical protocol to reproducibly administer CSI to mice harboring MB. CSI improved the survival of mice bearing very-high-risk G3- or SHH-MB PDOXs. However, radiation therapy dose responses across models suggested significant radioresponsiveness to conventionally-fractionated CSI ≥20 Gy. CSI was well tolerated; mice had no significant changes in body weight and acute leukopenia developed but resolved soon after therapy completion. Conclusion: Our protocol for preclinical CSI delivery was effective, well tolerated, and can be readily integrated into preclinical pipelines for MB and other central nervous system–seeding tumors.

SUMMARY Purpose Curing all children with brain tumors will require an understanding of how each subtype responds to conventional treatments and how best to combine existing and novel therapies. It is extremely challenging to acquire this knowledge in the clinic alone, especially among patients with rare tumors. Therefore, we developed a preclinical brain tumor platform to test combinations of conventional and novel therapies in a manner that closely recapitulates clinic trials. Experimental Design A multidisciplinary team was established to design and conduct neurosurgical, fractionated radiotherapy and chemotherapy studies, alone or in combination, in accurate mouse models of supratentorial ependymoma (SEP) subtypes and choroid plexus carcinoma (CPC). Extensive drug repurposing screens, pharmacokinetic, pharmacodynamic and efficacy studies were used to triage active compounds for combination preclinical trials with ‘standard-of-care’ surgery and radiotherapy. Results Mouse models displayed distinct patterns of response to surgery, irradiation and chemotherapy that varied with tumor subtype. Repurposing screens identified three hour infusions of gemcitabine as a relatively non-toxic and efficacious treatment of SEP and CPC. Combination neurosurgery, fractionated irradiation and gemcitabine proved significantly more effective than surgery and irradiation alone, curing one half of all animals with aggressive forms of SEP. Conclusions We report a comprehensive preclinical trial platform to assess the therapeutic activity of conventional and novel treatments among rare brain tumor subtypes. It also enables the development of complex, combination treatment regimens that should deliver optimal trial designs for clinical testing. Post-irradiation gemcitabine infusion should be tested as new treatments of SEP and CPC.

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Background Pediatric high-grade glioma (pHGG) is largely incurable and accounts for most brain tumor–related deaths in children. Radiation is a standard therapy, yet the benefit from this treatment modality is transient, and most children succumb to disease within 2 years. Recent large-scale genomic studies suggest that pHGG have alterations in DNA damage response (DDR) pathways that induce resistance to DNA damaging agents. The aim of this study was to evaluate the therapeutic potential and molecular consequences of combining radiation with selective DDR inhibition in pHGG. Methods We conducted an unbiased screen in pHGG cells that combined radiation with clinical candidates targeting the DDR and identified the ATM inhibitor AZD1390. Subsequently, we profiled AZD1390 + radiation in an extensive panel of early passage pHGG cell lines, mechanistically characterized response to the combination in vitro in sensitive and resistant cells and evaluated the combination in vivo using TP53 wild-type and TP53 mutant orthotopic xenografts. Results AZD1390 significantly potentiated radiation across molecular subgroups of pHGG by increasing mutagenic non-homologous end joining and augmenting genomic instability. In contrast to previous reports, ATM inhibition significantly improved the efficacy of radiation in both TP53 wild-type and TP53 mutant isogenic cell lines and distinct orthotopic xenograft models. Furthermore, we identified a novel mechanism of resistance to AZD1390 + radiation that was marked by an attenuated ATM pathway response which dampened sensitivity to ATM inhibition and induced synthetic lethality with ATR inhibition. Conclusions Our study supports the clinical evaluation of AZD1390 in combination with radiation in pediatric patients with HGG.

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