Faithful animal modelling of human glioma by using primary initiating cells and its implications for radiosensitization therapy [ARRIVE 1]

It has been reported that the ATM kinase inhibitor KU60019 preferentially radiosensitizes orthotopic high grade gliomas (HGG) driven by established U87 and U1242 cell lines bearing specific TP53 mutations. We wished to determine whether those results could be extended to tumors driven by primary glioma initiating cells (GIC) that closely mimic clinical tumors. Orthotopic HGG were developed in immunodeficient non-obese diabetic-severe combined immunodeficient (NOD-SCID) mice by intracranial injection of primary GIC isolated from the adult glioblastoma COMI (acronym of patient\u2019s name) and the pediatric anaplastic astrocytoma 239/12. Similar to the clinical tumors of origin, the orthotopic tumors COMI and 239/12 displayed different growth properties with a voluminous expansive lesion that exerted considerable mass effect on the adjacent structures and an infiltrating, gliomatosis-like growth pattern with limited compressive attitude, respectively. Significant elongations of median animal survival bearing the adult COMI tumor was observed after one KU60019 convection enhanced delivery followed by total 7.5 Gy of ionizing radiation delivered in fifteen 0.5 Gy fractions, as compared to animals treated with vehicle + ionizing radiation (105 vs 89 days; ratio: 0.847; 95% CI of ratio 0.4969 to 1.198; P:0.0417) [ARRIVE 16]. Similarly, a trend to increased median survival was observed with the radiosensitized pediatric tumor 239/12 (186 vs 167 days; ratio: 0.8978; 95% CI of ratio: 0.5352 to 1.260; P: 0.0891) [ARRIVE 16]. Our results indicate that radiosensitization by KU60019 is effective towards different orthotopic gliomas that faithfully mimic the clinical tumors and that multiple GIC-based animal models may be essential to develop novel therapeutic protocols for HGG transferable to the clinics

Image-guided delivery of therapeutics to the brain

CNS disorders still prevail to be one of the largest disease areas where current treatment options are limited and there has been growing interest among academia, industry, and research organizations to explore novel options to deliver therapeutics to the brain. Novel strategies encompassing invasive and noninvasive approaches for CNS delivery, to overcome physiological and technical challenges has been the current norm. CNS imaging offers improved diagnosis of disorders and techniques like X-ray computed tomography (CT), single photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI) have proved to be promising for cerebral imaging. Combinations of functional and structural imaging modalities such as PET/MRI and SPECT/MRI are known to be used for preclinical and clinical imaging. The concept of image-guided targeted delivery of therapeutics to the CNS is seen to be an effective strategy to compliment the current diagnosis regimen with a therapeutic end goal. Combination of nanoparticulate drug delivery with an imaging component has shown initial promise to improve targeting of therapeutics to the CNS