Childhood Brain Tumors: A Review of Strategies to Translate CNS Drug Delivery to Clinical Trials

Abstract

Brain and spinal tumors affect 1 in 1000 people by 25 years of age, and have diverse histological, biological, anatomical and dissemination characteristics. A mortality of 30–40% means the majority are cured, although two-thirds have life-long disability, linked to accumulated brain injury that is acquired prior to diagnosis, and after surgery or chemo-radiotherapy. Only four drugs have been licensed globally for brain tumors in 40 years and only one for children. Most new cancer drugs in clinical trials do not cross the blood–brain barrier (BBB). Techniques to enhance brain tumor drug delivery are explored in this review, and cover those that augment penetration of the BBB, and those that bypass the BBB. Developing appropriate delivery techniques could improve patient outcomes by ensuring efficacious drug exposure to tumors (including those that are drug-resistant), reducing systemic toxicities and targeting leptomeningeal metastases. Together, this drug delivery strategy seeks to enhance the efficacy of new drugs and enable re-evaluation of existing drugs that might have previously failed because of inadequate delivery. A literature review of repurposed drugs is reported, and a range of preclinical brain tumor models available for translational development are explored.

Targeted Radionuclide Therapy in Glioblastoma

“…The phase II study reported in 2005 corroborated the safety and efficacy of the same treatment method for a similar patient cohort. This study found a residence time of 131 I-81C6 within the surgical cavity, averaging 76 h, with a range from 34 to 169 h. The absorbed dose to the 2 cm margin was similar to their previous studies, at 48 Gy for all patients, with a range of 25−116 Gy, and a slightly higher average of 51 Gy for patients with GBM. SPECT/MRI revealed that the antibody was preferentially distributed in areas with vasogenic edema.…”

“…This approach has shown improved survival compared to previous treatments (14.6 months vs 12.1 months; hazard ratio [HR], 0.63; 95% CI, 0.52–0.75; P < 0.001) . The global licensing of approved medications is limited (temozolomide, lomustine, carmustine wafers, and everolimus for adults and only temozolomide for children) . Recently, the FDA approved dabrafenib with trametinib for pediatric patients with low-grade glioma with a BRAFV600E mutation based on the results of study CDRB436G2201 (NCT02684058).…”

“…47 The global licensing of approved medications is limited (temozolomide, lomustine, carmustine wafers, and everolimus for adults and only temozolomide for children). 48 Recently, the FDA approved dabrafenib with trametinib for pediatric patients with low-grade glioma with a been developed to further improve the survival of patients with GBM.…”

The Integration of Community-Dwelling Non-Human Companion Animals in Research Programs

“…Comparative oncology reviews (Anderson & Modiano, 2015;Beck et al, 2022;Bentley et al, 2017;Burton & Khanna, 2014;Dias et al, 2021;Finocchiaro & Glikin, 2017;Garden et al, 2018;Gardner et al, 2016;Gingrich et al, 2019;Giuliano, 2021;Gordon & Khanna, 2010;Kieslinger et al, 2019;Kleber et al, 2022;LeBlanc & Mazcko, 2020;Lollini et al, 2013;Mestrinho & Santos, 2021;Nickoloff et al, 2017;Oh & Cho, 2023;Page et al, 2016;Pinard et al, 2022;Porrello et al, 2004Porrello et al, , 2006Rahman et al, 2023;Regan et al, 2018;Riccardo et al, 2015;Vafaei et al, 2022;Vail & Thamm, 2000.;Vanhaezebrouck & Scarpelli, 2023;Withers et al, 2019;Withrow & Wilkins, 2010) Cell therapy review (Arzi et al, 2021) Thesis (Gruen, 2016) Ethical review (Bertout et al, 2021) One Health reviews (Arzi et al, 2022;Kol et al, 2015) Perianal fistulas review (Burdzinska et al, 2022) Osteoarthritis (Cimino Brown, 2017) Pain reviews (Iadarola et al, 2021;Lascelles et al, 2018Lascelles et al, , 2022 Cachex...…”