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.

Keywords: blood–brain barrier; brain tumor model; childhood brain tumors; companion animal; drug delivery; drug repurposing; preclinical; xenograft.

Figure 2

Intracranial drug delivery methods. Several methods can be utilized to maximize drug delivery to brain tumors: (A) intrathecal/intraventricular delivery via an Omaya reservoir (catheter) to administer drugs directly to the cerebrospinal fluid by the ventricle or subarachnoid space in the spine; (B) interstitial delivery using microcatheters and convection-enhanced delivery; (C,D) intra-arterial administration; (C) CSF concentration time profile following intraventricular etoposide administration (0.5 mg) on the first day of a 5-day schedule (mean ± standard deviation, in a total of 11 courses in 4 patients; the number of measurements is given above each data point); (D) CSF concentrations (mean ± standard deviation) following intraventricular (IVC) etoposide administration (0.5 mg per day) on 5 consecutive days in the main study group (◆) (peak and trough levels, 15 courses in 5 patients) compared with CSF concentration following continuous intravenous infusion (CIV, 400 mg m-2 over 96 h) in the second experimental group (▲) (trough and steady-state levels, 5 courses in 2 patients); (E–I) intra-arterial chemotherapy (IAC) for retinoblastoma-super-selective catheterization and MRI before and after three sessions of IAC: (E) lateral roadmap shows a 4-French catheter (arrowhead) in the cervical ICA of the ophthalmic artery (arrow); (F) unsubtracted and (G) subtracted lateral views from a super-selective ophthalmic artery catheterization (white arrows denote the microcatheter, whose tip is at the ophthalmic artery origin); (H) axial T2 MRI of the orbits prior to IAC and (I) after 3 cycles show a marked reduction in tumor volume bilaterally. Figure 2E–I reprinted with permission from [18]. Copyright year 2023; copyright owner, Ruman Rahman [18].

Figure 1

Anatomical features of ten common brain tumors in children, highlighting the predominance of low-grade glioma (green box) and range of malignant tumor types (red box). Low-grade tumors account for ~40% of all childhood brain tumors, are slow-growing and have a very low risk of metastasis. Malignant tumors are fast-growing and have a higher risk of metastasis. Symbols illustrate typical late consequences of the tumor and its treatment, for survivors. Posterior fossa syndrome refers to motor, cognitive and speech consequences of cerebellar mutism syndrome, brainstem damage and prolonged hydrocephalus. Focal injury refers to the risk of other regional focal brain injuries related to tumor growth/invasion of brain structures or the consequences of surgery. Blindness is a consequence of tumor damage to optic nerves, chiasm and tracts or prolonged raised intracranial pressure. Endocrinopathy is due to hypothalamic/pituitary damage from tumor, surgery or radiation therapy to these regions of the brain. The figures illustrate typical population-based 5-year survival rates. See Table S1 for a more detailed description of molecular factors and prognostic criteria. Abbreviations: NF1 OPG, neurofibromatosis type I optic pathway glioma; LG, low-grade; MB, medulloblastoma; GCT, germ cell tumor (germinomatous/non-germinomatous); EPEN, ependymoma; Ca, carcinoma; HGG, high-grade glioma; ET, embryonal tumor; ATRT, atypical teratoid rhabdoid tumor; DMG: diffuse midline glioma. Figure reprinted with permission from textbook “Brain and Spinal Tumors of Childhood” under a PLSclear FPL License; Informa UK Limited License No. 78206.

Figure 3

Diagrammatic illustration of the differences in drug distribution achieved by convection-enhanced delivery and intra-parenchymal injection. (A) Convection-enhanced delivery is a method of direct infusion of drug into the brain parenchyma under positive pressure with the aim of driving fluid through the extracellular space to cover large regions of parenchyma with a therapeutic drug concentration. In comparison, local injection, which does not create a positive pressure wave, causes local high concentration of the drug to regions of the brain only short distances from the infusion site. (B) Pictorial illustration of the difference between injection and convection using a blue dye infused into an agarose gel phantom. Black lines represent the position of the catheter. Injection causes local trauma and poor heterogeneous infusate distribution. Convection-enhanced delivery of the same volume of infusion causes homogenous distribution over a large volume of distribution (unpublished; doctoral thesis of co-author Will Singleton).

Figure 4

Drug screening data relevant to pediatric brain tumors. A database search identified six publications reporting drug screens conducted on pediatric brain tumor models. These screens were relevant to high-grade glioma (HGG)/diffuse midline glioma (DMG), medulloblastoma (MB) and embryonal tumors with multilayered rosettes (ETMRs). For all studies, most compounds used in the screens were either already approved (41–56% of drugs) or unapproved (41–59% of drugs), suggesting that almost half of drugs tested could be repurposed (original figure) [83,84,85,86,87,88].

Figure 5

In vitro/in silico predictive brain tumor models identify candidate therapeutic compounds for preclinical drug delivery assessment (original figure).

Figure 6

Suite of existing in vivo orthotopic brain tumor models. (Top) Carcinogen-induced, genetically engineered and patient-derived rodent brain tumor models. (Bottom) Large animal models including engineered (swine, rabbit) and naturally occurring de novo animals (dog, non-human primates) (original figure).