Figure 2.

Overview of factors that conceptually affect the efficacy of genotype-matched targeted therapies in brain tumors. (A) Illustration of several features that may limit the accumulation of targeted therapies in the brain and their clinical efficacy. The integrity of the blood-brain barrier (BBB) may be compromised in primary brain tumors, allowing drugs to cross into the tumor irrespective of their biochemical properties. The BBB represents the intact barrier composed of endothelial cells, pericytes, and astrocytes that is present in non-enhancing brain regions. The tight junctions at the blood–brain barrier and efflux transporters such as (ABCB1 and ABCG2) limit the ability of drugs to permeate an intact blood–brain barrier. Other biochemical features, such as the drugs’ surface area, lipophilicity, and reversible binding, can also affect the ability of those drugs to concentrate in the brain. Drugs with a small surface area, elevated lipid solubility, and irreversible binding require a lower IC₅₀ to adequately inhibit their target on tumor cells. The opposite holds true for drugs with a large surface area, low lipid solubility, and reversible binding. (B) Illustration of the most commonly altered signaling pathways observed in GBM, a representative example of high-grade glioma, based on the TCGA data. The PI3K/AKT/mTOR and RAS/Raf/MAPK pathways are frequently altered and conceptually represent a viable therapeutic target. Alterations within cell cycle regulating genes, such as, in MDM2, MDM4, CKDN2A/B, and CDK4/6 are actionable. Chromatin regulation can be targeted through IDH1, ARID1A, and EZH2 targeted therapies. Alterations in DNA damage repair are exemplified by targetable BRCA1/2 mutations.