Abstract A042: Evolution of resistance in brain tumors: Effects of the blood brain barrier

Abstract Background: Therapeutic treatment of brain tumors is uniquely challenging due to the presence of the blood brain barrier (BBB), which impedes drug penetration of the brain. This typically results in lower drug concentrations and slower time to steady-state in the brain relative to the body. In this analysis, we investigate the effects of the blood brain barrier on the evolution of resistance in brain tumors and accordingly seek optimal drug transport and clearance properties. Methods: To investigate the relationship between a drug’s BBB penetration parameters and its efficacy against brain tumors, we simulated drug penetration and tumor response in terms of total volume and resistant fraction. Brain pharmacokinetics (PK) are simulated by a two-compartment model in which the body and brain are represented. A series of differential equations transfer between compartments—across the blood brain barrier—and correspond to active and passive transport. Drug clearance in the brain and body are also considered. The tumor kinetics model consists of sensitive and resistance cells which are in competition, represented by a logistic growth function. For sensitive cells, the growth rate is reduced by the concentration of drug while resistant cells are unaffected. Results: We demonstrate that drug PK in the brain is characterized by a latency phase followed by steady-state dynamics. The tumor growth may continue during this latency. As the drug exerts its effect, sensitive cells die off. As the sensitive population is reduced, the effect of drug properties such as transport across the BBB and clearance diminishes. In general, the effect of active transport into the brain was found to be small compared to passive diffusion. Conclusions: Due to a longer time-to-steady state in the brain, therapeutic concentrations are reached more slowly in the brain. BBB penetration parameters impact tumor volume in the treatment phase where sensitive cells are present in significant number. Citation Format: Madison Stoddard, Lin Yuan, T Ryan. Gregory, Arijit Chakravarty. Evolution of resistance in brain tumors: Effects of the blood brain barrier [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr A042.