Abstract B104: A smarter route to the brain: Preserving the BBB in preclinical brain tumor models

Abstract More than 90% of drugs that demonstrate efficacy in preclinical brain tumor models ultimately fail in clinical trials, often due to insufficient blood-brain barrier (BBB) penetration. This high rate of translational failure highlights a fundamental shortcoming in the design of standard preclinical brain tumor models: compromised BBB integrity. Although widely used, orthotopic models generated via direct intracranial injection inherently disrupt the BBB, limiting their predictive value for assessing drug delivery and therapeutic response in the brain. To address this gap, we investigated alternative tumor inoculation strategies that preserve the BBB while allowing robust brain colonization. Intravenous (IV) and intracardiac (IC) injection has shown promise, yielding reproducible brain metastases in several tumor types. However, widespread systemic dissemination frequently leads to off-target tumor burden and premature study termination. To overcome this limitation, we developed an intra-carotid inoculation technique for brain tumor development. This approach results in localized tumor growth within the brain and head/neck region, while minimizing metastatic spread to peripheral organs. The intra-carotid inoculation method enables more accurate assessment of drug efficacy in the context of an intact BBB. This refined model system is applicable across a range of tumor types with brain tropism and offers a physiologically relevant platform for evaluating BBB-penetrant therapeutics. By better recapitulating clinical patterns of brain tumor growth/metastasis and preserving critical BBB function, our intra-carotid inoculation model has the potential to enhance the predictive power of preclinical brain tumor drug development. Citation Format: Cheryl Davis, T. Liz. Bailey, Melissa Tran, Ben Hoerner, Helen Ketteringham, Marcus Josey, Victoria Caruso, Corrine Silvio, Shannan Paul, Shorena Nadaraia-Hoke, Chris Holding, Dawn Lusk. A smarter route to the brain: Preserving the BBB in preclinical brain tumor models [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 B104.