Abstract Cancer drug discovery and development rely on preclinical models that accurately reflect the molecular and functional characteristics of human tumors, while accounting for in vivo factors that influence drug efficacy, such as pharmacokinetics, metabolism and toxicity. Malignant gliomas are highly aggressive brain tumors that develop within the brain parenchyma, where their heterogeneous cellular composition engage in complex interactions with highly specialized brain cells, and a blood brain barrier that restricts drug penetration. When removed from this native environment, such as in culture or heterotopic in vivo environments (e.g., flank), gliomas either lose their molecular diversity or fail to grow altogether. Therefore, there is a critical need for physiologically relevant models that capture both the intra and inter-tumor diversity of glioma, as well as the organismal context required for drug development. Here, we present GliomaPDOX - a direct brain to brain glioma orthotopic xenograft biobank, consisting of more than 200 unique models that faithfully recapitulate the key molecular, histopathological, and proliferative features of their parental tumors. By incorporating a non-invasive, secreted reporter system to monitor tumor burden in real time—including drug-induced changes in intracranial tumor growth—we demonstrate the utility of GliomaPDOX for therapeutic evaluation. Together, this robust platform provides a physiologically relevant system to accelerate drug discovery and development for glioma. Citation Format: Elizabeth G. Fernandez, Christopher Tse, Jennifer Salinas, Nicholas Bayley, Lisa H. Ta, Laura Gosa, Henan Zhu, Michael Vigman, Francesco Sanvito, Benjamin M. Ellingson, Linda M. Liau, Timothy Cloughsey, Thomas G. Graeber, Nathanson David. GliomaPDOX - A direct brain-to-brain glioma xenograft library for drug discovery and development abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2162.
Fernández et al. (Fri,) studied this question.