Farias, Virgínea

Abstract Glioma stem cells (GSCs) are considered a major driver of glioblastoma (GBM) progression and are highly resistant to standard cytotoxic treatments. BMP4 has been shown to promote GSC differentiation, enhance radiosensitivity, slow tumor growth, and extend survival in animal models. Despite this promise, BMP4 has yet to achieve clinical impact, owing largely to heterogeneous and nonlinear responses across preclinical experimental systems. To elucidate how BMP4 could function as an effective targeted differentiation therapy in GBM, we develop a mathematical model that describes the growth of a GBM tumor via a hierarchy of GSCs, progenitor and terminally differentiated cells. We parameterize our model using new radiotherapy and proliferation assay data (with and without BMP4 exposure) from twelve patient-derived GSC lines. This integration of model and data allows us, for the first time, to quantitatively capture patient-specific heterogeneity in BMP4 sensitivity. We perform global sensitivity analysis on the model, identifying proliferation rate and GSC self-renewal sensitivity as key determinants of BMP4 efficacy. These parameters act as model-derived biomarkers that distinguish BMP4-responsive tumors from non-responsive ones. In an in silico analysis across a broad cohort of virtual patients, we find that continuous BMP4 delivery from surgical resection through radiotherapy consistently outperforms a single-dose strategy. Virtual clinical trials further show that, without stratification using these model-derived biomarkers, BMP4 yields little observable therapeutic benefit. In contrast, selecting patients with more proliferative, BMP4-responsive GSCs markedly increases the likelihood of observing a significant treatment effect. Citation Format: Nicholas Harbour, Lee Curtin, Loizos Michaelides, Matthew E. Hubbard, Pamela Jackson, Vinitha Rani, Rajappa Kenchappa, Virginea Farias, Anna Carrano, Markus Owen, Alfredo Quinones-Hinojosa, Kristin Swanson. Virtual clinical trials of BMP4 differentiation therapy [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 6831.

Abstract Glioblastomas (GBM), also known as glioblastoma multiforme, are the most aggressive type of brain cancers. Currently, there is no real treatment for GBM and thus there is a compelling need for new therapeutic strategies for such type of cancers. Recently, we demonstrated that specific combinations of epigenetic modifiers significantly affect the metabolism and proliferation rate of two most aggressive GBM cell lines D54 and U-87. Importantly, these combinations exhibited minimal effect on normal stem cells growth. In this study we demonstrated that the combinations of modulators of histone and DNA covalent modifying enzymes that synergistically suppress D54 and U87 cell lines growth, also impair the viability of a patient freshly-derived GBM stem cell line. These data suggest that epigenetic modifiers alone or in specific combinations exhibit cytotoxic effect on established and low passage patient derived GB cell lines and thus could be a promising therapeutic approach for such type of brain cancers.