Abstract A015: Predicting efficacious drugs and drug-biomarker relationships for targeted glioblastoma treatment

Abstract Glioblastoma multiforme (GBM) is the deadliest, most heterogeneous, and common brain cancer in adults. Despite major advancements in neurosurgery as well as chemotherapy and radiotherapy techniques, overall prognosis has changed little over the decades. Not only is there an urgent need to identify efficacious therapeutics but there is also a great need to pair these therapeutics with biomarkers that can help tailor treatment to the right patient populations given the heterogeneous nature of the disease. Here, we implement several machine learning and statistical based pipelines for drug and biomarker discovery, leveraging previous work building patient drug response models using high-throughput cell line drug screening data as well as Bayesian network structure learning. Through these discovery pipelines, we identified multiple agents of interest for GBM, including MEK inhibitors (MEKis). MEKis were consistently predicted to be effective against GBM in multiple cross platform (microarray and RNA-sequencing) patient and patient derived xenograft (PDX) datasets. Additionally, they were experimentally shown to be more efficacious in tumor samples than standard of care agents (Temozolomide and Carmustine). We also predicted PHGDH gene expression levels to be causally associated with MEKi efficacy, which increased tumor sensitivity to a MEKi (Trametinib) during experimental testing in GBM cell lines with knockdown. These findings support our drug and biomarker discovery pipelines as an effective strategy to unite multiple cross platform and cross species datasets to help achieve GBM precision medicine. They also demonstrate that patient PHGDH levels can help inform Trametinib response in the fight against GBM. Citation Format: Danielle Maeser, Robert Gruener, Robert Galvin, Stephanie Huang, Tomo Koga, Florina Grigore. Predicting efficacious drugs and drug-biomarker relationships for targeted glioblastoma treatment abstract. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84 (5 Suppl₁): Abstract nr A015.