Uncovering the subtype-specific disease module and the development of drug response prediction models for glioma

Abstract

The poor prognosis of glioma patients brought attention to the need for effective therapeutic approaches for precision therapy. Here, we deployed algorithms relying on network medicine and artificial intelligence to design the framework for subtype-specific target identification and drug response prediction in glioma. We identified the driver mutations that were differentially expressed in each subtype of lower-grade glioma and glioblastoma multiforme and were linked to cancer-specific processes. Driver mutations that were differentially expressed were also subjected to subtype-specific disease module identification. The drugs from the drug bank database were retrieved to target these disease modules. However, the efficacy of anticancer drugs depends on the molecular profile of the cancer and varies among cancer patients due to intratumor heterogeneity. Hence, we developed a deep-learning-based drug response prediction framework using the experimental drug screening data. Models for 30 drugs that can target the disease module were developed, where drug response measured by IC50 was considered a response and gene expression and mutation data were considered predictor variables. The model construction consists of three steps: feature selection, data integration, and classification. We observed the consistent performance of the models in training, test, and validation datasets. Drug responses were predicted for particular cell lines derived from distinct subtypes of gliomas. We found that subtypes of gliomas respond differently to the drug, highlighting the importance of subtype-specific drug response prediction. Therefore, the development of personalized therapy by integrating network medicine and a deep learning-based approach can lead to cancer-specific treatment and improved patient care.