Simulation Predicts IGFBP2-HIF1α Interaction Drives Glioblastoma Growth

Tremendous strides have been made in improving patients’ survival from cancer with one glaring exception: brain cancer. Glioblastoma is the most common, aggressive and highly malignant type of primary brain tumor. The average overall survival remains less than 1 year. Notably, cancer patients with obesity and diabetes have worse outcomes and accelerated progression of glioblastoma. The root cause of this accelerated progression has been hypothesized to involve the insulin signaling pathway. However, while the process of invasive glioblastoma progression has been extensively studied macroscopically, it has not yet been well characterized with regards to intracellular insulin signaling. In this study we connect for the first time microscale insulin signaling activity with macroscale glioblastoma growth through the use of computational modeling. Results of the model suggest a novel observation: feedback from IGFBP2 to HIF1α is integral to the sustained growth of glioblastoma. Our study suggests that downstream signaling from IGFI to HIF1α, which has been the target of many insulin signaling drugs in clinical trials, plays a smaller role in overall tumor growth. These predictions strongly suggest redirecting the focus of glioma drug candidates on controlling the feedback between IGFBP2 and HIF1α.Author Summary: Current treatment for glioblastoma patients is limited to nonspecific methods: surgery followed by a combination of radio- and chemotherapy. With these methods, glioma patient survival is less than one year post-diagnosis. Targeting specific protein signaling pathways offers potentially more potent therapies. One promising potential target is the insulin signaling pathway, which is known to contribute to glioblastoma progression. However, drugs targeting this pathway have shown mixed results in clinical trials, and the detailed mechanisms of how the insulin signaling pathway promotes glioblastoma growth remain to be elucidated. Here, we developed a computational model of insulin signaling in glioblastoma in order to study this pathway’s role in tumor progression. Using the model, we systematically test contributions of different insulin signaling protein interactions on glioblastoma growth. Our model highlights a key driver for the growth of glioblastoma: IGFBP2-HIF1α feedback. This interaction provides a target that could open the door for new therapies in glioma and other solid tumors.