Mapping Radiosensitivity in Glioblastoma Using MR Elastography and Biomechanical Modeling.

Glioblastoma multiforme (GBM) remains a devastating disease with a poor prognosis. GBM progression generates mechanical forces that compromise blood vessels' functionality, impair perfusion, and create hypoxic regions, which in turn reduce radiosensitivity. While the link between hypoxia and radiosensitivity is known, a quantitative methodology to predict this effect is lacking. Here, we developed a patient-specific mechanistic mathematical model of radiotherapy that integrates Magnetic Resonance Elastography (MRE) imaging. The model can translate MRE-derived stiffness into spatial maps of mechanical stress and simulate subsequent events, such as compression of vessels and impaired intratumoral oxygen distribution which impacts radiosensitivity. Our simulations show that biomechanical properties of both tumor and host tissue control patterns of radiosensitivity. Notably, heterogeneous distribution of tumor elastic properties as well as the presence of regions of higher host-tissue stiffness adjacent to the tumor boundary, generate increased and heterogenous mechanical stresses within the tumor. The results are compressed vessels with hypo-perfused and hypoxic tumor tissue, and consequently compromised radiotherapy efficacy. Results show the importance of tumor microenvironment (TME) parameters and suggest that strategies to normalize the TME could improve treatment outcomes and help stratify treatments. Taking together, our work establishes a quantitative pipeline linking MRE biomechanics to oxygen-modulated radiosensitivity.