Chalmers Conferences, 9th European Conference on Mathematical and Theoretical Biology

Therapies targeting hypoxia reduce tumor volume and delay the malignant transition in gliomas
Alicia Martínez-González, Mario Durán-Prado, Gabriel F Calvo, Francisco J Alcaín, Luis A Pérez-Romasanta, Victor M Pérez-García

Last modified: 2014-06-12


Glioblastoma Multiforme (GBM) is a rapidly evolving high-grade astrocytoma that is dis-tinguished from lower grade glioma by the presence of necrosis, hypercellularity and mi-crovascular hyperplasia, which leads in an aberrant vasculature. As a consequence of this vascular dysfunction it is generated a fluctuating chronic hypoxia which also increases the oxidative stress inducing the transition to more invasive tumor cell phenotypes which accelerates tumor front velocity and infiltration in a diffuse manner. This exacerbated infiltrative ability is one of the reasons of the high recidive cases, which added to its hypercoagulative activity, both have a profound negative impact on patients survival. Some evidences appoint to oxidative stress as the molecular switch driving the hypoxic response, by activation of Hypoxia Inducible Factors, Vascular Endothelial Growth Factors and other angiogenic and growth factors. Moreover, oxidative stress is responsible of the low effect of radiotherapy and chemotherapy on GBM, however it can be reduced improving vasculature functionality with antithrombotics or balancing the redox equilibrium with antioxidants. We studied different therapeutic modalities considering antithrombotics, antioxidants and radiotherapy based in a GBM computational model that incorporates the spatio-temporal interplay among two tumor cell phenotypes corresponding to oxygenated and hypoxic cells, a necrotic core and the vasculature which is degenerating with the tumor progression. Our insilico approach reveals that the treatment of GBM with anti-thrombotics and anti-oxidants would improve vessels functionality, avoiding vaso-occlusions and reducing oxidative stress and the subsequent hypoxic response. This combined treatment would reduce tumor invasion in a synergistic way and sensitize GBM to conventional radiotherapy, hopefully increasing patients survival, which due to the poor prognosis of this kind of tumor, it is considered a big success.


glioma; hypoxia; thrombosis; radioterapia;