Preclinical and clinical advances to overcome hypoxia in glioblastoma multiforme

Abstract

Glioblastoma multiforme (GBM) is the most common adult primary brain tumor. The standard clinical treatment of GBM includes a maximal surgical resection followed by concomitant radiotherapy (RT) and chemotherapy sessions with Temozolomide (TMZ) in addition to adjuvant TMZ cycles. Despite the severity of this protocol, GBM is highly resistant and recurs in almost all cases while the protocol remains unchanged since 2005. Limited-diffusion or chronic hypoxia has been identified as one of the major key players driving this aggressive phenotype. The presence of hypoxia within the tumor bulk contributes to the activation of hypoxia signaling pathway mediated by the hypoxia-inducing factors (HIFs), which in turn activate biological mechanisms to ensure the adaptation and survival of GBM under limited oxygen and nutrient supply. Activated downstream pathways are involved in maintaining stem cell-like phenotype, inducing mesenchymal shift, invasion, and migration, altering the cellular and oxygen metabolism, and increasing angiogenesis, autophagy, and immunosuppression. Therefore, in this review will discuss the recent preclinical and clinical approaches that aim at targeting tumor hypoxia to enhance the response of GBM to conventional therapies along with their results and limitations upon clinical translation.

Fig. 1. Tumor reoxygenation strategies and their respective biological outcome on GBM.

The presence of oxygen upon treatment delivery, especially radiotherapy, increases the damage caused by such treatments on the DNA. In the presence of oxygen, more indirect DNA damage is generated due to the formation of ROS and the persistence of peroxyl adducts that are harder to repair, in addition to an increase in the cell cycle arrest, thus sensitizing GBM to conventional treatments. As the diffusion of oxygen increases through the tumor, other hypoxia-induced adaptations are reversed such as the increased degradation of HIF-1/2α in the presence of oxygen.

Fig. 2. Preclinical and clinical approaches to target tumor hypoxia in GBM.

The first-line therapy constitutes of a multimodal approach including surgery and chemoradiotherapy, yet GBM has been shown to exhibit resistance to such medical intervention. Although chronic or diffusion-limited hypoxia represents one of the pillars driving this aggressive behavior, it is overlooked in the diagnosis and treatment of GBM. Several preclinical and clinical approaches have been suggested as methods to reverse the effect of hypoxia on GBM response to conventional treatments. These include the inhibition of the hypoxia signaling pathway via HIFs, increasing the presence of oxygen within the tumor bulk or reoxygenation, targeting angiogenesis the main driver of tumor hypoxia, and reducing the cellular oxygen consumption via mitochondrial or cellular metabolism.