Factors affecting the radiation response in glioblastoma

Abstract

Glioblastoma (GBM) is a highly invasive primary brain tumour in adults with a 5-year survival rate of less than 10%. Conventional radiotherapy with photons, along with concurrent and adjuvant temozolomide, is the mainstay for treatment of GBM although no significant improvement in survival rates has been observed over the last twenty years. Inherent factors such as tumour hypoxia, radioresistant GBM stem cells, and upregulated DNA damage response (DDR) mechanisms are well established as contributing to treatment resistance and tumour recurrence. While it is understandable that efforts have focussed on targeting these factors to overcome this phenotype, there have also been striking advances in precision radiotherapy techniques, including proton beam therapy (PBT) and carbon ion radiotherapy (CIRT). These enable higher doses of radiation to be delivered precisely to the tumour while minimising doses to surrounding normal tissues and organs at risk. These alternative radiotherapy techniques also benefit from increased biological effectiveness, particularly in the case of CIRT. Although not researched extensively to date, combining these new radiation modalities with radio-enhancing agents may be particularly effective in improving outcomes for patients with GBM.

Combining Pr3+-Doped Nanoradiosensitizers and Endogenous Protoporphyrin IX for X-ray-Mediated Photodynamic Therapy of Glioblastoma Cells

“…They may survive, proliferate, and modulate signaling and other events, or they may die after multiple replication cycles. 53 GBM fate decisions are based on the accumulation of cell damage, which can instigate further cell death, transition to cellular senescence, or continued proliferation. To define these parameters, we examined crude cell extracts for established biomarkers that report on DNA damage, apoptosis (Figure 4C), and components of cellular support systems that promote GBM cell survival (Figure S13).…”

“…The properties of these surviving/early apoptotic cells will ultimately determine the success of the treatment. They may survive, proliferate, and modulate signaling and other events, or they may die after multiple replication cycles …”

Sp1 Upregulation Bolsters the Radioresistance of Glioblastoma Cells by Promoting Double Strand Breaks Repair

“…Radioresistance is a major barrier to effective radiotherapy outcomes in GBM patients [ 18 ]. Activation of the DNA damage response pathway and the resulting increase in the DNA repair capacity mainly contribute to developing GBM radioresistance [ 19 , 20 , 21 ]. Therefore, it is crucial to understand its underlying mechanisms to improve the therapeutic outcomes.…”

Understanding Glioblastoma Signaling, Heterogeneity, Invasiveness, and Drug Delivery Barriers

“…Glioblastomas are among the most radio-resistant aggressive forms of cancer [ 35 ]. Several efforts were made to identify biomarkers to determine and select patients with radio-sensitive tumors [ 36 ].…”