Abstract:
Despite numerous innovative treatment strategies, the treatment of glioblastoma (GB)
remains challenging. With the current state-of-the-art therapy, most GB patients succumb after about
a year. In the evolution of personalized medicine, targeted radionuclide therapy (TRT) is gaining
momentum, for example, to stratify patients based on specific biomarkers. One of these biomarkers is
deficiencies in DNA damage repair (DDR), which give rise to genomic instability and cancer initiation.
However, these deficiencies also provide targets to specifically kill cancer cells following the synthetic
lethality principle. This led to the increased interest in targeted drugs that inhibit essential DDR
kinases (DDRi), of which multiple are undergoing clinical validation. In this review, the current status
of DDRi for the treatment of GB is given for selected targets: ATM/ATR, CHK1/2, DNA-PK, and
PARP. Furthermore, this review provides a perspective on the use of radiopharmaceuticals targeting
these DDR kinases to (1) evaluate the DNA repair phenotype of GB before treatment decisions are
made and (2) induce DNA damage via TRT. Finally, by applying in-house selection criteria and
analyzing the structural characteristics of the DDRi, four drugs with the potential to become new
therapeutic GB radiopharmaceuticals are suggested.
