Perspective on the Use of DNA Repair Inhibitors as a Tool for Imaging and Radionuclide Therapy of Glioblastoma

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.

Maintaining Genome Integrity: Protein Kinases and Phosphatases Orchestrate the Balancing Act of DNA Double-Strand Breaks Repair in Cancer

“…It can act as a single agent or in combination with other drugs, such as gemcitabine and cytarabine (NCT00779584). MK-8776 was previously known as SCH 900776, a pyrazolo[1,5-a]pyrimidine derivative that binds with the hinge region located in the kinase ATP-binding site [ 341 , 345 ]. Previous studies show that MK-8776 treatment can enhance cancer-cell sensitivity to hydroxyurea, gemcitabine, and radiation, leading to DNA damage accumulation [ 346 , 347 ].…”

Poly (ADP-ribose) polymerases as PET imaging targets for central nervous system diseases

“…PARP1-mediated PARylation is sufficient for oligodendrocyte progenitor cell differentiation ( 53 ), and PARP1 polymorphisms was regarded as one of the potential risk factors for spinal cord injury (SCI) in a clinical study ( 54 ). Besides, brain or spinal cord tumors remain difficult types of cancers to treat, such as glioblastoma (GBM), even after four PARP inhibitors were approved by FDA as PARP1 overexpression is present in various cancers ( 55 ). For other diseases that are resulted from structural damage of the nervous system, such as Bell's palsy, carpal tunnel syndrome, cervical spondylosis, Guillain-Barré syndrome, and peripheral neuropathy, PARP affects neuronal recovery albeit no direct evidence exists to prove the exact roles of PARP in these pathological changes.…”

New perspective on DNA response pathway (DDR) in glioblastoma, focus on classic biomarkers and emerging roles of ncRNAs

“…Since both, RT and chemotherapy induce DNA damage and activate DDR, molecules that target DDR inhibition are investigated for their therapeutic role in overcoming treatment resistance (Ref. 14). Surprisingly, even though the DDR pathway activates post-irradiation in both parent cells and recurrent cells, Kaur et al .…”

“…Since both, RT and chemotherapy induce DNA damage and activate DDR, molecules that target DDR inhibition are investigated for their therapeutic role in overcoming treatment resistance (Ref. 14). Surprisingly, even though the DDR pathway activates post-irradiation in both parent cells and recurrent cells, Kaur et al demonstrated on GBM cell line models (U87MG and SF268) that there are differences in the DDR pathway activation in primary versus recurrent post-treatment GBM cells.…”