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

Liesbeth Everix; Shankari Nair; Cathryn H S Driver; Ingeborg Goethals; Mike M Sathekge; Thomas Ebenhan; Charlot Vandevoorde; Julie Bolcaen

doi:10.3390/cancers14071821

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

Cancers (Basel). 2022 Apr 3;14(7):1821. doi: 10.3390/cancers14071821.

Authors

Liesbeth Everix¹, Shankari Nair², Cathryn H S Driver^{3

4}, Ingeborg Goethals⁵, Mike M Sathekge^{3

6}, Thomas Ebenhan^{3

6}, Charlot Vandevoorde², Julie Bolcaen²

Affiliations

¹ Molecular Imaging Center Antwerp (MICA), University of Antwerp, 2610 Wilrijk, Belgium.
² Radiation Biophysics Division, SSC Laboratory, iThemba LABS, Cape Town 7131, South Africa.
³ Pre-Clinical Imaging Facility, Nuclear Medicine Research Infrastructur e NOC, Pelindaba, Brits 0242, South Africa.
⁴ Department of Radiochemistry, South African Nuclear Energy Corporation, Pelindaba, Brits 0240, South Africa.
⁵ Department of Nuclear Medicine, Ghent University Hospital, 9000 Ghent, Belgium.
⁶ Nuclear Medicine Department, University of Pretoria and Steve Biko Academic Hospital, Pretoria 0001, South Africa.

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.

Keywords: DNA damage; DNA repair inhibitors; glioblastoma; molecular imaging; nuclear medicine; radiochemistry; radiopharmaceuticals; targeted radionuclide therapy; theranostics.

Publication types

Review