Everix Liesbeth, Nair Shankari, Driver Cathryn H S, Goethals Ingeborg, Sathekge Mike M, Ebenhan Thomas, Vandevoorde Charlot, Bolcaen Julie
Molecular Imaging Center Antwerp (MICA), University of Antwerp, 2610 Wilrijk, Belgium.
Radiation Biophysics Division, SSC Laboratory, iThemba LABS, Cape Town 7131, South Africa.
Cancers (Basel). 2022 Apr 3;14(7):1821. doi: 10.3390/cancers14071821.
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.
尽管有众多创新的治疗策略，但胶质母细胞瘤（GB）的治疗仍然具有挑战性。采用当前的先进疗法，大多数GB患者在大约一年后就会死亡。在个性化医疗的发展过程中，靶向放射性核素疗法（TRT）正逐渐兴起，例如，根据特定生物标志物对患者进行分层。其中一种生物标志物是DNA损伤修复（DDR）缺陷，这会导致基因组不稳定和癌症发生。然而，这些缺陷也根据合成致死原理提供了特异性杀死癌细胞的靶点。这使得人们对抑制关键DDR激酶（DDRi）的靶向药物的兴趣增加，其中多种药物正在进行临床验证。在本综述中，针对选定的靶点：ATM/ATR、CHK1/2、DNA-PK和PARP，给出了DDRi治疗GB的现状。此外，本综述还对靶向这些DDR激酶的放射性药物的应用前景进行了展望，以（1）在做出治疗决策前评估GB的DNA修复表型，以及（2）通过TRT诱导DNA损伤。最后，通过应用内部选择标准并分析DDRi的结构特征，提出了四种有潜力成为新型治疗GB放射性药物的药物。
