Biology and Development of DNA-Targeted Drugs, Focusing on Synthetic Lethality, DNA Repair, and Epigenetic Modifications for Cancer: A Review
Abstract
:1. Introduction
2. Understanding DNA Structure and Function
3. Characterizing Cancers to Targeted Treatments
4. Precision Medicine and Molecular Markers
5. Strategies for Incorporating Drugs That Target DNA
5.1. PARP Inhibitors
5.2. SLFN11
Drug | Indication | Phase | Cancer Type | Clinical Trial | Efficacy | Reference |
---|---|---|---|---|---|---|
niraparib | maintenance | 2 | extensive disease small cell lung | NCT05718323 | n/a | |
talazoparib | maintenance | 2 | extensive disease small cell lung | NCT04334941 | atezolizumab plus talazoparib 4.2 months vs. atezolizumab 2.8 months, HR 0.70 | [54] |
olaparib | combination | 2 | relapsed small cell lung | NCT04939662 | n/a | |
olaparib | combination | 2 | uterine leiomyosarcoma | NCT03880019 | PFS 6.9 months | [55] |
5.3. Methylguanine Methyltransferase (MGMT)
5.4. Ataxia Telangiectasia and RAD3-Related (ATR) Kinase
5.5. Binding Strength between Anticancer Drugs and DNA
5.6. Targeting DNA Hypermethylation
6. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Drug | Indication | Phase | Cancer Type | Clinical Trial | Efficacy | Reference |
---|---|---|---|---|---|---|
olaparib | maintenance | 3 | ovary | SOLO2/ENGOT-Ov21, NCT01874353 | PFS 19.1 months vs. placebo 5.5 months, HR 0.30 | [23] |
olaparib | maintenance | 3 | ovary | SOLO1/GOG 3004, NCT01844986 | PF ratio at 3 years 60% vs. placebo 27%, HR 0.30 OS ratio at 7 years 67% vs. placebo 46.5%, HR 0.55 | [24,25] |
olaparib | maintenance | 3 | ovary | NCT03534453 | PFS 16.1 m | [26] |
niraparib | maintenance | 3 | ovary | ENGOT-OV16/NOVA, NCT01847274 (gBRCA Cohort) | PFS 21.0 months vs. placebo 5.5 months, HR 0.27 | [18] |
niraparib | maintenance | 3 | ovary | NCT02655016 | PFS 21.9 months vs. placebo 10.4 months, HR 0.43 | [27] |
rucaparib | maintenance | 3 | ovary | ARIEL3, NCT01968213 (BRCA-Mutant cohort) | PFS 16.6 months vs. placebo 5.4 months, HR 0.23 | [28] |
rucaparib | monotherapy | 3 | ovary fallopian tube, or primary peritoneal | ARIEL4, NCT02855944 (Efficacy Population) | PFS 7.4 months vs. chemo 5.7 months, HR 0.64 | [19] |
rucaparib | monotherapy | 3 | ovary | NCT03522246 | PFS 28.7 months vs. placebo 11.3 months, HR 0.47 | [29] |
Olaparib | monotherapy | 3 | breast | OlympiAD, NCT02000622 | PFS 7.0 months vs. chemo 4.2 months, HR 0.58 | [16] |
olaparib | maintenance | 3 | breast | OlympiA, NCT02032823 | PF at 3 years 85.9% vs. placebo 77.1%, HR 0.58 OS at 4 years 89.8% vs. placebo 86.4%, HR 0.68 | [30,31] |
olaparib | neoadjuvant | 2/3 | breast | NCT03150576 | n/a | [32] |
olaparib | monotherapy | 3 | breast | NCT03286842 | PFS 8.11 months | [33] |
talazoparib | monotherapy | 3 | breast | EMBRACA, NCT01945775 | PFS 8.6 months vs. chemo 5.6 months, HR 0.54 | [17] |
niraparib | monotherapy | 3 | breast | NCT01905592 | PFS 4.1 months vs. chemo 3.1 months, HR 0.96(censored) | [34] |
niraparib | monotherapy | 3 | breast | NCT04915755 | n/a | [35] |
olaparib | monotherapy | 3 | prostate | PROfound, NCT02987543 (Cohort A) | PFS 7.4 months vs. control 3.6 months, HR 0.34 | [22] |
talazoparib | combination | 3 | prostate | NCT04821622 | n/a | [36] |
olaparib | maintenance | 3 | pancreas | POLO, NCT02184195 | PFS 7.4 months vs. 3.8 months, HR 0.53 | [37] |
niraparib | maintenance | 3 | small cell lung | NCT03516084 | PFS 1.54 months vs. placebo 1.36 months, HR 0.66(censored) | [38] |
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Watanabe, K.; Seki, N. Biology and Development of DNA-Targeted Drugs, Focusing on Synthetic Lethality, DNA Repair, and Epigenetic Modifications for Cancer: A Review. Int. J. Mol. Sci. 2024, 25, 752. https://doi.org/10.3390/ijms25020752
Watanabe K, Seki N. Biology and Development of DNA-Targeted Drugs, Focusing on Synthetic Lethality, DNA Repair, and Epigenetic Modifications for Cancer: A Review. International Journal of Molecular Sciences. 2024; 25(2):752. https://doi.org/10.3390/ijms25020752
Chicago/Turabian StyleWatanabe, Kiyotaka, and Nobuhiko Seki. 2024. "Biology and Development of DNA-Targeted Drugs, Focusing on Synthetic Lethality, DNA Repair, and Epigenetic Modifications for Cancer: A Review" International Journal of Molecular Sciences 25, no. 2: 752. https://doi.org/10.3390/ijms25020752