Recent Research Advances in Double-Strand Break and Mismatch Repair Defects in Prostate Cancer and Potential Clinical Applications
Abstract
:1. Introduction
2. Mechanisms of the DNA Damage Repair
3. Immune Checkpoint Molecules: PD-L1 and CTLA-4
4. Implications of the MMR on Tumorigenesis and Its Alterations in Prostate Cancer
4.1. MLH1
4.2. MSH2
4.3. MSH6
4.4. PMS2
4.5. Clinical Implications of MMR Alterations in Prostate Cancer
4.5.1. Impact of MMR Alterations on Treatment Strategies in Prostate Cancer
4.5.2. Immune Checkpoint Inhibitors
4.5.3. PARP Inhibitors
4.5.4. Novel Treatment Strategies Aiming MMR Genes
5. Implications of the DSBR on Tumorigenesis and Its Alterations in PC
5.1. Homologous Recombination
5.1.1. BRCA1 and BRCA2
5.1.2. MDC1
5.1.3. The RAD Family of Genes: RAD51 and RAD54
5.1.4. MRN Complex
5.2. Non-Homologous End Joining
5.2.1. TP53 and TP53BP1
5.2.2. Ku70 and Ku80
5.2.3. DNA-Dependent Protein Kinase Catalytic Subunit (DNA-PKcs)
5.2.4. LIG4
5.2.5. ATM
5.2.6. XRCC1, XRCC2 and XRCC3
6. Current Role of DDR Mutation in Prostate Cancer Treatment
7. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Drug Name | Clinical Trial Number | Efficacy/Results | Annotation | |
---|---|---|---|---|
Pembrolizumab | NCT02054806 [70] Phase 1 | ORR: 17.4% | Investigated in locally advanced and/or metastatic PC | |
PFS: 3.5 months | ||||
OS: 7.9 months | ||||
NCT03093428 [72] (active) Phase 2 | Pembrolizumab + Radium 223 | Radium 223 | Pembrolizumab + Radium 223 vs. Radium 223 alone in mCRPC | |
OS: 16.9 m | OS: 16.0 m | |||
PFS: 6.1 m | PFS: 5.7 m | |||
NCT02787005 [73] Phase 2 | Full description of the results available in the citation | mCRPC patients divided into 5 cohorts. Accelerated FDA-approval in May 2017 for unresectable/metastatic, MSI-H or MMR-deficient solid tumors | ||
NCT03658447 NCT03582475 NCT04148937 NCT03849469 Phase 1 | ||||
Nivolumab | NCT02601014 [74] Phase 2 | Nivolumab + Ipilimumab | Enzalutamide + Nivolumab + Ipilimumab | Investigated in mCRPC |
ORR: 25% | ORR: 0% | |||
OS: 8.2% | OS: 14.2% | |||
PFS: 3.7 m | PFS: 2.9 m | |||
NCT03554317 NCT00441337 NCT03532217 NCT03835533 Phase 1 | ||||
Atezolizumab | NCT03016312 [75] Phase 3 | Atezolizumab + enzalutamide | Enzalutamide | Investigated in combination with enzalutamide in mCRPC |
OS: 15.2 m | OS: 16.6 m | |||
rPFS: 4.2 m | rPFS: 4.1 m | |||
OR: 13.7% | OR: 7.4% | |||
NCT04404140 NCT03024216 NCT02814669 NCT02655822 Phase 1 | ||||
Durvalumab | NCT04089553 [76] (active) Phase 2 | AZD4635 + Durvalumab | AZD4635 + Oleclumab | Investigated in combination with AZD4635 in mCRPC |
% of patients with rPRFS at 6 months: 8.8% | % of patients with rPRFS at 6 months: 11.1% | |||
NCT03204812 [77] Phase 2 | rPFS: 3.7 m OS: 28.1 m | Durvalumab + Tremelimumab in naive patients with mCRPC | ||
NCT04495179 Phase 2, NCT02643303 Phase 1 | ||||
Ipilimumab | NCT00861614 [78] Phase 3 | Ipilimumab + RTH | Placebo + RTH | Investigated as monotherapy or in combination with RTH in mCRPC |
OS: 11.04 m | OS: 10.02 m | |||
OSR at year 5: 7.9% | OSR at year 5: 2.7% | |||
PFS: 4.01 m | PFS: 3.06 m | |||
NCT01057810 [79] Phase 3 | Ipilimumab | Placebo | ||
OS: 28.65 m | OS: 29.73 m | |||
PFS: 5.59 m | PFS: 3.81 m | |||
NCT01194271 NCT02279862 NCT00323882 NCT00170157 NCT00050596 NCT02601014 NCT01498978 NCT01804465 Phase 2 NCT03532217 NCT00064129 NCT02113657 NCT00323882 NCT01832870 Phase 1 |
Drug Name | Clinical Trial Number/Phase | Efficacy/Results | Annotation | ||||
---|---|---|---|---|---|---|---|
Olaparib | NCT02987543 [83] Phase 3 | Cohort A with olaparib | Cohort A with Investigators Choice of NHA | Cohort B with olaparib | Cohort B with Investigators Choice of NHA | Approved by FDA for mCRPC with HRR gene alterations, including BRCA1/2, ATM (PROfound clinical trial). Cohort A: mCRPC with either BRCA1/2/ATM mutation Cohort B: 12 other genes involved in the HRR. Investigators Choice of NHA: enzalutamide or abiraterone acetate | |
ORR: 33.3% | ORR: 2.3% | n/a | n/a | ||||
OS: 56.2% | OS: 68.7% | n/a | n/a | ||||
RPFS: 7.39 m | RPFS: 3.55 m | n/a | n/a | ||||
RPFS in cohort A + B with olaparib: 5.82 m | RPFS in cohort A + B with Investigators Choice of NHA: 3.52 m | ||||||
NCT03205176, NCT02324998 Phase 1 NCT03434158 Phase 2 | |||||||
Rucaparib | NCT02952534 [84] Phase 2 | BRCA | ATM | CDK12 | CHEK2 | Others | Approved by FDA for mCRPC with BRCA1/2 mutations that have been previously treated with androgen receptor-directed therapy and a taxane-based chemotherapy (TRITON2 clinical trial) mCRPC patients divided into 5 groups with: either BRCA, ATM, CDK12, CHEK or other HRR gene mutation. |
ORR: 45.7% | ORR: 0% | ORR: 0% | ORR: 0% | ORR: 41.2% | |||
RPFS: 10.7 m | RPFS: 5.3 m | RPFS:3.7 m | RPFS: 9.4 m | RPFS: 11.6 m | |||
OS: 17.2 m | OS: 14.6 m | OS: 13.9 m | OS: 11.1 m | OS: 11.6 m | |||
NCT03840200 Phase 1 | |||||||
Niraparib | NCT02854436 (active) Phase 2 | ORR: 50%; mPFS: 11 months [85] | Investigated in combination with abiraterone and prednisone in mCRPC with HRR gene alterations, including BRCA1/2, ATM | ||||
NCT02924766 Phase 1b NCT03076203, NCT00749502 Phase 1 | |||||||
Talazoparib | NCT03148795 Phase 2 (active) [86] | ORR: 29.8% PFS: 5.6 m | Investigated in mCRPC who previously received taxane-based chemotherapy and progressed on at least 1 novel hormonal agent | ||||
NCT03330405 Phase 2 | Investigated in solid tumors including PC | ||||||
NCT01286987 Phase 1 | |||||||
Veliparib | NCT01576172 [87] Phase 2 | Abiraterone Acetate + Prednisone | Abiraterone Acetate + Prednisone + Veliparib | Investigated in combination with abiraterone in mCRPC | |||
ORR: 45% | ORR: 52.2% | ||||||
PFS: 10.1 m | PFS: 11.0 m | ||||||
NCT01085422, NCT00892736 Phase 1 |
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Jaworski, D.; Brzoszczyk, B.; Szylberg, Ł. Recent Research Advances in Double-Strand Break and Mismatch Repair Defects in Prostate Cancer and Potential Clinical Applications. Cells 2023, 12, 1375. https://doi.org/10.3390/cells12101375
Jaworski D, Brzoszczyk B, Szylberg Ł. Recent Research Advances in Double-Strand Break and Mismatch Repair Defects in Prostate Cancer and Potential Clinical Applications. Cells. 2023; 12(10):1375. https://doi.org/10.3390/cells12101375
Chicago/Turabian StyleJaworski, Damian, Bartosz Brzoszczyk, and Łukasz Szylberg. 2023. "Recent Research Advances in Double-Strand Break and Mismatch Repair Defects in Prostate Cancer and Potential Clinical Applications" Cells 12, no. 10: 1375. https://doi.org/10.3390/cells12101375