scholarly journals The Role of PARP Inhibitors in the Treatment of Prostate Cancer: Recent Advances in Clinical Trials

Biomolecules ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 722
Author(s):  
Mingyue Xia ◽  
Zhigang Guo ◽  
Zhigang Hu
Keyword(s):  
Prostate Cancer ◽  
Drug Resistance ◽  
Synthetic Lethality ◽  
Adenosine Diphosphate ◽  
Parp Inhibitors ◽  
Parp Inhibition ◽  
Castration Resistant Prostate Cancer ◽  
Brca Mutations ◽  
Combination Treatments ◽  
Bet Inhibitors

Poly (adenosine diphosphate-ribose) polymerase inhibitors (PARPis) belong to a class of targeted drugs developed for the treatment of homologous recombination repair (HRR)-defective tumors. Preclinical and limited clinical data suggest that PARP inhibition is effective against prostate cancer (PC) in patients with HRR-deficient tumors and that PARPis can improve the mortality rate of PC in patients with BRCA1/2 mutations through a synthetic lethality. Olaparib has been approved by the FDA for advanced ovarian and breast cancer with BRCA mutations, and as a maintenance therapy for ovarian cancer after platinum chemotherapy. PARPis are also a new and emerging clinical treatment for metastatic castration-resistant prostate cancer (mCRPC). Although PARPis have shown great efficacy, their widespread use is restricted by various factors, including drug resistance and the limited population who benefit from treatment. It is necessary to study the combination of PARPis and other therapeutic agents such as anti-hormone drugs, USP7 inhibitors, BET inhibitors, and immunotherapy. This article reviews the mechanism of PARP inhibition in the treatment of PC, the progress of clinical research, the mechanisms of drug resistance, and the strategies of combination treatments.

scholarly journals BRCA Mutations in Prostate Cancer: Prognostic and Predictive Implications

2020 ◽  
Vol 2020 ◽  
pp. 1-7 ◽  
Author(s):  
Carlo Messina ◽  
Carlo Cattrini ◽  
Davide Soldato ◽  
Giacomo Vallome ◽  
Orazio Caffo ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Parp Inhibitors ◽  
Castration Resistant Prostate Cancer ◽  
Brca Mutations ◽  
Primary Tumors ◽  
Receptor Signalling ◽  
Castration Resistant ◽  
Damage Repair ◽  
Poor Outcomes

Despite chemotherapy and novel androgen-receptor signalling inhibitors (ARSi) have been approved during the last decades, metastatic castration-resistant prostate cancer (mCRPC) remains a lethal disease with poor clinical outcomes. Several studies found that germline or acquired DNA damage repair (DDR) defects affect a high percentage of mCRPC patients. Among DDR defects, BRCA mutations show relevant clinical implications. BRCA mutations are associated with adverse clinical features in primary tumors and with poor outcomes in patients with mCRPC. In addition, BRCA mutations predict good response to poly-ADP ribose polymerase (PARP) inhibitors, such as olaparib, rucaparib, and niraparib. However, concerns still remain on the role of extensive mutational testing in prostate cancer patients, given the implications for patients and for their progeny. The present comprehensive review attempts to provide an overview of BRCA mutations in prostate cancer, focusing on their prognostic and predictive roles.

scholarly journals BRCA Mutations in Prostate Cancer: Assessment, Implications and Treatment Considerations

2021 ◽  
Vol 22 (23) ◽  
pp. 12628
Author(s):  
Sidrah Shah ◽  
Rachelle Rachmat ◽  
Synthia Enyioma ◽  
Aruni Ghose ◽  
Antonios Revythis ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Damage ◽  
Synthetic Lethality ◽  
Genomic Analysis ◽  
Parp Inhibitors ◽  
Brca Mutations ◽  
Prostate Carcinogenesis ◽  
Damage Response ◽  
Treatment Considerations ◽  
Related Mortality

Prostate cancer ranks fifth in cancer-related mortality in men worldwide. DNA damage is implicated in cancer and DNA damage response (DDR) pathways are in place against this to maintain genomic stability. Impaired DDR pathways play a role in prostate carcinogenesis and germline or somatic mutations in DDR genes have been found in both primary and metastatic prostate cancer. Among these, BRCA mutations have been found to be especially clinically relevant with a role for germline or somatic testing. Prostate cancer with DDR defects may be sensitive to poly(ADP-ribose) polymerase (PARP) inhibitors which target proteins in a process called PARylation. Initially they were used to target BRCA-mutated tumor cells in a process of synthetic lethality. However, recent studies have found potential for PARP inhibitors in a variety of other genetic settings. In this review, we explore the mechanisms of DNA repair, potential for genomic analysis of prostate cancer and therapeutics of PARP inhibitors along with their safety profile.

scholarly journals Therapeutic Potential of PARP Inhibitors in the Treatment of Metastatic Castration-Resistant Prostate Cancer

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3467
Author(s):  
Albert Jang ◽  
Oliver Sartor ◽  
Pedro C. Barata ◽  
Channing J. Paller
Keyword(s):  
Prostate Cancer ◽  
Mechanism Of Action ◽  
Therapeutic Potential ◽  
Synthetic Lethality ◽  
Gene Mutations ◽  
Parp Inhibitors ◽  
Cellular Level ◽  
Tumor Control ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant

Metastatic castration-resistant prostate cancer (mCRPC) is an incurable malignancy with a poor prognosis. Up to 30% of patients with mCRPC have mutations in homologous recombination repair (HRR) genes. Poly (ADP-ribose) polymerase (PARP) inhibitors take advantage of HRR deficiency to kill tumor cells based on the concept of synthetic lethality. Several PARP inhibitors (PARPis) have been successful in various malignancies with HRR gene mutations including BRCA1/2, especially in breast cancer and ovarian cancer. More recently, olaparib and rucaparib were approved for mCRPC refractory to novel hormonal therapies, and other PARPis will likely follow. This article highlights the mechanism of action of PARPis at the cellular level, the preclinical data regarding a proposed mechanism of action and the effectiveness of PARPis in cancer cell lines and animal models. The article expands on the clinical development of PARPis in mCRPC, discusses potential biomarkers that may predict successful tumor control, and summarizes present and future clinical research on PARPis in the metastatic disease landscape.

scholarly journals PARP Inhibitors in Melanoma—An Expanding Therapeutic Option?

Cancers ◽  
2021 ◽  
Vol 13 (18) ◽  
pp. 4520
Author(s):  
Wei Yen Chan ◽  
Lauren J. Brown ◽  
Lee Reid ◽  
Anthony M. Joshua
Keyword(s):  
Homologous Recombination ◽  
Synthetic Lethality ◽  
Checkpoint Inhibitors ◽  
Therapeutic Option ◽  
Parp Inhibitors ◽  
Parp Inhibition ◽  
Brca Mutations ◽  
Immune Priming ◽  
Combination Strategies ◽  
Damage Repair

Immunotherapy has transformed the treatment landscape of melanoma; however, despite improvements in patient outcomes, monotherapy can often lead to resistance and tumour escape. Therefore, there is a need for new therapies, combination strategies and biomarker-guided decision making to increase the subset of patients most likely to benefit from treatment. Poly (ADP-ribose) polymerase (PARP) inhibitors act by synthetic lethality to target tumour cells with homologous recombination deficiencies such as BRCA mutations. However, the application of PARP inhibitors could be extended to a broad range of BRCA-negative cancers with high rates of DNA damage repair pathway mutations, such as melanoma. Additionally, PARP inhibition has the potential to augment the therapeutic effect of immunotherapy through multi-faceted immune-priming capabilities. In this review, we detail the immunological role of PARP and rationale for combining PARP and immune checkpoint inhibitors, with a particular focus on a subset of melanoma with homologous recombination defects that may benefit most from this targeted approach. We summarise the biology supporting this combined regimen and discuss preclinical results as well as ongoing clinical trials in melanoma which may impact future treatment.

scholarly journals Differential Activity of PARP Inhibitors in BRCA1- Versus BRCA2-Altered Metastatic Castration-Resistant Prostate Cancer

2021 ◽  
pp. 1200-1220
Author(s):  
Fadi Taza ◽  
Albert E. Holler ◽  
Wei Fu ◽  
Hao Wang ◽  
Nabil Adra ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Overall Survival ◽  
Parp Inhibitor ◽  
Specific Antigen ◽  
Germline Mutations ◽  
Parp Inhibitors ◽  
Parp Inhibition ◽  
Missense Mutations ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant

PURPOSE Two poly (ADP-ribose) polymerase (PARP) inhibitors (olaparib and rucaparib) are US Food and Drug Administration–approved for patients with metastatic castration-resistant prostate cancer (mCRPC) harboring BRCA1/ 2 mutations, but the relative efficacy of PARP inhibition in BRCA1- versus BRCA2-altered mCRPC is understudied. METHODS We conducted a multicenter retrospective analysis involving 12 sites. We collected genomic and clinical data from 123 patients with BRCA1/ 2-altered mCRPC who were treated with PARP inhibitors. The primary efficacy end point was the prostate-specific antigen (PSA) response (≥ 50% PSA decline) rate. Secondary end points were PSA progression-free survival (PSA-PFS), clinical or radiographic PFS, and overall survival. We compared clinical outcomes, and other genomic characteristics, among BRCA1- versus BRCA2-altered mCRPC. RESULTS A total of 123 patients (13 BRCA1 and 110 BRCA2) were included. PARP inhibitors used were olaparib (n = 116), rucaparib (n = 3), talazoparib (n = 2), and veliparib (n = 2). At diagnosis, 72% of patients had Gleason 8-10 disease. BRCA1 patients were more likely to have metastatic disease at presentation (69% v 37%; P = .04). Age, baseline PSA, metastatic distribution, and types of previous systemic therapies were similar between groups. There were equal proportions of germline mutations (51% v 46%; P = .78) in both groups. BRCA1 patients had more monoallelic (56% v 41%; P = .49) and concurrent TP53 (55% v 36%; P = .32) mutations. PSA50 responses in BRCA1- versus BRCA2-altered patients were 23% versus 63%, respectively ( P = .01). BRCA2 patients achieved longer PSA-PFS (HR, 1.94; 95% CI, 0.92 to 4.09; P = .08), PFS (HR, 2.08; 95% CI, 0.99 to 4.40; P = .05), and overall survival (HR, 3.01; 95% CI, 1.32 to 6.83; P = .008). Biallelic (compared with monoallelic) mutations, truncating (compared with missense) mutations, and absence of a concurrent TP53 mutation were associated with PARP inhibitor sensitivity. CONCLUSION PARP inhibitor efficacy is diminished in BRCA1- versus BRCA2-altered mCRPC. This is not due to an imbalance in germline mutations but might be related to more monoallelic mutations and/or concurrent TP53 alterations in the BRCA1 group.

Targeting checkpoint kinases in prostate cancer cells resistant to poly ADP-ribose polymerase inhibitors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e16543-e16543
Author(s):  
Mohammad Omar Atiq ◽  
Goutam Chakraborty ◽  
Subhiksha Nandakumar ◽  
Ying Zhang Mazzu ◽  
Konrad Hermann Stopsack ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Growth ◽  
Molecular Mechanisms ◽  
Brca2 Gene ◽  
Parp Inhibitors ◽  
Parp Inhibition ◽  
Castration Resistant Prostate Cancer ◽  
Genomic Deletions ◽  
Mechanism Of Resistance ◽  
Castration Resistant

e16543 Background: The identification of DNA damage response (DDR) gene abnormalities in various cancers has provided potential therapeutic targets including the poly ADP-ribose polymerase enzyme (PARP). PARP inhibitors are now approved for use in ovarian, breast, and prostate cancer (PC). Olaparib and rucaparib have been given Breakthrough Therapy designation by the FDA for use in patients with metastatic castration-resistant prostate cancer and germline BRCA1/2 or ATM mutations. However, drug resistance limits the efficacy of PARPi. Somatic reversion mutations of BRCA1/2 have been described as one potential mechanism of resistance to PARPi in patients with germline BRCA1/2 mutations. However, in PC, the BRCA2 gene is frequently deleted, in contrast to other cancers, where it is mutated. Thus, we hypothesize that resistance to PARPi in PC may involve alternative molecular mechanisms. Methods: We performed cell viability assays to determine the inhibitory growth (IG) concentrations of olaparib and talazoparib on human castration-resistant PC cell lines (PC-3 and LNCaP-Abl) that have heterozygous genomic deletions of BRCA2. Parental PC-3 cells were cultured in sublethal concentrations (IG 50% and IG 90%) of talazoparib-supplemented media for approximately 2 months to develop talazoparib-resistant cells. We then performed an analysis of phosphorylation status in untreated and treated parental PC-3 and talazoparib-resistant clones with a phosphokinase array. We confirmed this with Western blot. Results: Talazoparib-resistant PC-3 clones showed significantly enhanced cell growth compared to parental cells when cultured in media supplemented with the IG 90% concentration of talazoparib or olaparib. The phosphokinase array revealed a significant increase in the phosphorylation of CHEK2 in talazoparib-resistant clones compared to parental PC-3 cells. Interestingly, a similar increase was seen after 72 hours of treatment with talazoparib, indicating an early connection between PARP inhibition and CHEK2 phosphorylation in PC cells. Moreover, a pan-CHEK inhibitor, prexasertib, led to significant cell growth inhibition in talazoparib-resistant PC-3 clones and a significantly lower IG 50% concentration compared to parental PC-3 cells. Conclusions: We speculate that early activation of CHEK2 may be a primary mechanism of resistance to PARPi in PC cells with deletion of BRCA2. Furthermore, our preliminary data showed that CHEK inhibition can overcome PARPi resistance, indicating a potential for CHEK inhibitor-based therapy for PC patients.

scholarly journals HDAC inhibitors with potential to overcome drug resistance in castration-resistant prostate cancer

2022 ◽  
Author(s):  
Bernhard Biersack ◽  
Bianca Nitzsche ◽  
Michael Höpfner
Keyword(s):  
Prostate Cancer ◽  
Drug Resistance ◽  
Anticancer Drugs ◽  
Synergistic Effects ◽  
Hdac Inhibitors ◽  
Resistance Mechanisms ◽  
Castration Resistant Prostate Cancer ◽  
Combination Treatments ◽  
Castration Resistant ◽  
The One

Epigenetic mechanisms play an important role in the development and persistence of cancer, and histone deacetylase (HDAC) inhibitors are promising anticancer drugs targeting epigenetic modes. Efficient anticancer drugs for the treatment of castration-resistant prostate cancer (CRPC) are sought, and approved HDAC inhibitors have shown promising results on the one hand and severe drawbacks on the other hand. Hence, ways to break the drug resistance mechanisms of existing HDAC inhibitors as well as the design of new promising HDAC inhibitors which can overcome the disadvantages of the classic HDAC inhibitors are of great importance. In this work, HDAC inhibitors with the potential to become a mainstay for the treatment of CRPC in the future as well as suitable combination treatments of HDAC inhibitors with other anticancer drugs leading to considerable synergistic effects in treated CRPCs are discussed.

scholarly journals Changing the History of Prostate Cancer with New Targeted Therapies

Biomedicines ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 392
Author(s):  
Susana Hernando Polo ◽  
Diana Moreno Muñoz ◽  
Adriana Carolina Rosero Rodríguez ◽  
Jorge Silva Ruiz ◽  
Diana Isabel Rosero Rodríguez ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Targeted Therapies ◽  
Synthetic Lethality ◽  
Castration Resistant Prostate Cancer ◽  
Phosphatidylinositol 3 Kinase ◽  
Castration Resistant ◽  
Therapeutic Landscape ◽  
Important Benefit ◽  
History Of ◽  
Repair Genes

The therapeutic landscape of metastatic castration-resistant prostate cancer (mCRPC) is changing due to the emergence of new targeted therapies for the treatment of different molecular subtypes. Some biomarkers are described as potential molecular targets different from classic androgen receptors (AR). Approximately 20–25% of mCRPCs have somatic or germline alterations in DNA repair genes involved in homologous recombination. These subtypes are usually associated with more aggressive disease. Inhibitors of the enzyme poly ADP ribose polymerase (PARPi) have demonstrated an important benefit in the treatment of these subtypes of tumors. However, tumors that resistant to PARPi and wildtype BRCA tumors do not benefit from these therapies. Recent studies are exploring drug combinations with phosphatidylinositol-3-kinase (PI3K) or protein kinase B (AKT) inhibitors, as mechanisms to overcome resistance or to induce BRCAness and synthetic lethality. This article reviews various different novel strategies to improve outcomes in patients with prostate cancer.

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