scholarly journals PARP Inhibitors as a Therapeutic Agent for Homologous Recombination Deficiency in Breast Cancers

2019 ◽  
Vol 8 (4) ◽  
pp. 435 ◽  
Author(s):  
Man Keung ◽  
Yanyuan Wu ◽  
Jaydutt Vadgama
Keyword(s):  
Dna Repair ◽  
Homologous Recombination ◽  
Cancer Cells ◽  
Anticancer Agents ◽  
Excision Repair ◽  
Parp Inhibitor ◽  
Predictive Biomarkers ◽  
Parp Inhibitors ◽  
Homologous Recombination Deficiency ◽  
Repair Pathways

Poly (ADP-ribose) polymerases (PARPs) play an important role in various cellular processes, such as replication, recombination, chromatin remodeling, and DNA repair. Emphasizing PARP’s role in facilitating DNA repair, the PARP pathway has been a target for cancer researchers in developing compounds which selectively target cancer cells and increase sensitivity of cancer cells to other anticancer agents, but which also leave normal cells unaffected. Since certain tumors (BRCA1/2 mutants) have deficient homologous recombination repair pathways, they depend on PARP-mediated base excision repair for survival. Thus, inhibition of PARP is a promising strategy to selectively kill cancer cells by inactivating complementary DNA repair pathways. Although PARP inhibitor therapy has predominantly targeted BRCA-mutated cancers, this review also highlights the growing conversation around PARP inhibitor treatment for non-BRCA-mutant tumors, those which exhibit BRCAness and homologous recombination deficiency. We provide an update on the field’s progress by considering PARP inhibitor mechanisms, predictive biomarkers, and clinical trials of PARP inhibitors in development. Bringing light to these findings would provide a basis for expanding the use of PARP inhibitors beyond BRCA-mutant breast tumors.

scholarly journals Biomarkers for Homologous Recombination Deficiency in Cancer

2021 ◽  
Vol 11 (7) ◽  
pp. 612
Author(s):  
Svenja Wagener-Ryczek ◽  
Sabine Merkelbach-Bruse ◽  
Janna Siemanowski
Keyword(s):  
Dna Repair ◽  
Homologous Recombination ◽  
Molecular Mechanisms ◽  
Brca Mutation ◽  
Parp Inhibitor ◽  
Parp Inhibitors ◽  
Clinical Diagnostics ◽  
Clinical Samples ◽  
Dna Double Strand Breaks ◽  
Homologous Recombination Deficiency

DNA double-strand breaks foster tumorigenesis and cell death. Two distinct mechanisms can be activated by the cell for DNA repair: the accurate mechanism of homologous recombination repair or the error-prone non-homologous end joining. Homologous Recombination Deficiency (HRD) is associated with sensitivity towards PARP inhibitors (PARPi) and its determination is used as a biomarker for therapy decision making. Nevertheless, the biology of HRD is rather complex and the application, as well as the benefit of the different HRD biomarker assays, is controversial. Acquiring knowledge of the underlying molecular mechanisms is the main prerequisite for integration of new biomarker tests. This study presents an overview of the major DNA repair mechanisms and defines the concepts of HRR, HRD and BRCAness. Moreover, currently available biomarker assays are described and discussed with respect to their application for routine clinical diagnostics. Since patient stratification for efficient PARP inhibitor therapy requires determination of the BRCA mutation status and genomic instability, both should be established comprehensively. For this purpose, a broad spectrum of distinct assays to determine such combined HRD scores is already available. Nevertheless, all tests require careful validation using clinical samples to meet the criteria for their establishment in clinical testing.

scholarly journals How to measure homologous recombination deficiency in ovarian cancer

2017 ◽  
Vol 5 (1) ◽  
pp. 15-20 ◽  
Author(s):  
Claudia Marchetti ◽  
Iain A. McNeish
Keyword(s):  
Dna Repair ◽  
Homologous Recombination ◽  
Somatic Mutations ◽  
Parp Inhibitors ◽  
Important Advance ◽  
Brca1 And Brca2 ◽  
Homologous Recombination Deficiency ◽  
Repair Pathways ◽  
Defective Dna Repair ◽  
Important Therapeutic Target

Defective DNA repair via homologous recombination (HR) is common in ovarian high grade serous carcinomas, and homologous recombination deficiency (HRD) represents an important therapeutic target in epithelial ovarian cancers (EOCs). The development of poly(ADP ribose) polymerase (PARP) inhibitors (PARPi) has been an important advance in the treatment of HR-deficient EOCs with the potential to change daily clinical practice. However, while germline and somatic mutations in BRCA1 and BRCA2 are still the most important mechanisms of HRD, alterations in other DNA repair pathways might also contribute to defective HR. In this review, we focus on current and emerging approaches for identifying and targeting HR-deficient EOCs, and discuss the challenges associated with these approaches.

scholarly journals WIP1 Promotes Homologous Recombination and Modulates Sensitivity to PARP Inhibitors

Cells ◽  
2019 ◽  
Vol 8 (10) ◽  
pp. 1258 ◽  
Author(s):  
Kamila Burdova ◽  
Radka Storchova ◽  
Matous Palek ◽  
Libor Macurek
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Homologous Recombination ◽  
Cancer Cells ◽  
Genotoxic Stress ◽  
Parp Inhibitors ◽  
Cell Cycle Checkpoint ◽  
Dna Lesion ◽  
Cycle Checkpoint ◽  
G2 Cells

Genotoxic stress triggers a combined action of DNA repair and cell cycle checkpoint pathways. Protein phosphatase 2C delta (referred to as WIP1) is involved in timely inactivation of DNA damage response by suppressing function of p53 and other targets at chromatin. Here we show that WIP1 promotes DNA repair through homologous recombination. Loss or inhibition of WIP1 delayed disappearance of the ionizing radiation-induced 53BP1 foci in S/G2 cells and promoted cell death. We identify breast cancer associated protein 1 (BRCA1) as interactor and substrate of WIP1 and demonstrate that WIP1 activity is needed for correct dynamics of BRCA1 recruitment to chromatin flanking the DNA lesion. In addition, WIP1 dephosphorylates 53BP1 at Threonine 543 that was previously implicated in mediating interaction with RIF1. Finally, we report that inhibition of WIP1 allowed accumulation of DNA damage in S/G2 cells and increased sensitivity of cancer cells to a poly-(ADP-ribose) polymerase inhibitor olaparib. We propose that inhibition of WIP1 may increase sensitivity of BRCA1-proficient cancer cells to olaparib.

scholarly journals PARP Inhibitors in Ovarian Cancer: The Route to “Ithaca”

Diagnostics ◽  
2019 ◽  
Vol 9 (2) ◽  
pp. 55 ◽  
Author(s):  
Boussios ◽  
Karathanasi ◽  
Cooke ◽  
Neille ◽  
Sadauskaite ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Repair ◽  
Homologous Recombination ◽  
Brca Mutation ◽  
Parp Inhibitor ◽  
Parp Inhibitors ◽  
Parp Inhibition ◽  
Current Evidence ◽  
Repair Pathway ◽  
Significant Efficacy

Poly (ADP-ribose) polymerase (PARP) inhibitors are a novel class of therapeutic agents that target tumors with deficiencies in the homologous recombination DNA repair pathway. Genomic instability characterizes high-grade serous ovarian cancer (HGSOC), with one half of all tumors displaying defects in the important DNA repair pathway of homologous recombination. Early studies have shown significant efficacy for PARP inhibitors in patients with germline breast related cancer antigens 1 and 2 (BRCA1/2) mutations. It has also become evident that BRCA wild-type patients with other defects in the homologous recombination repair pathway benefit from this treatment. Companion homologous recombination deficiency (HRD) scores are being developed to guide the selection of patients that are most likely to benefit from PARP inhibition. The choice of which PARP inhibitor is mainly based upon the number of prior therapies and the presence of a BRCA mutation or HRD. The identification of patients most likely to benefit from PARP inhibitor therapy in view of HRD and other biomarker assessments is still challenging. The aim of this review is to describe the current evidence for PARP inhibitors in ovarian cancer, their mechanism of action, and the outstanding issues, including the rate of long-term toxicities and the evolution of resistance.

scholarly journals Identification of Novel Biomarkers of Homologous Recombination Defect in DNA Repair to Predict Sensitivity of Prostate Cancer Cells to PARP-Inhibitors

2019 ◽  
Vol 20 (12) ◽  
pp. 3100 ◽  
Author(s):  
Daniela Criscuolo ◽  
Francesco Morra ◽  
Riccardo Giannella ◽  
Aniello Cerrato ◽  
Angela Celetti
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
Homologous Recombination ◽  
Cancer Cells ◽  
Synthetic Lethality ◽  
Parp Inhibitors ◽  
Androgen Deprivation ◽  
Prostate Cancer Cells ◽  
Castration Resistant ◽  
Novel Biomarkers

One of the most common malignancies in men is prostate cancer, for which androgen deprivation is the standard therapy. However, prostate cancer cells become insensitive to anti-androgen treatment and proceed to a castration-resistant state with limited therapeutic options. Therefore, besides the androgen deprivation approach, novel biomarkers are urgently required for specific targeting in this deadly disease. Recently, germline or somatic mutations in the homologous recombination (HR) DNA repair genes have been identified in at least 20–25% of metastatic castration-resistant prostate cancers (mCRPC). Defects in genes involved in HR DNA repair can sensitize cancer cells to poly(ADP-ribose) polymerase (PARP) inhibitors, a class of drugs already approved by the Food and Drug Administration (FDA) for breast and ovarian cancer carrying germline mutations in BRCA1/2 genes. For advanced prostate cancer carrying Breast cancer1/2 (BRCA1/2) or ataxia telengiectasia mutated (ATM) mutations, preclinical studies and clinical trials support the use of PARP-inhibitors, which received breakthrough therapy designation by the FDA. Based on these assumptions, several trials including DNA damage response and repair (DDR) targeting have been launched and are ongoing for prostate cancer. Here, we review the state-of-the-art potential biomarkers that could be predictive of cancer cell synthetic lethality with PARP inhibitors. The identification of key molecules that are affected in prostate cancer could be assayed in future clinical studies to better stratify prostate cancer patients who might benefit from target therapy.

scholarly journals Alternate therapeutic pathways for PARP inhibitors and potential mechanisms of resistance

2021 ◽  
Vol 53 (1) ◽  
pp. 42-51
Author(s):  
Dae-Seok Kim ◽  
Cristel V. Camacho ◽  
W. Lee Kraus
Keyword(s):  
Clinical Trials ◽  
Homologous Recombination ◽  
Cancer Cells ◽  
Synthetic Lethality ◽  
Parp Inhibitor ◽  
Cancer Therapeutics ◽  
Progression Free Survival ◽  
Parp Inhibitors ◽  
Parp Inhibition ◽  
Combination Strategies

AbstractHomologous recombination (HR) repair deficiency impairs the proper maintenance of genomic stability, thus rendering cancer cells vulnerable to loss or inhibition of DNA repair proteins, such as poly(ADP-ribose) polymerase-1 (PARP-1). Inhibitors of nuclear PARPs are effective therapeutics for a number of different types of cancers. Here we review key concepts and current progress on the therapeutic use of PARP inhibitors (PARPi). PARPi selectively induce synthetic lethality in cancer cells with homologous recombination deficiencies (HRDs), the most notable being cancer cells harboring mutations in the BRCA1 and BRCA2 genes. Recent clinical evidence, however, shows that PARPi can be effective as cancer therapeutics regardless of BRCA1/2 or HRD status, suggesting that a broader population of patients might benefit from PARPi therapy. Currently, four PARPi have been approved by the Food and Drug Administration (FDA) for the treatment of advanced ovarian and breast cancer with deleterious BRCA mutations. Although PARPi have been shown to improve progression-free survival, cancer cells inevitably develop resistance, which poses a significant obstacle to the prolonged use of PARP inhibitors. For example, somatic BRCA1/2 reversion mutations are often identified in patients with BRCA1/2-mutated cancers after treatment with platinum-based therapy, causing restoration of HR capacity and thus conferring PARPi resistance. Accordingly, PARPi have been studied in combination with other targeted therapies to overcome PARPi resistance, enhance PARPi efficacy, and sensitize tumors to PARP inhibition. Moreover, multiple clinical trials are now actively underway to evaluate novel combinations of PARPi with other anticancer therapies for the treatment of PARPi-resistant cancer. In this review, we highlight the mechanisms of action of PARP inhibitors with or without BRCA1/2 defects and provide an overview of the ongoing clinical trials of PARPi. We also review the current progress on PARPi-based combination strategies and PARP inhibitor resistance.

scholarly journals SPDR-01 INHIBITION OF HOMOLOGOUS RECOMBINATION, PARP INHIBITOR, OR DIANHYDROGALACTITOL OVERCOMES TEMOZOLOMIDE-RESISTANCE IN GLIOMA CELLS

2019 ◽  
Vol 1 (Supplement_2) ◽  
pp. ii7-ii7
Author(s):  
Shigeo Ohba ◽  
Yuichi Hirose
Keyword(s):  
Homologous Recombination ◽  
Dna Methyltransferase ◽  
Excision Repair ◽  
Parp Inhibitor ◽  
Survival Rates ◽  
Glioma Cells ◽  
Parp Inhibitors ◽  
Mechanisms Of Resistance ◽  
Dna Crosslinks ◽  
Base Excision

Abstract Glioblastoma is one of the most aggressive tumors, with 5-year survival rates of less than 10%. The standard therapy for glioblastomas is maximal safe resection, followed by radiation therapy and chemotherapy with temozolomide (TMZ). The poor prognosis is partially contributed to the acquisition of resistance to TMZ and intratumoral heterogeneity. The mechanisms of resistance to TMZ are various due to tumor heterogeneity. TMZ is a DNA-methylating agent, delivering a methyl group to DNA (O6-guanine, N7-guanine and N3-adenine). The primary cytotoxic lesion, O6-methylguanine, mispairs with thymine, leading to futile DNA mismatch repair (MMR), formation of double strand breaks (DSBs) and eventual cell death, when O6-methylguanine DNA methyltransferase (MGMT) is absent. N7-methylguanine and N3-methyladenine are repaired by base excision repair (BER). The object of the study was to reveal the mechanisms of resistance to TMZ and to find the way to overcome the resistance in glioma. Several clones of TMZ-resistant U251 or U87 were obtained and analyzed. Increased homologous recombination (HR) and deficiency of MMR system, not MGMT were revealed to be contributed to the resistance to TMZ. Inhibition of HR resensitized cells with high HR to TMZ, but it could not resensitize cells with deficient MMR. For the cells with deficient MMR, Inhibition of BER by PARP inhibitor was revealed to potentiate the TMZ-induced cytotoxicity. PARP inhibitors also potentiate the cytotoxicity of TMZ to cells with expressed MGMT. Dianhydrogalactitol (DAG) is a bifunctional DNA-targeting agent, forming N7 alkylguanine and inter-strand DNA crosslinks. DAG reduced the proliferation of cells independent of MGMT and MMR, inducing DNA DSBs, G2/M arrest, and apoptosis in TMZ-resistant glioma cells. Inhibition of chk1, or HR could enhance the cytotoxicity of DAG, increasing apoptosis cells. By selecting the appropriate treatments to the types of resistant mechanisms, these new treatments have the potential to improve the prognosis of glioblastoma.

scholarly journals Combined Strategies with Poly (ADP-Ribose) Polymerase (PARP) Inhibitors for the Treatment of Ovarian Cancer: A Literature Review

Diagnostics ◽  
2019 ◽  
Vol 9 (3) ◽  
pp. 87 ◽  
Author(s):  
Stergios Boussios ◽  
Peeter Karihtala ◽  
Michele Moschetta ◽  
Afroditi Karathanasi ◽  
Agne Sadauskaite ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Repair ◽  
Synthetic Lethality ◽  
Excision Repair ◽  
Parp Inhibitor ◽  
Advanced Ovarian Cancer ◽  
Pegylated Liposomal Doxorubicin ◽  
Parp Inhibitors ◽  
Parp Inhibition ◽  
Biologic Agent

Poly (ADP-ribose) polymerase (PARP) inhibitors are the first clinically approved drugs designed to exploit synthetic lethality, and were first introduced as a cancer-targeting strategy in 2005. They have led to a major change in the treatment of advanced ovarian cancer, and altered the natural history of a disease with extreme genetic complexity and defective DNA repair via homologous recombination (HR) pathway. Furthermore, additional mechanisms apart from breast related cancer antigens 1 and 2 (BRCA1/2) mutations can also result in HR pathway alterations and consequently lead to a clinical benefit from PARP inhibitors. Novel combinations of PARP inhibitors with other anticancer therapies are challenging, and better understanding of PARP biology, DNA repair mechanisms, and PARP inhibitor mechanisms of action is crucial. It seems that PARP inhibitor and biologic agent combinations appear well tolerated and clinically effective in both BRCA-mutated and wild-type cancers. They target differing aberrant and exploitable pathways in ovarian cancer, and may induce greater DNA damage and HR deficiency. The input of immunotherapy in ovarian cancer is based on the observation that immunosuppressive microenvironments can affect tumour growth, metastasis, and even treatment resistance. Several biologic agents have been studied in combination with PARP inhibitors, including inhibitors of vascular endothelial growth factor (VEGF; bevacizumab, cediranib), and PD-1 or PD-L1 (durvalumab, pembrolizumab, nivolumab), anti-CTLA4 monoclonal antibodies (tremelimumab), mTOR-(vistusertib), AKT-(capivasertib), and PI3K inhibitors (buparlisib, alpelisib), as well as MEK 1/2, and WEE1 inhibitors (selumetinib and adavosertib, respectively). Olaparib and veliparib have also been combined with chemotherapy with the rationale of disrupting base excision repair via PARP inhibition. Olaparib has been investigated with carboplatin and paclitaxel, whereas veliparib has been tested additionally in combination with temozolomide vs. pegylated liposomal doxorubicin, as well as with oral cyclophosphamide, and topoisomerase inhibitors. However, overlapping myelosuppression observed with PARP inhibitor and chemotherapy combinations requires further investigation with dose escalation studies. In this review, we discuss multiple clinical trials that are underway examining the antitumor activity of such combination strategies.

scholarly journals Efficacy of PARP Inhibitors in the Treatment of Ovarian Cancer: A Literature-Based Review

2019 ◽  
Vol 05 (01) ◽  
pp. 01-18
Author(s):  
Vikas Goswami ◽  
Venkata Pradeep Babu Koyyala ◽  
Sumit Goyal ◽  
Manish Sharma ◽  
Varun Goel ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Repair ◽  
Homologous Recombination ◽  
Germ Line ◽  
Brca Mutation ◽  
Parp Inhibitor ◽  
Parp Inhibitors ◽  
Parp Inhibition ◽  
Repair Mechanism ◽  
Selection Of

AbstractPoly (ADP-ribose) polymerase (PARP) inhibitors are a unique class of therapeutic agents that focus on tumors with deficiencies in the homologous recombination DNA repair mechanism. Genomic instability outlines high-grade serous ovarian cancer, with 50% of all tumors displaying defects in the important DNA repair mechanism of homologous recombination. Earlier research studies have demonstrated considerable efficiency for PARP inhibitors in patients with germ line breast-related cancer antigens 1 and 2 (BRCA-1/BRCA-2) mutations. It has also been observed that BRCA wild-type patients with other defects in the homologous recombination repair mechanism get benefited from this therapy. Companion homologous recombination deficiency (HRD) scores are being developed to guide the selection of patients that are most likely to benefit from PARP inhibition. The selection of PARP inhibitor is mainly dependent upon the number of prior therapies and the presence of a BRCA mutation or HRD. The identification of cases which are most likely to get benefited from PARP inhibitor therapy in view of HRD and other biomarker assessments is still challenging. The purpose of this review is to focus and describe the current evidences for PARP inhibitors in ovarian malignancy, their mechanism of action, and the outstanding issues, including the rate of long-term toxicities and the evolving resistance.

DNA Repair Pathways in Clinical Practice: Lessons From Pediatric Cancer Susceptibility Syndromes

2006 ◽  
Vol 24 (23) ◽  
pp. 3799-3808 ◽  
Author(s):  
Richard D. Kennedy ◽  
Alan D. D'Andrea
Keyword(s):  
Dna Repair ◽  
Cancer Cells ◽  
Fanconi Anemia ◽  
Drug Sensitivity ◽  
Cancer Susceptibility ◽  
Excision Repair ◽  
Cancer Management ◽  
Ovarian Epithelial Tumors ◽  
Repair Pathways ◽  
Base Excision

Human cancers exhibit genomic instability and an increased mutation rate due to underlying defects in DNA repair. Cancer cells are often defective in one of six major DNA repair pathways, namely: mismatch repair, base excision repair, nucleotide excision repair, homologous recombination, nonhomologous endjoining and translesion synthesis. The specific DNA repair pathway affected is predictive of the kinds of mutations, the tumor drug sensitivity, and the treatment outcome. The study of rare inherited DNA repair disorders, such as Fanconi anemia, has yielded new insights to drug sensitivity and treatment of sporadic cancers, such as breast or ovarian epithelial tumors, in the general population. The Fanconi anemia pathway is an example of how DNA repair pathways can be deregulated in cancer cells and how biomarkers of the integrity of these pathways could be useful as a guide to cancer management and may be used in the development of novel therapeutic agents.

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