Abstract A46: A novel immunoassay (ELISA) for quantitative gamma-H2AX detection and pharmacodynamic monitoring of DNA damage induced by chemotherapeutic agents and PARP inhibitors.

Abstract Diffuse infiltrating gliomas are a clinically and molecularly heterogeneous group of tumors that are uniformly incurable. Despite our growing knowledge of genomic and epigenomic alterations in gliomas, standard treatments have not changed in the past 2 decades and remain limited to surgical resection, ionizing radiation, and alkylating chemotherapeutic agents. Development of novel therapeutics for diffuse gliomas has been challenging due to inter- and intra-tumoral heterogeneity, diffuse infiltrative nature of gliomas, inadequate tumor/drug concentration due to blood–brain barrier, and an immunosuppressive tumor microenvironment. Given the high frequency of DNA damage pathway alterations in gliomas, researchers have focused their efforts in targeting the DNA damage pathways for the treatment of gliomas. A growing body of data has shed light on the role of poly(ADP-ribose) polymerase (PARP) in combination with radiation and temozolomide in high-grade gliomas. Furthermore, a novel therapeutic strategy in low-grade glioma is the recent elucidation for a potential role of PARP inhibitors in gliomas with IDH1/2 mutations. This review highlights the concepts behind targeting PARP in gliomas with a focus on putative predictive biomarkers of response. We further discuss the challenges involved in the successful development of PARP inhibitors in gliomas, including the intracranial location of the tumor and overlapping toxicities with current standards of care, and promising strategies to overcome these hurdles.

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PARP Inhibitors as Therapeutics: Beyond Modulation of PARylation

Cancers ◽

10.3390/cancers12020394 ◽

2020 ◽

Vol 12 (2) ◽

pp. 394 ◽

Cited By ~ 16

Author(s):

Ahrum Min ◽

Seock-Ah Im

Keyword(s):

Dna Damage ◽

Posttranslational Modification ◽

Parp Inhibitors ◽

Mechanisms Of Action ◽

Chemotherapeutic Agents ◽

Antitumor Activities ◽

Current State ◽

Damage Response ◽

Clinical Benefits ◽

Parp 1

Poly (ADP-ribose) polymerase (PARP) 1 is an essential molecule in DNA damage response by sensing DNA damage and docking DNA repair proteins on the damaged DNA site through a type of posttranslational modification, poly (ADP-Ribosyl)ation (PARylation). PARP inhibitors, which inhibit PARylation through competitively binding to NAD+ binding site of PARP1 and PARP2, have improved clinical benefits for BRCA mutated tumors, leading to their accelerated clinical application. However, the antitumor activities of PARP inhibitors in clinical development are different, due to PARP trapping activity beyond blocking PARylation reactions. In this review, we comprehensively address the current state of knowledge regarding the mechanisms of action of PARP inhibitors. We will also discuss the different effects of PARP inhibitors in combination with cytotoxic chemotherapeutic agents regarding the mechanism of regulating PARylation.

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Acceleration or Brakes: Which Is Rational for Cell Cycle-Targeting Neuroblastoma Therapy?

Biomolecules ◽

10.3390/biom11050750 ◽

2021 ◽

Vol 11 (5) ◽

pp. 750

Author(s):

Kiyohiro Ando ◽

Akira Nakagawara

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Cell Cycle Progression ◽

Parp Inhibitors ◽

Cell Cycle Checkpoint ◽

Mitotic Catastrophe ◽

Malignant Neoplasms ◽

Checkpoint Kinases ◽

Molecular Features ◽

Cycle Checkpoint

Unrestrained proliferation is a common feature of malignant neoplasms. Targeting the cell cycle is a therapeutic strategy to prevent unlimited cell division. Recently developed rationales for these selective inhibitors can be subdivided into two categories with antithetical functionality. One applies a “brake” to the cell cycle to halt cell proliferation, such as with inhibitors of cell cycle kinases. The other “accelerates” the cell cycle to initiate replication/mitotic catastrophe, such as with inhibitors of cell cycle checkpoint kinases. The fate of cell cycle progression or arrest is tightly regulated by the presence of tolerable or excessive DNA damage, respectively. This suggests that there is compatibility between inhibitors of DNA repair kinases, such as PARP inhibitors, and inhibitors of cell cycle checkpoint kinases. In the present review, we explore alterations to the cell cycle that are concomitant with altered DNA damage repair machinery in unfavorable neuroblastomas, with respect to their unique genomic and molecular features. We highlight the vulnerabilities of these alterations that are attributable to the features of each. Based on the assessment, we offer possible therapeutic approaches for personalized medicine, which are seemingly antithetical, but both are promising strategies for targeting the altered cell cycle in unfavorable neuroblastomas.

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PARP Power: A Structural Perspective on PARP1, PARP2, and PARP3 in DNA Damage Repair and Nucleosome Remodelling

International Journal of Molecular Sciences ◽

10.3390/ijms22105112 ◽

2021 ◽

Vol 22 (10) ◽

pp. 5112

Author(s):

Lotte van Beek ◽

Éilís McClay ◽

Saleha Patel ◽

Marianne Schimpl ◽

Laura Spagnolo ◽

...

Keyword(s):

Dna Damage ◽

Dna Binding ◽

Parp Inhibitors ◽

Covalent Modification ◽

Activation Mechanism ◽

Cancer Therapies ◽

Damage Repair ◽

Complementary Role ◽

Functional Understanding

Poly (ADP-ribose) polymerases (PARP) 1-3 are well-known multi-domain enzymes, catalysing the covalent modification of proteins, DNA, and themselves. They attach mono- or poly-ADP-ribose to targets using NAD+ as a substrate. Poly-ADP-ribosylation (PARylation) is central to the important functions of PARP enzymes in the DNA damage response and nucleosome remodelling. Activation of PARP happens through DNA binding via zinc fingers and/or the WGR domain. Modulation of their activity using PARP inhibitors occupying the NAD+ binding site has proven successful in cancer therapies. For decades, studies set out to elucidate their full-length molecular structure and activation mechanism. In the last five years, significant advances have progressed the structural and functional understanding of PARP1-3, such as understanding allosteric activation via inter-domain contacts, how PARP senses damaged DNA in the crowded nucleus, and the complementary role of histone PARylation factor 1 in modulating the active site of PARP. Here, we review these advances together with the versatility of PARP domains involved in DNA binding, the targets and shape of PARylation and the role of PARPs in nucleosome remodelling.

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Differences in PARP Inhibitors for the Treatment of Ovarian Cancer: Mechanisms of Action, Pharmacology, Safety, and Efficacy

International Journal of Molecular Sciences ◽

10.3390/ijms22084203 ◽

2021 ◽

Vol 22 (8) ◽

pp. 4203

Author(s):

Giorgio Valabrega ◽

Giulia Scotto ◽

Valentina Tuninetti ◽

Arianna Pani ◽

Francesco Scaglione

Keyword(s):

Ovarian Cancer ◽

Signal Transduction ◽

Dna Damage ◽

Chemical Structure ◽

Parp Inhibitors ◽

Mechanisms Of Action ◽

Point Of View ◽

Safety And Efficacy ◽

Damage Repair ◽

Pharmacokinetic Properties

Poly(ADP-ribose) polymerases (PARP) are proteins responsible for DNA damage detection and signal transduction. PARP inhibitors (PARPi) are able to interact with the binding site for PARP cofactor (NAD+) and trapping PARP on the DNA. In this way, they inhibit single-strand DNA damage repair. These drugs have been approved in recent years for the treatment of ovarian cancer. Although they share some similarities, from the point of view of the chemical structure and pharmacodynamic, pharmacokinetic properties, these drugs also have some substantial differences. These differences may underlie the different safety profiles and activity of PARPi.

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Regulation of p73-mediated apoptosis by c-Jun N-terminal kinase

Biochemical Journal ◽

10.1042/bj20061778 ◽

2007 ◽

Vol 405 (3) ◽

pp. 617-623 ◽

Cited By ~ 50

Author(s):

Emma V. Jones ◽

Mark J. Dickman ◽

Alan J. Whitmarsh

Keyword(s):

Dna Damage ◽

Stress Responses ◽

Tumour Progression ◽

Chemotherapeutic Agents ◽

Signalling Pathway ◽

Mitogen Activated Protein Kinase ◽

P53 Family ◽

Jnk Pathway ◽

Mitogen Activated Protein ◽

Induced Apoptosis

The JNK (c-Jun N-terminal kinase)/mitogen-activated protein kinase signalling pathway is a major mediator of stress responses in cells, including the response to DNA damage. DNA damage also causes the stabilization and activation of p73, a member of the p53 family of transcription factors. p73, like p53, can mediate apoptosis by up-regulating the expression of pro-apoptotic genes, including Bax (Bcl2-associated X protein) and PUMA (p53 up-regulated modulator of apoptosis). Changes in p73 expression have been linked to tumour progression, particularly in neuroblastomas, whereas in tumours that feature inactivated p53 there is evidence that p73 may mediate the apoptotic response to chemotherapeutic agents. In the present study, we demonstrate a novel link between the JNK signalling pathway and p73. We use pharmacological and genetic approaches to show that JNK is required for p73-mediated apoptosis induced by the DNA damaging agent cisplatin. JNK forms a complex with p73 and phosphorylates it at several serine and threonine residues. The mutation of JNK phosphorylation sites in p73 abrogates cisplatin-induced stabilization of p73 protein, leading to a reduction in p73 transcriptional activity and reduced p73-mediated apoptosis. Our results demonstrate that the JNK pathway is an important regulator of DNA damage-induced apoptosis mediated by p73.

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CBIO-22. PARP INHIBITION SYNERGIZES WITH DNA DAMAGING DRUGS IN PEDIATRIC CNS TUMORS

Neuro-Oncology ◽

10.1093/neuonc/noab196.121 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi31-vi31

Author(s):

Anna Laemmerer ◽

Dominik Kirchhofer ◽

Sibylle Madlener ◽

Daniela Loetsch-Gojo ◽

Carola Jaunecker ◽

...

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Predictive Biomarkers ◽

High Grade Glioma ◽

Parp Inhibitors ◽

Cns Tumors ◽

Parp Inhibition ◽

Tumor Subtypes ◽

Synergistic Cytotoxicity ◽

Anti Cancer

Abstract BACKGROUND Central nervous system (CNS) tumors are the second most common childhood cancer. Despite innovations in surgery and chemo-/radiotherapy, CNS tumors remain the major cause of cancer-related death in children. Previous sequencing analyses in a pediatric cancer cohort identified BRCA and DSB repair signatures as potentially targetable events. Based on these findings, we propose the use of PARP inhibitors (PARPi) for aggressive CNS tumor subtypes, including high-grade glioma (HGG), medulloblastoma (MB) and ependymoma (EPN). METHODS We tested multiple PARPi in tumor cell lines (n=8) as well as primary patient-derived models (n=11) of pediatric HGG, MB, EPN and atypical teratoid/rhabdoid tumors (ATRTs). Based on PARPi sensitivity, selected models were further exposed to a combination of PARPi and DNA-damaging/modifying agents. The mode of action was investigated using Western blot and flow cytometry. RESULTS We show that a fraction of pediatric MB, EPN and ATRT demonstrate sensitivity towards PARP inhibition, which is paralleled by susceptibility to the DNA damaging drugs cisplatin and irinotecan. Interestingly, talazoparib, the most potent PARPi, showed synergistic cytotoxicity with DNA-damaging/modifying drugs. In addition, cell cycle blockade and increased DNA damage combined with reduced DNA repair signaling, such as activation of the ATR/Chk1 pathway were observed. Corroboratively, talazoparib exhibited a synergistic anti-cancer effect in combination with inhibitors of ATR, a major regulator of DNA damage response. CONCLUSION/OUTLOOK To sum up, we demonstrate that PARP inhibition synergizes with DNA damaging anti-cancer compounds or DNA repair inhibitors and, thus, represents a promising therapeutic strategy for a defined subgroup of pediatric high-risk CNS tumors patients. More in depth characterization of the underlying molecular events will most likely allow the identification of predictive biomarkers for most efficient implementation of this strategy into clinical application.

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PARP inhibitors synergize with gemcitabine by potentiating DNA damage in non-small-cell lung cancer

International Journal of Cancer ◽

10.1002/ijc.31770 ◽

2018 ◽

Vol 144 (5) ◽

pp. 1092-1103 ◽

Cited By ~ 12

Author(s):

Yu Jiang ◽

Hui Dai ◽

Yang Li ◽

Jun Yin ◽

Shuliang Guo ◽

...

Keyword(s):

Lung Cancer ◽

Dna Damage ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Parp Inhibitors ◽

Small Cell ◽

Small Cell Lung

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A Review on DNA Repair Inhibition by PARP Inhibitors in Cancer Therapy

Folia Medica ◽

10.1515/folmed-2017-0067 ◽

2018 ◽

Vol 60 (1) ◽

pp. 39-47 ◽

Cited By ~ 8

Author(s):

Ashish P. Shah ◽

Chhagan N. Patel ◽

Dipen K. Sureja ◽

Kirtan P. Sanghavi

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Cancer Therapy ◽

Repair Process ◽

Parp Inhibitors ◽

Brca Mutations ◽

Development Of Resistance ◽

Damage Repair ◽

Future Therapy

AbstractThe DNA repair process protects the cells from DNA damaging agent by multiple pathways. Majority of the cancer therapy cause DNA damage which leads to apoptosis. The cell has natural ability to repair this damage which ultimately leads to development of resistance of drugs. The key enzymes involved in DNA repair process are poly(ADP-ribose) (PAR) and poly(ADP-ribose) polymerases (PARP). Tumor cells repair their defective gene via defective homologues recombination (HR) in the presence of enzyme PARP. PARP inhibitors inhibit the enzyme poly(ADP-ribose) polymerases (PARPs) which lead to apoptosis of cancer cells. Current clinical data shows the role of PARP inhibitors is not restricted to BRCA mutations but also effective in HR dysfunctions related tumors. Therefore, investigation in this area could be very helpful for future therapy of cancer. This review gives detail information on the role of PARP in DNA damage repair, the role of PARP inhibitors and chemistry of currently available PARP inhibitors.

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Ubiquitin and Ubiquitin-Like Proteins Are Essential Regulators of DNA Damage Bypass

Cancers ◽

10.3390/cancers12102848 ◽

2020 ◽

Vol 12 (10) ◽

pp. 2848

Author(s):

Nicole A. Wilkinson ◽

Katherine S. Mnuskin ◽

Nicholas W. Ashton ◽

Roger Woodgate

Keyword(s):

Dna Damage ◽

Cancer Progression ◽

Chemotherapeutic Agents ◽

Tumor Formation ◽

Human Cells ◽

Double Strand Breaks ◽

Template Switching ◽

Post Translational Modifications ◽

Strand Breaks ◽

Exogenous Factors

Many endogenous and exogenous factors can induce genomic instability in human cells, in the form of DNA damage and mutations, that predispose them to cancer development. Normal cells rely on DNA damage bypass pathways such as translesion synthesis (TLS) and template switching (TS) to replicate past lesions that might otherwise result in prolonged replication stress and lethal double-strand breaks (DSBs). However, due to the lower fidelity of the specialized polymerases involved in TLS, the activation and suppression of these pathways must be tightly regulated by post-translational modifications such as ubiquitination in order to limit the risk of mutagenesis. Many cancer cells rely on the deregulation of DNA damage bypass to promote carcinogenesis and tumor formation, often giving them heightened resistance to DNA damage from chemotherapeutic agents. In this review, we discuss the key functions of ubiquitin and ubiquitin-like proteins in regulating DNA damage bypass in human cells, and highlight ways in which these processes are both deregulated in cancer progression and might be targeted in cancer therapy.

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