Дисертації з теми "PARP1 Inhibitors"
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Alkhateeb, Hebah, Gregory A. Ordway, W. Drew Gill, Joshua B. Coleman, Hui Wang-Heaton, Russell W. Brown, Michelle Chandley, et al. "PARP1 inhibition produces unique antidepressant effects in an animal model of treatment-resistant depression." Digital Commons @ East Tennessee State University, 2019. https://dc.etsu.edu/asrf/2019/schedule/49.
Повний текст джерелаD'Angeli, Floriana. "Biomolecular effects and bioclinical applications of PARPs inhibitors." Doctoral thesis, Università di Catania, 2017. http://hdl.handle.net/10761/3832.
Повний текст джерелаGeraets, Liesbeth. "Dietary PARP-1 inhibitors as anti-inflammatory compounds." Maastricht : Maastricht : Universitaire Pers ; University Library, Universiteit Maastricht [host], 2008. http://arno.unimaas.nl/show.cgi?fid=14252.
Повний текст джерелаKumpan, Katerina. "Structure-activity studies on inhibitors of the tankyrases." Thesis, University of Bath, 2014. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.619223.
Повний текст джерелаAhmed, Zina. "Poly-ADP ribos polymeras (PARP) inhibitorers effekt på bröstcancer : Poly-ADP ribos polymeras (PARP) inhibitorers effekt på bröstcancer." Thesis, Umeå universitet, Kemiska institutionen, 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-103397.
Повний текст джерелаAlmeida, Gilberto Serrano de. "Pre-clinical imaging evaluation of the PARP inhibitor rucaparib." Thesis, University of Newcastle upon Tyne, 2013. http://hdl.handle.net/10443/2033.
Повний текст джерелаHukkanen, M. (Mikko). "DNA damage sensitization of breast cancer cells with PARP10/ARTD10 inhibitor." Master's thesis, University of Oulu, 2019. http://jultika.oulu.fi/Record/nbnfioulu-201909062843.
Повний текст джерелаCastroviejo, Bermejo Marta. "RAD51 as functional biomarker to select tumors for PARP inhibitor treatment." Doctoral thesis, Universitat Autònoma de Barcelona, 2019. http://hdl.handle.net/10803/667273.
Повний текст джерелаPoly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) are effective anticancer drugs in cancers with defective homologous recombination DNA repair (HRR), including cancers with mutations in BRCA1 and BRCA2 (BRCA1/2), which also display enhanced sensitivity to DNA damaging chemotherapy such as platinum salts. Several mechanisms of PARPi resistance have been described in tumors with germline mutations in BRCA1/2 (gBRCA) and there are also other tumors with wild type BRCA1/2 (non-BRCA) that benefit from PARPi treatment. Therefore, there is a need to develop robust biomarkers to better select HRR- deficient tumors and extend the use of PARP inhibition in new indications, as well as identify PARPi-resistant tumors and study combination treatment options that enhance clinical efficacy and utility of PARPi. We evaluated the activity of the PARPi olaparib in patient-derived tumor xenografts (PDXs) from patients with breast or ovarian cancer, both with and without gBRCA mutation, exhibiting differential response to PARPi. We studied the in vivo mechanisms of PARPi resistance and sensitivity in these models and tested the formation of RAD51 nuclear foci by immunofluorescence as biomarker of HRR functionality and PARPi response in PDXs and routine clinical samples. We also tested the antitumor activity of the WEE1i AZD1775 and the ATMi AZD0156 as single agent and in combination with PARPi in PDXs. The measurement of replication stress biomarkers was assessed to study the mechanisms of action of these treatment strategies. Within the gBRCA PDXs panel, no BRCA1/2 secondary mutations were found in the PARPi resistant models. BRCA1 nuclear foci were detected in six out of ten PARPi-resistant PDXs, in keeping with expression of hypomorphic BRCA1 isoforms. Loss of 53BP1 and FAM35A were identified in three PDXs, one of which concomitantly expressed an hypomorphic BRCA1 protein. The common feature in all PDXs with primary or acquired PARPi resistance was the formation of RAD51 nuclear foci. Consistently, lack of RAD51 foci was always associated with clinical response to PARPi in patients treated with these agents. When studying the mechanisms of PARPi sensitivity in the non-gBRCA PDX cohort, BRCA1 promoter hypermethylation and alterations in HRR-related genes were found in PARPi- sensitive models. Again, the unique common feature in all PDXs that exhibited tumor regression upon PARPi treatment is the absence of RAD51 nuclear foci. The RAD51 assay could be performed in untreated samples and was highly discriminative of PARPi sensitivity versus PARPi resistance in different PDX cohorts and outperformed the Myriad’s myChoice® HRD genomic test. In routine clinical samples from patients with hereditary breast and ovarian cancer (HBOC) syndrome, all PALB2-related tumors were classified as HRR-deficient by the RAD51 score. In PDXs, PARPi resistance in BRCA1-altered tumors could be reverted upon combination of PARPi with WEE1 or ATM inhibitors and both combination strategies resulted in exacerbated induction of replication stress (RS) in combination- sensitive PDXs. With the results obtained in this thesis, it can be concluded that gBRCA tumors achieve PARPi resistance by several mechanisms that restore HRR function, all detected by the presence of RAD51 nuclear foci. This functional assay also enables the identification of PARPi-sensitive non-gBRCA tumors independently of the mechanisms of HRR-deficiency, thereby being a promising biomarker to better select patients for PARP inhibition and broaden the population who may benefit from this therapy. Our study also supports the clinical development of PARPi combinations such as those with WEE1 and ATM inhibitors and highlighted the induction of RS as the major mechanisms of action of these drugs.
Löser, Dana A. "Investigating the mechanisms by which PARP inhibitors increase sensitivity to DNA damaging agents." Thesis, University of Sussex, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.505912.
Повний текст джерелаGuillot, Clément. "Potentiel des inhibiteurs de poly(ADP-ribose) polymérases seuls ou en combinaison avec la radiothérapie comme nouvelle option thérapeutique pour le carcinome hépatocellulaire." Thesis, Lyon 1, 2013. http://www.theses.fr/2013LYO10281.
Повний текст джерелаHepatocellular carcinoma is the third cause of cancer related death. Due its often late diagnosis and advanced stage, a limited number of patients can benefit from curative treatments. There is thus a constant need for new treatment strategies for patients with hepatocellular carcinoma. Targeting DNA repair pathways to sensitize tumor cells to chemoor radiotherapeutic treatments is now a common strategy under investigation for cancer treatment with inhibitors of poly(ADP-ribose) polymerases (PARP) showing great potential. The aim of this work was to evaluate the potential of PARP inhibitors alone and in combination with radiation therapy as a new strategy for the treatment of hepatocellular carcinoma. We first analyzed the expression and activity of different PARP genes in a panel of liver cancer cell lines and primary human hepatocytes as well as their DNA repair capacity and assess the impact of PARP inhibitors alone and in combination with ionizing radiation in these models on cell survival. A large range in expression of PARP family members, PARP activity and sensitivity to ABT-888 in the panel of liver cells was observed as well as differential excision/synthesis repair capacity. Finally, we showed that ABT-888 sensitizes liver cancer cells to the cell killing effects of ionizing radiation. PARP inhibitors show great potential for improving radiation therapy strategies used in the management of hepatocellular carcinoma
Michels, Judith. "Les Inhibiteurs de PARP dans le Traitement des Cancers Chimio-Résistants. Etude pré-clinique sur la Dépendance à PARP." Phd thesis, Université Paris Sud - Paris XI, 2013. http://tel.archives-ouvertes.fr/tel-01063796.
Повний текст джерелаMichels, Judith. "Les inhibiteurs de PARP dans le traitement des cancers chimio-résistants : étude pré-clinique sur la dépendance à PARP." Thesis, Paris 11, 2013. http://www.theses.fr/2013PA11T049/document.
Повний текст джерелаIntroduction Driven by the facts that non small cell lung cancer (NSCLC) is the leading cause of cancer-related morbidity and mortality worldwide and that NSCLC patients often develop resistance against Cisplatin (CDDP)-based therapies, we addressed the question of the combination therapy of CDDP with poly(ADP-ribose) polymerases (PARP) inhibitors. Inhibitors of PARP have raised great expectations for the treatment of a variety of cancers, either as monotherapeutic agent against DNA repair-deficient tumours or combined to DNA-damaging compounds.Material and methods We generated nine CDDP-resistant clones by prolonged exposure to low dose CDDP of the A549 NSCLC parental cell line. Two distinct PARP inhibitors, CEP8983 (CEP) and PJ34 (PJ) as well as PARP1 knockdown with small interfering RNAs (siRNAs) were used for PARP inhibition. Apoptosis was measured by the simultaneous assessment for the loss of the mitochondrial transmembrane potential (m) and the breakdown of the plasma membrane using the m-sensitive fluorochrome DiOC6(3) and the vital dye propidium iodide, respectively. Moreover clonogenic survival was assessed. In vitro assessments of the enzymatic activity of cells were based on the reduction of the colorless tetrazolium salt. Immunofluorescence microscopy determinations were performed with antibodies specific for DNA damage (γH2AX), intrinsic apoptosis (cleaved Caspase-3 and cytochrome c), and homologous recombination (RAD51 and BRCA1). Immunoblotting was assed for PARP1 expression and activity (PAR) and base excision repair (BER) effectors (XRCC1 and polymerase β). We developed an immunohistochemical staining method that specifically detects PAR on paraffin-embedded cell pellets and tissue sections.Results We found that PARP inhibitors and PARP1 siRNAs synergized with CDDP in the killing of NSCLC cells in vitro. Unexpectedly, CDDP-resistant NSCLC cell clones developed addiction to PARP hyperactivation, thereby becoming susceptible to apoptosis induction by PARP inhibition. We showed that these cisplatin-resistant clones, exhibited high PARP protein levels and increased PARP activity, leading to an increased poly-ADP ribosylation of cellular proteins, as compared to their parental, cisplatin-sensitive counterparts. These cisplatin-resistant cells become susceptible to cell death as induced by PARP inhibition, correlating with the hyperactivity of PARP (elevated PAR levels) more accuratly than with the overexpression of PARP. Suggesting that PAR levels may constitute a more accurate biomarker than PARP to predict the sensitivity of cells to PARP inhibition. We expanded the observation that cisplatin resistance causes PARP upregulation and hyperactivation and subsequent sensitization to PARP inhibition to additional five human cancer cell lines including two NSCLC (H1650 and H460), one mesothelioma (P31), one ovarian (TOV112D) and one cervical cancer (HeLa) cell line. To get further insight into this issue, we generated in vivo experiments. Tumors derived from CDDP-resistant cells were characterized by elevated levels of PAR suggesting that PAR levels are preserved during tumor formation. Those PAR-overexpressing tumors responded to the administration of PJ in vivo with a consistent reduction in PAR immunoreactivity. CDDP resistant clones that are specifically killed by PARP inhibitors assessed efficient homologous recombination repair however deficient BER elongation.Conclusion We showed a beneficial effect for the association therapy of PARP inhibitors with CDDP in several NSCLC cell lines. We have identified an addiction to PARP in CDDP resistant cell lines with deficient BER elongation. We postulate that PAR is a specific predictive biomarker for the response to PARP inhibitors
Raithel, Kerstin. "Effekt von S-Lost in HaCaT-Zellkulturen : Induktion der Apoptose und Effekt eines PARP-Inhibitors /." München, 2008. http://opac.nebis.ch/cgi-bin/showAbstract.pl?sys=000254372.
Повний текст джерелаOrdway, Gregory A., W. D. Gill, J. B. Coleman, Hui Wang-Heaton, and Russell W. Brown. "Anti-Inflammatory PARP Inhibitor Demonstrates Antidepressant Activity in Animal Model of Treatment Resistant Depression." Digital Commons @ East Tennessee State University, 2019. https://dc.etsu.edu/etsu-works/8643.
Повний текст джерелаMaier, Christian. "Auswirkungen des PARP-1 Inhibitors INO-1001 auf Ischämie-Reperfusionsbedingte Organschädigungen nach thorakalem Aortencrossclamping am Schwein." [S.l. : s.n.], 2008. http://nbn-resolving.de/urn:nbn:de:bsz:289-vts-64137.
Повний текст джерелаOrdway, Gregory A., Attila Szebeni, Liza J. Hernandez, Jessica D. Crawford, Katalin Szebeni, Michelle J. Chandley, Katherine C. Burgess, Corwin Miller, Erol Bakkalbasi, and Russell W. Brown. "Antidepressant-Like Actions of Inhibitors of Poly(ADP-Ribose) Polymerase in Rodent Models." Digital Commons @ East Tennessee State University, 2017. https://dc.etsu.edu/etsu-works/2768.
Повний текст джерелаMorel, Daphné. "Identifying Synthetic Lethal and Selective Approaches to Target PBRM1-Deficiency in Clear Cell Renal Cell Carcinoma PBRM1 Deficiency in Cancer is Synthetic Lethal with DNA Repair Inhibitors Exploiting Epigenetic Vulnerabilities in Solid Tumors: Novel Therapeutic Opportunities in the Treatment of SWI/SNF-Defective Cancers Combining Epigenetic Drugs with other Therapies for Solid Tumours — Past Lessons and Future Promise Targeting Chromatin Defects in Selected Solid Tumors Based on Oncogene Addiction, Synthetic Lethality and Epigenetic Antagonism." Thesis, université Paris-Saclay, 2020. http://www.theses.fr/2020UPASL017.
Повний текст джерелаPolybromo-1 (PBRM1) inactivation occurs in multiple malignancies and is of particular importance in clear cell renal cell carcinomas (ccRCC), as it drives 40 to 50% of cases. Currently, no precision-medicine approach uses PBRM1 deficiency to specifically target tumour cells. To uncover novel synthetic lethal approaches to treat PBRM1-defective cancers, we performed (i) a high-throughput pharmacological screening, evaluating the sensitivity to 167 small molecules in a PBRM1-isogenic cellular model, and the (ii) systematic mapping of the whole transcriptomic and proteomic profiles associated with PBRM1 loss-of-function within this model. We further investigated the mechanism underlying this synthetic lethal relationship.We identified and validated synthetic lethal effects between PBRM1 loss and both PARP and ATR inhibition. Combinatorial use of PARP with ATR inhibitors exerted additive cytotoxic effects in PBRM1-defective tumor cells. These synthetic lethal relationships were characterized by a pre-existing replication stress in PBRM1-deficient cells associated with mitosis and DNA damage repair abnormalities, which were exacerbated upon PARP inhibition selectively in PBRM1-defective cells.These data provide the preclinical basis for evaluating PARP inhibitors as a monotherapy or in combination in patients with PBRM1-deficient ccRCC
Block, Katherine M. "Design of Novel Cancer Therapeutics Through The Validation of PARG as a Therapeutic Target and the Evaluation of Small Molecule Inhibitors of Hypoxia-Induced Transcription." Diss., The University of Arizona, 2010. http://hdl.handle.net/10150/194826.
Повний текст джерелаCherry, K. E. "The poly (ADP-ribose) polymerase (PARP) inhibitors AG14361 and AG014699 : mechanisms of action and implications for clinical application." Thesis, Queen's University Belfast, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.546027.
Повний текст джерелаChabanon, Roman. "Exploiting DNA Repair Vulnerabilities to Modulate Anti-Cancer Immunity : a Study of the Immunological Potential of PARP inhibitors." Thesis, Université Paris-Saclay (ComUE), 2019. http://www.theses.fr/2019SACLS007.
Повний текст джерелаPoly(ADP-ribose) polymerase inhibitors (PARPi) selectively target cancer cells with DNA repair deficiencies such as BRCA1/2 mutations or ERCC1 defects. Clinically, several PARPi are currently approved for the treatment of BRCA-mutant or platinum-sensitive advanced ovarian and breast cancers, and ongoing clinical trials are investigating the efficacy of PARPi in platinum-sensitive Non-Small Cell Lung Cancer (NSCLC). While PARPi constitute potent targeted therapies for the treatment of DNA repair-deficient malignancies, an increasing number of clinical trials are also evaluating their efficacy in combination with immune checkpoint inhibitor (ICI) in various populations. In this context, it is of critical importance to better understand how PARPi might modulate immune responses against cancer, and to investigate the inherent immunological potential of these agents.In this study, we show that ERCC1-defective NSCLC cells exhibit an enhanced type I interferon (IFN) transcriptomic signature and that low ERCC1 expression correlates with increased lymphocytic infiltration in human NSCLC tumours. Using isogenic cell lines and patient-derived xenografts, we further demonstrate that several clinical PARPi, including olaparib and rucaparib, display cell-autonomous immunomodulatory properties in ERCC1-defective NSCLC and BRCA1-mutant triple-negative breast cancer (TNBC) models. Mechanistically, PARPi generate cytoplasmic chromatin fragments with micronuclei characteristics; this activates the cGAS/STING pathway and elicits downstream type I IFN signalling and CCL5 secretion. Importantly, these effects are suppressed in BRCA1-reverted TNBC cells and ERCC1-rescued NSCLC cells, suggesting that DNA repair defects exacerbate the innate immunity-related phenotypes triggered by PARPi. Similarly, these effects are totally abrogated in PARP1-null TNBC cells, supporting the on-target effect of PARPi in mediating such phenotypes. Besides this potential to activate tumour cell-autonomous immunity through cGAS/STING and type I IFN signalling, we also observed that PARPi synergize with type II IFN to induce PD-L1 expression in NSCLC cell lines and fresh patient tumour cells, especially in the ERCC1-deficient setting. Moreover, we show that lethal concentrations of some PARPi independently activate the key damage-associated molecular patterns dictating the immunogenicity of cancer cell death, including calreticulin exposure at the tumour cell surface, ATP secretion and HMGB1 release in the extracellular compartment.Together, these preclinical data suggest that PARPi have intrinsic immunomodulatory properties that activate anti-cancer immune responses; this could be exploited clinically in combination with ICI in appropriately molecularly-selected populations
Kohl, Vanessa [Verfasser], and Alice [Akademischer Betreuer] Fabarius. "Synthetische Letalität von PARP- und APE1-Inhibitoren bei hämatologischen Neoplasien / Vanessa Kohl ; Betreuer: Alice Fabarius." Heidelberg : Universitätsbibliothek Heidelberg, 2021. http://d-nb.info/1237750598/34.
Повний текст джерелаHarand, Kristina Marie. "Assessment of Acrolein-induced Toxicity Using In-vitro Modeling to Evaluate the Role of PARP Inhibitors in Reducing Cytotoxicity." Scholar Commons, 2016. http://scholarcommons.usf.edu/etd/6091.
Повний текст джерелаDrew, Yvette Claire. "The potential of the PARP-1 inhibitor, AGO14699, in human cancers defective in homologous recombination DNA repair." Thesis, University of Newcastle upon Tyne, 2012. http://hdl.handle.net/10443/1551.
Повний текст джерелаJdey, Wael. "Mécanismes de sensibilité/résistance des cellules tumorales aux inhibiteurs de réparation de l'ADN Dbait." Thesis, Université Paris-Saclay (ComUE), 2016. http://www.theses.fr/2016SACLS463/document.
Повний текст джерелаDefects in the DNA repair pathways are now widely exploited for the treatment of cancer. Indeed, the ability of tumors to repair the damage induced by genotoxic treatments (chemotherapy and radiotherapy) gives them an intrinsic or acquired resistance to these treatments. Developing DNA repair inhibitors would help to counteract this resistance and sensitize tumors to these conventional therapies. Poly(ADP-ribose) polymerase inhibitors (PARPi), first candidates for this family of DNA repair inhibitors, have shown encouraging results but are nevertheless restricted to a tumor subpopulation with Deficiencies in the Homologous Recombination repair pathway (HRD). In addition, resistances to these PARPi were observed following the reactivation of the HR pathway or alternative pathways. It is therefore urgent to develop more effective agents to limit the resistance problem. In the laboratory, we have identified a new class of DNA repair inhibitors, Dbait, consisting of a small double-stranded DNA molecule that mimics a double-strand break (DSB). AsiDNA, a molecule of the Dbait family, acts by hijacking and hyper activating the PARP protein and its partners, as well as DNA-PK protein that modifies chromatin, thereby inhibiting recruitment at the damage site of several DNA repair proteins. In this manuscript, we studied the issue of mechanisms of sensitivity to AsiDNA, and we identified the genetic instability, generated mainly by defects in the DSBs’ repair, as major feature to be sensitive to AsiDNA in different models of tumor cells and xenografts. Interestingly, genetic instability does not correlate with sensitivity to PARPi, which also had a different action profile than AsiDNA. Based on these differences, and on the mode of action of AsiDNA acting as an inhibitor of the HR pathway, the combination of these two molecules would allow bypassing the genetic restriction (HRD) essential for PARPi efficiency. To validate this hypothesis, we have shown by molecular analyzes that olaparib, a PARPi, and AsiDNA prevent the recruitment at damage sites of the repair proteins XRCC1 and RAD51 / 53BP1, respectively. The combination of these two inhibitors allowed the accumulation of unrepaired damage resulting in an increase of tumor cells’ death, and a significant delay in the growth of xenografts. However, non-tumor cells were not sensitive to this combined treatment. These results highlight the therapeutic interest of combining AsiDNA with PARPi to recapitulate synthetic lethality in all tumors independently of their HR status. In this thesis, we also addressed the issue of acquired resistance to AsiDNA. Indeed, contrary to imatinib and 6-thioguanine, we didn’t recover resistant clones to AsiDNA after mutagenesis or after repeated cycles of treatment on different cell models. Such behavior challenges our common acceptation of a Darwin evolution theory to explain tumor cells resistance to treatment
Coleman, Joshua B., Wesley Drew Gill, Allee C. Maxwell, and Russell W. Brown. "Analysis of a Poly(ADP-ribose) Polymerase (PARP) Inhibitor in a Treatment-resistant Depression Model in the Rat." Digital Commons @ East Tennessee State University, 2020. https://dc.etsu.edu/asrf/2020/presentations/53.
Повний текст джерелаJewett, Benjamin E., Merry N. Miller, Libby A. Ligon, Zachary Carter, Ibrahim Mohammad, and Gregory A. Ordway. "Rapid and Temporary Improvement of Depression and Anxiety Observed Following Niraparib Administration: A Case Report." Digital Commons @ East Tennessee State University, 2020. https://dc.etsu.edu/etsu-works/8592.
Повний текст джерелаCartwright, Luke. "The potential of poly (ADP-ribose) polymerase (PARP) inhibitors to improve plant growth and yield : novel crop protection agents under stressed conditions." Thesis, University of Sheffield, 2017. http://etheses.whiterose.ac.uk/19289/.
Повний текст джерелаBurckel, Hélène. "Synthèse et évaluation de molécules bifonctionnelles alkylantes de l’ADN et inhibitrices de la PARP pour la radiochimiothérapie concomitante." Thesis, Strasbourg, 2012. http://www.theses.fr/2012STRAJ092.
Повний текст джерелаThe main topic of this work was the development and biological evaluation of dual molecules for concomitant chemoradiotherapy. To this end, new dual chemotherapeutic agents were designed by linking covalently two radiosensitizers: a PARP inhibitor and an alkylating agent (platinum complex or temozolomide). This study led to an efficient PARP inhibitor/platinum dual molecule. A complementary approach was to develop affinity probes to study PARP inhibitors by a chemical proteomic method. This study permitted to validate the selectivity of an affinity probe for PARP1 and PARP2. Finally, fluorescent PARP inhibitor probes were synthesised and evaluated for a PARP3 screening by fluorescence anisotropy
Weigert, Verena [Verfasser], Rainer [Akademischer Betreuer] Fietkau, and Luitpold [Gutachter] Distel. "PARP inhibitors combined with ionizing radiation induce different effects in melanoma cells and healthy fibroblasts / Verena Weigert ; Gutachter: Luitpold Distel ; Betreuer: Rainer Fietkau." Erlangen : Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 2021. http://d-nb.info/1231077956/34.
Повний текст джерелаMorice, Pierre-Marie. "Evaluation de la déficience de la recombinaison homologue et de la réponse des tumeurs ovariennes aux inhibiteurs de PARP grâce à l'utilisation de modèles de culture 3D en vue du développement d'un test prédictif Identifying eligible patients to PARP inhibitors: from NGS-based tests to promising 3D functional assays Automated scoring for assessment of RAD51-mediated homologous recombination in patient-derived tumor organoids of ovarian cancers Risk of myelodysplastic syndrome and acute myeloid leukemia related to PARP inhibitors: a combined approach using a safety meta-analysis of placebo randomized controlled trials and the World Health Organization's pharmacovigilance database The long non-coding RNA ‘UCA1’ modulates the response to chemotherapy of ovarian cancer through direct binding to miR-27a-5p and control of UBE2N levels." Thesis, Normandie, 2020. http://www.theses.fr/2020NORMC414.
Повний текст джерелаWorldwide each year, more than 150 000 women die from epithelial ovarian cancer largely due to emergence of resistance to chemotherapy. Approximately half of these cancers display molecular alterations that cause deficiency of DNA repair via homologous recombination (HRD), which confer sensitivity to PARP protein inhibitors (PARPi). To date, there is no test capable of fully identifying the HRD phenotype, thus limiting access to these treatments. In this context, we are developing functional assays based on the use of tumor explant slices and then, on the use of tumor organoids derived from ovarian tumors of chemotherapy-naive or previously treated patients. The culture of explants was unsuitable for this application and we then focused our work on tumor organoids. Tumor organoids were exposed to carboplatin (first-line treatment) and two PARP inhibitors (olaparib and niraparib) used for maintenance therapy. In parallel, we collected clinical data from patients (survival, platinum-free interval, RECIST, treatments) to evaluate the predictive potential of these models. The established tumor organoids responded heterogeneously to different drugs, and our results show that the organoid-based assay is capable of identifying patients highly resistant to carboplatin, suggesting that this functional assay could have a predictive value for patients treated with carboplatin. Regarding the potential of organoids in predicting PARPi response, multiple sensitivity profiles have been identified, but the correlation with clinical response has yet to be determined by studies conducted on tumor samples from patients treated with these drugs
Sulier, Kiaya Minh-Li. "Developing 1,2,3,4-tetrahydro-5H-aryl[1,4]diazepin-5-ones and Related Scaffolds as Poly-(ADP-ribosyl) Polymerase (PARP) Inhibitors and Exploring Their Targeted Polypharmacology with Kinases." Thesis, Virginia Tech, 2017. http://hdl.handle.net/10919/86200.
Повний текст джерелаMaster of Science
Chuang, Hsiao-Ching. "Mechanistic Validation of Potential Anti-Breast Cancer Therapeutics." The Ohio State University, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=osu1338213365.
Повний текст джерелаGrivas, Paul Christopher. "The role of poly (ADP-ribose) polymerase-1 inhibitors : prevention of non glutathione-dependent carbon tetrachloride-induced hepatotoxicity." [Tampa, Fla] : University of South Florida, 2007. http://purl.fcla.edu/usf/dc/et/SFE0001953.
Повний текст джерелаEngert, Florian [Verfasser], Volker Gutachter] Dötsch, and Simone [Gutachter] [Fulda. "PARP inhibitors in combination with chemotherapeutics target the underlying genetic phenotype of Ewing’s sarcoma and osteosarcoma to induce cell death or synthetic lethality / Florian Engert. Gutachter: Volker Dötsch ; Simone Fulda." Frankfurt am Main : Universitätsbibliothek Johann Christian Senckenberg, 2016. http://d-nb.info/1112601538/34.
Повний текст джерелаEngert, Florian Verfasser], Volker [Gutachter] Dötsch, and Simone [Gutachter] [Fulda. "PARP inhibitors in combination with chemotherapeutics target the underlying genetic phenotype of Ewing’s sarcoma and osteosarcoma to induce cell death or synthetic lethality / Florian Engert. Gutachter: Volker Dötsch ; Simone Fulda." Frankfurt am Main : Universitätsbibliothek Johann Christian Senckenberg, 2016. http://d-nb.info/1112601538/34.
Повний текст джерелаSteinbichler, Teresa Bernadette [Verfasser], Heinz Karl [Akademischer Betreuer] Höfler, and Irene [Akademischer Betreuer] Esposito. "Der Einfluss des PARP Inhibitors AZD2281 (Olaparib) auf das Wachstum von Mantelzelllymphomen in Abhängigkeit vom ATM und p53 Mutationsstatus / Teresa Bernadette Steinbichler. Gutachter: Irene Esposito ; Heinz Karl Höfler. Betreuer: Heinz Karl Höfler." München : Universitätsbibliothek der TU München, 2015. http://d-nb.info/1070624195/34.
Повний текст джерелаKwan, Jair Chau Clinical School St Vincent's Hospital Faculty of Medicine UNSW. "Pharmacological activation of pro-survival pathways as a strategy for improving donor heart preservation." Awarded by:University of New South Wales. Clinical School - St Vincent's Hospital, 2009. http://handle.unsw.edu.au/1959.4/44663.
Повний текст джерелаCroset, Amélie. "Identification et caractérisation des mécanismes d'action des molécules appats, les SiDNA, dans l'inhibition des voies de réparation des cassures simple-brin." Thesis, Paris 11, 2013. http://www.theses.fr/2013PA11T018.
Повний текст джерелаMost conventional cancer treatments, such as chemotherapy or radiotherapy, are cytotoxic and cause DNA damages in the tumoral treated cells, which ultimately lead to their death. However, several intrinsic and acquired resistances of tumors to these treatments are due to the tumor efficient DNA repair activities. One of the major early steps of DNA repair is the recruitment of repair proteins at the damage site and this is coordinated by a cascade of modifications controlled by sensor proteins such as DNA-dependent protein kinase (DNA-PK) and/or poly (ADP-ribose) polymerase (PARP). In this manuscript, we identify and characterize the mechanism of action of short interfering DNA molecules (siDNA), mimicking double-strand breaks (called Dbait) or single-strand breaks (called Pbait) in Single Strand Break Repair pathway (SSBR/BER) inhibition. We demonstrate that Dbait bound and induced both PARP and DNA-PK activities, whereas Pbait acts only on PARP. The comparative study of the two molecules allows analysis of the respective roles of the two signaling pathways: both molecules recruit proteins involved in single-strand break repair (such as PARP, XRCC1 and PCNA) and prevent their recruitment at chromosomal damage. Dbait, but not Pbait, also inhibits recruitment of proteins involved in double-strand break (DSB) repair. By these ways, Pbait and Dbait disorganized DNA repair, thereby sensitizing cells to treatments. SSB repair inhibition depends upon a direct trapping of the main proteins on both molecules and an indirect trapping in PAR polymers. DSB repair inhibition may be indirect, resulting from the phosphorylation of DSB repair proteins by activated DNA-PK. The DNA repair inhibition by both molecules is confirmed by their synthetic lethality with BRCA mutations tumoral cell lines. However, BRCA mutation could be sufficient but not necessary to induce breast cancer cell lines and tumors sensitivity to Dbait treatment. In fact, we demonstrate that Dbait molecules could also have a stand-alone effect in BRCA wild type cells with a high genetic instability. We found a correlation between DNA repair proteins basal level (ɣH2AX, PARP and PAR), DNA break basal level, presence of micronucleus (MN) and tumoral cell lines sensitivity to Dbait treatment. We hypothesis that this genetic instability, determined by MN in tumor biopsies, could be a predictive biomarker of Dbait stand-alone effect, not only in breast cancer treatment, but also in glioblastoma, melanoma, uveal melanoma and colon cancer treatment
Billaud, Amandine. "Analyse moléculaire, enjeux et limites des thérapies ciblées en oncologie : extension des sensibilités aux anti-PARP dans les cancers ovariens par caractérisation de variants non annotés et nouveaux mécanismes de résistance dans les cancers bronchiques. Caractérisation moléculaire de l’EGFR dans les cancers bronchiques non à petites cellules : étude prospective comparative des technologies NGS et automate Idylla Somatic mRNA analysis of BRCA1 splice variants provides a direct theranostic impact on PARP inhibitors." Thesis, Angers, 2020. http://www.theses.fr/2020ANGE0003.
Повний текст джерелаDespite significant clinical benefit from the consideration of molecular context, targeted therapies are still challenging. First part of this work focused on tyrosine kinase inhibitors targeting EGFR in non small cell lung cancers. Thus, improvement of biomarkers detection methods was completed by in vitro characterization of an unreported mechanism of acquired resistance. Briefly, pulmonary cells were exposed to a mutagen agent and a selection pressure was applied with EGFR inhibitors allowing the detection of TBK1 signature. Finally, synergic effect of that co-inhibition was highlighted. Now essentials in gynaecological cancers management, PARP inhibitors represent the second part of that work. Those targeted therapies are based on synthetic lethality. Consequently, BRCA1/2 pathogenic mutations are required for their administration, illustrating the issue of variants of uncertain significance. Toward their functional characterization necessity, a transcriptional analysis of splicing variant was first conducted on mRNA extracted from FFPE samples. Then, to evaluate functional signification of all types of variants, genomic edition was developed. Editing efficiencies of the unknown variant and a silent control one were compared in a haploid model where those genes are essentials. Functional signification of BRCA1/2 variants, and thereby mutations from all essential tumor suppressor genes in our model, can be evaluated in three weeks which is compatible with clinical management
Martin, Nadine. "Rôle de la SUMO E3 ligase PIASy dans les mécanismes de contrôle de la prolifération cellulaire et de réponse aux dommages." Paris 6, 2007. http://www.theses.fr/2007PA066243.
Повний текст джерелаHassanein, Mohamed. "Facteurs prédictifs de mutation germinale BRCA1 dans le cancer du sein héréditaire." Thesis, Aix-Marseille 2, 2010. http://www.theses.fr/2010AIX20714.
Повний текст джерелаFamily structure, lack of reliable information, cost and delay are usual concerns faced with when deciding to perform BRCA analyses. Testing the breast cancer tissues with four antibodies (MS110, lys27H3, Vimentin, KI67) in addition to grade evaluation enabled to rapidly select patients to carry out genetic testing identification. We constituted an initial breast cancer tissue micro-array, considered as a learning set comprising 27 BRCA1 and 81 sporadic tumours. A second independent validation set of 28 BRCA1 tumours was matched to 28 sporadic tumours using the same original conditions.We have investigated morphological parameters and 21 markers by immunohistochemistry.A logistic regression model was used to select the minimal number of markers providing the best model to predict BRCA1 status. The model was applied to the validation set to estimate specificity and sensibility.In the initial set, the univariate analysis identified 11 markers significantly associated with BRCA1 status. Then the best multivariate model comprised only Grade 3, MS110, Lys27H3, Vimentin and KI67. When applied to the validation set, BRCA1 tumours were correctly classified with a sensitivity of 83% and a specificity of 81%. The performance of this model was superior when compared to other profiles.This work offers a new rapid and economic method for the pre-screening of patients at high risk of being BRCA1mutation carriers, then to guide genetic testing, and finally to provide appropriate preventive measure, advices and treatments including targeted therapy to patients and their families
Magro, Tatiana Natália Tavares. "Testing the combinatory use of PARP1 and RPA inhibitors in breast cancer cell lines." Master's thesis, 2019. http://hdl.handle.net/10773/29527.
Повний текст джерелаA perda do supressor tumoral BRCA2 está fortemente associada ao cancro da mama. O BRCA2 é essencial para a recombinação homóloga, que é uma via de reparação de ADN crucial para a estabilidade genómica. Quando as células sofrem mutações neste gene, elas não conseguem reparar os danos no ADN através da recombinação homóloga, que é uma via de reparação precisa, e em vez disso, tornam-se dependentes de vias alternativas, propensas a erros, para reparação de ADN. Deste modo, as células tumorais mutantes para BRCA2 tornam-se dependentes destas vias alternativas para sobreviverem. A geração mais recente de terapias direcionadas são os inibidores da PARP1. A PARP1 é uma proteína essencial para a iniciação de várias vias de reparação de ADN, incluindo as tais vias de reparação alternativas, como a non-homologous end joining (NHEJ). A utilização destes inibidores compromete as vias alternativas levando à morte das células tumorais. Embora as células tumorais mutantes para BRCA2 sejam particularmente sensíveis aos inibidores da PARP1, o aparecimento da resistência tumoral tem sido observado frequentemente após tratamentos de longo-prazo. Este problema motivou-nos a procurar proteínas alternativas cuja inibição prejudicasse especificamente, à semelhança da PARP1, a viabilidade e/ou crescimento das células tumorais. Foi recentemente reportado que o BRCA2 regula a transcrição da ARN polimerase II e previne a formação de R-loops, que são estruturas de ácidos nucleicos de 3 cadeias compostas por híbridos de ADN:ARN. A acumulação destes R-loops está implicada no processo de carcinogénese devido à acumulação de ADN de cadeia simples (do inglês ssDNA) e ao aumento de instabilidade genómica. O RPA é uma proteína que se liga ao ssDNA e evita que se formem estruturas secundárias, sendo crucial para a replicação e reparação de ADN. O nosso objetivo é identificar novos alvos terapêuticos cuja inibição possa ser usada em combinação ou como alternativa aos inibidores da PARP1, minimizando o risco de resistência tumoral. A nossa hipótese de trabalho é que a inibição combinatória de PARP1 e RPA aumentará especificamente a perda de viabilidade das células de cancro da mama.
Mestrado em Biomedicina Molecular
Dziaková, Lucia. "Studium interakcí PARP inhibitorů s ABC lékovými efluxními transportéry." Master's thesis, 2020. http://www.nusl.cz/ntk/nusl-411910.
Повний текст джерелаAubert-Jürgens, Ana. "STAT3 inhibitors for cancer treatment." Phd thesis, 2005. https://tuprints.ulb.tu-darmstadt.de/563/1/aubert-jurgens-part1.pdf.
Повний текст джерелаSohail, Honeah. "PARP inhibitor ABT-888 as potentiating agent for topoisomerase inhibitor SN-38." 2009. http://hdl.rutgers.edu/1782.2/rucore10001600001.ETD.000051407.
Повний текст джерелаAllison, Simon J., Maria Sadiq, Efstathia Baronou, Patricia A. Cooper, C. Dunnill, N. T. Georgopoulos, A. Latif, et al. "Preclinical anti-cancer activity and multiple mechanisms of action of a cationic silver complex bearing N-heterocyclic carbene ligands." 2017. http://hdl.handle.net/10454/11960.
Повний текст джерелаOrganometallic complexes offer the prospect of targeting multiple pathways that are important in cancer biology. Here, the preclinical activity and mechanism(s) of action of a silver-bis(N-heterocyclic carbine) complex (Ag8) were evaluated. Ag8 induced DNA damage via several mechanisms including topoisomerase I/II and thioredoxin reductase inhibition and induction of reactive oxygen species. DNA damage induction was consistent with cytotoxicity observed against proliferating cells and Ag8 induced cell death by apoptosis. Ag8 also inhibited DNA repair enzyme PARP1, showed preferential activity against cisplatin resistant A2780 cells and potentiated the activity of temozolomide. Ag8 was substantially less active against non-proliferating non-cancer cells and selectively inhibited glycolysis in cancer cells. Ag8 also induced significant anti-tumour effects against cells implanted intraperitoneally in hollow fibres but lacked activity against hollow fibres implanted subcutaneously. Thus, Ag8 targets multiple pathways of importance in cancer biology, is less active against non-cancer cells and shows activity in vivo in a loco-regional setting.
RMP and MS funded by Yorkshire Cancer Research (pump priming grant BPP 046). IJS and AL funded by NIHR Research & Innovation Division, Strategic Project Funding 2013 and Manchester Pharmacy School Fellowship.
Nikoloska, Irena. "Towards the Synthesis of Novel PARP Inhibitors through Diels-Alder Chemistry." Thesis, 2012. http://hdl.handle.net/10214/3561.
Повний текст джерелаNSERC
Mishra, Anup. "Targeting RAD51C Pathological Mutants by Synthetic Lethality and Extended Functions of RAD51C/XRCC3 in Mitochondrial Genome Maintenance." Thesis, 2017. http://etd.iisc.ac.in/handle/2005/4155.
Повний текст джерелаWang, Wei-Jie, and 王為婕. "Mechanisms of SAHA and PARP Inhibitors Induced Cell Death in Cancer Cells." Thesis, 2015. http://ndltd.ncl.edu.tw/handle/34790258374946152730.
Повний текст джерела國立陽明大學
生命科學系暨基因體科學研究所
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I. Combination therapy of SAHA and PARP inhibitors in HCC treatment Genomic instability is one of the cancer hallmarks. Because severe DNA damage results in cell death, inhibitors of the DNA repair system can be used as anticancer drugs. An inhibitor of histone deacetylases (HDACs) - suberoylanilide hydroxamic acid (SAHA), is being evaluated for phase2/3 clinical trial to treat several types of cancers. Mechanism of SAHA-induced cell death is not totally clear, but reactive oxygen species (ROS) release and double strand break (DSB) may play a role in apoptosis of SAHA-treated cells. Upon DNA damage, p53 activates its downstream target genes and triggers DNA repair or apoptosis. In our previous study, mutation of TP53 and down-regulation of PARP4 were found to be associated with chromosome 4q loss of heterozygosity in hepatocellular carcinoma (HCC), implicating that sensitivity to DNA-damaging agents in HCC cells might depend on the TP53 status and PARP4 expression level. A pan-PARP inhibitor 3-aminobenzamide (3-ABA), known to inhibit the single strand break repairing system by targeting PARP1/2, was chosen as a candidate to be combined with SAHA for treating HCC cells with TP53 mutation. As a result of impaired DNA repair, DSB and apoptosis were enhanced, as measured by γ-H2AX staining and caspase 3/PARP1 cleavage, respectively. Sensitivity to SAHA and 3-ABA was reduced in TP53 knocked down or mutant TP53 stably transfected HepG2 cells. Depending on genetic background, SAHA/3-ABA-induced cytotoxicity was variable and could be attributed to cell cycle arrest and cell death. In HepG2 cells, SAHA-induced up-regulation of CDKN1A was enhanced by 3-ABA. In Hep3B cells, TXNIP level was further elevated by 3-ABA, contributing to ROS release and DSB. Consistently, N-acetylcysteine, a ROS inhibitor, reduced the expression of the targeted genes, GRP94 and CHOP, of unfolded protein response, and blunted SAHA/3-ABA induced cell death. Another PARP inhibitor rucaparib, when combining with SAHA, induced prominent cell death, and it was accompanied by up-regulation of p21 (WAF1/CIP). Unlike 3-ABA, rucaparib did not enhance SAHA-induced DSB. Thus our results support that multiple pathways and effectors are involved in SAHA-induced cancer cell death, and, contingent on TP53, a new strategy of therapeutic development can be designed by adding PARP inhibitors, to achieve personalized medicine for HCC. II. Cellular characterization of PARP4 Poly(ADP-ribose) polymerase family, member 4 (PARP4) catalyzes poly(ADP-ribosyl)ation PARsylation of numerous proteins localized in cytosol and nuclei. In previous studies, PARsylation of targeted proteins were known to be involved in regulating DNA damage detection, DNA repair, and cell death pathways. To investigate whether PARP4 also participates in the maintenance of genome integrity, subcellular localization of PARP4 was analyzed. Nuclear translocation of PARP4 was observed with DSBs induced by various DNA-damaging agents. In H2O2-treated HeLa cells, PARP4 localized with γ-H2AX, a DSB marker, while in etoposide-treated HEK293T cells, co-localization of PARP4 and PAR was observed. Notably, PARP4 nuclear localization is an early event and it became detectable by fluorescence microscopy two hours after addition of 4 μM SAHA. PARP4 knockdown enhanced DSBs and cell death in SAHA/3-ABA-treated cancer cells. Finally, SAHA targeted on PARP4 by down-regulation of mRNA and protein expression, suggesting that enhancement of cell death by combining SAHA with PARP inhibitors might work through their effects on the PARP4 level and DNA repair. Taken together, our data support that PARP4 may function in the maintenance of genome integrity, and it could be served as a target to design anticancer drugs.
Meyer, Stephanie C. "Synergistic effects of combining PARP inhibitor (AZD2281) and ATR inhibitor (AZD6738) in Ewing Sarcoma cell lines." Thesis, 2018. https://hdl.handle.net/2144/30818.
Повний текст джерела2020-07-03T00:00:00Z