A5001137841- PARP inhibition in cancer therapy
- Toxin Mechanisms and Immunotoxins
- Phytochemicals and Medicinal Plants
- DNA Repair Mechanisms
- CRISPR and Genetic Engineering
- Health Systems, Economic Evaluations, Quality of Life
- Sphingolipid Metabolism and Signaling
- Biosimilars and Bioanalytical Methods
- Caveolin-1 and cellular processes
- Glycosylation and Glycoproteins Research
- Lipid Membrane Structure and Behavior
- Integrated Circuits and Semiconductor Failure Analysis
- Galectins and Cancer Biology
- Economic and Financial Impacts of Cancer
- Retinoids in leukemia and cellular processes
- Cardiac electrophysiology and arrhythmias
- Cancer therapeutics and mechanisms
- Biomedical Research and Pathophysiology
- Signaling Pathways in Disease
- Ovarian cancer diagnosis and treatment
- Single-cell and spatial transcriptomics
- Calcium signaling and nucleotide metabolism
- Cancer Genomics and Diagnostics
- Lysosomal Storage Disorders Research
- Cellular transport and secretion
AstraZeneca (Brazil)
2025
AstraZeneca (United Kingdom)
2018-2024
Saffron Walden Museum
2022
Université de Strasbourg
2012-2016
Centre National de la Recherche Scientifique
2014-2016
Biotechnologie et Signalisation Cellulaire
2012-2015
École Supérieure de Biotechnologie de Strasbourg
2014
University of Milan
2009-2011
Abstract The poly (ADP-ribose) polymerase (PARP) inhibitor olaparib is FDA approved for the treatment of BRCA -mutated breast, ovarian and pancreatic cancers. Olaparib inhibits PARP1/2 enzymatic activity traps PARP1 on DNA at single-strand breaks, leading to replication-induced damage that requires BRCA1/2-dependent homologous recombination repair. Moreover, response pathways mediated by ataxia-telangiectasia mutated (ATM) Rad3-related (ATR) kinases are hypothesised be important survival in...
Abstract Purpose: We hypothesized that inhibition and trapping of PARP1 alone would be sufficient to achieve antitumor activity. In particular, we aimed selectivity over PARP2, which has been shown play a role in the survival hematopoietic/stem progenitor cells animal models. developed AZD5305 with aim achieving improved clinical efficacy wider therapeutic window. This next-generation PARP inhibitor (PARPi) could provide paradigm shift outcomes achieved by first-generation PARPi,...
Poly-ADP-ribose-polymerase (PARP) inhibitors have achieved regulatory approval in oncology for homologous recombination repair deficient tumors including BRCA mutation. However, some failed combination with first-line chemotherapies, usually due to overlapping hematological toxicities. Currently approved PARP lack selectivity PARP1 over PARP2 and other 16 family members, we hypothesized that this could contribute toxicity. Recent literature has demonstrated inhibition PARP1–DNA trapping are...
The repair of toxic double-strand breaks (DSB) is critical for the maintenance genome integrity. major mechanisms that cope with DSB are: homologous recombination (HR) and classical or alternative nonhomologous end joining (C-NHEJ versus A-EJ). Because these pathways compete DSB, choice appropriate pathway pivotal. Among influence this choice, deoxyribonucleic acid (DNA) resection plays a role by driving cells to HR, while accurate C-NHEJ suppressed. Furthermore, promotes error-prone A-EJ....
Abstract Drug resistance is a principal limitation to the long-term efficacy of cancer therapies. Cancer genome sequencing can retrospectively delineate genetic basis drug resistance, but this requires large numbers post-treatment samples nominate causal variants. Here we prospectively identify mechanisms ten oncology drugs from CRISPR base editing mutagenesis screens in four cell lines using guide RNA library predicted install 32,476 variants 11 genes. We functional classes protein...
Poly(ADP-ribosyl)ation is involved in numerous bio-logical processes including DNA repair, transcription and cell death. Cellular levels of poly(ADP-ribose) (PAR) are regulated by PAR polymerases (PARPs) the degrading enzyme glycohydrolase (PARG), controlling fate decision between life death response to damage. Replication stress a source damage, leading transient stalling replication forks or their collapse followed generation double-strand breaks (DSB). The involvement PARP-1 replicative...
AMPK is a central energy sensor linking extracellular milieu fluctuations with the autophagic machinery. In current study we uncover that Poly(ADP-ribosyl)ation (PARylation), post-translational modification (PTM) of proteins, accounts for spatial and temporal regulation autophagy by modulating subcellular localisation activation. More particularly, show minority pool needs to be exported cytosol in PARylation-dependent manner optimal induction autophagy, including ULK1 phosphorylation mTORC1...
Abstract Purpose: We evaluated the properties and activity of AZD9574, a blood–brain barrier (BBB) penetrant selective inhibitor PARP1, assessed its efficacy safety alone in combination with temozolomide (TMZ) preclinical models. Experimental Design: AZD9574 was interrogated vitro for selectivity, PARylation inhibition, PARP-DNA trapping, ability to cross BBB, potential inhibit cancer cell proliferation. In vivo determined using subcutaneous as well intracranial mouse xenograft Mouse, rat,...
Recent phase 3 clinical trial readouts have shown benefit of the combination poly(ADP-ribose) polymerase inhibitors (PARPi) with androgen receptor (AR) pathway (ARPi) in metastatic, castration-resistant prostate cancer (mCRPC). While was particularly evident patients tumours harbouring mutations homologous recombination repair (HRR) genes, improved outcomes were also observed no such defined alterations their cancers. Although there is literature linking AR activity DNA pathways, basis...
Human fibroblasts produce ceramide from sialyllactosylceramide on the plasma membranes. Sialidase Neu3 is known to be membrane associated, while only indirect data suggest association of beta-galactosidase and beta-glucosidase. To determine presence beta-glucosidase membrane, cells were submitted cell surface biotinylation. Biotinylated proteins purified by affinity column analyzed for enzymatic activities artificial substrates. Both enzyme found associated with up-regulated in...
In this paper, we describe the effects of expression GM3 synthase at high levels in human ovarian carcinoma cells. Overexpression A2780 cells consistently resulted elevated ganglioside (GM3, GM2 and GD1a) levels. overexpressing had a growth rate similar to wild-type cells, but showed strongly reduced vitro cell motility accompanied by epithelial-mesenchymal transition marker α smooth muscle actin. A reduction was observed upon treatment with exogenous GM3, GM2, GM1, not GD1a. photolabeling...
A2780 human ovarian carcinoma cells respond to treatment with the synthetic retinoid N-(4-hydroxyphenyl)retinamide (HPR) production of dihydroceramide and a concomitant reduction cell proliferation induction apoptosis. The derived HPR-resistant clonal line, A2780/HPR, is less responsive HPR in terms generation. In this report, we show that sphingosine 1-phosphate (S1P) significantly higher A2780/HPR versus due an increased kinase (SK) activity SK-1 mRNA protein levels. Treatment potent...
The genetic (stable overexpression of sialyltransferase I, GM3 synthase) or pharmacological (selective pressure by N-(4-hydroxyphenyl)retinamide)) manipulation A2780 human ovarian cancer cells allowed us to obtain clones characterized higher synthase activity compared with wild-type cells. Clones high expression had elevated ganglioside levels, reduced in vitro cell motility, and enhanced the membrane adaptor protein caveolin-1 respect In synthase-expressing clones, both depletion...
High grade serous ovarian cancer (HGSOC) is a major cause of female mortality. The approval poly (ADP-ribose) polymerase (PARP) inhibitors for clinical use has greatly improved treatment options patients with homologous recombination repair (HRR)-deficient HGSOC, although the development PARP inhibitor resistance in some revealing limitations to outcome. A proportion HRR-proficient cancers also benefit from therapy. Our aim compare mechanisms olaparib these two main molecular categories...
Poly(ADP-ribose) polymerase (PARP) inhibitors have entered the clinics for their promising anticancer effect as adjuvant in chemo- and radiotherapy single agent on BRCA-mutated tumours. glycohydrolase (PARG) deficiency was also shown to potentiate cytotoxicity of genotoxic agents irradiation. The aim this study is investigate PARG BRCA1- and/or PTEN-deficient tumour cells.Since no are available vivo studies, depleted by siRNA several cancer cell lines, proficient or deficient BRCA1 PTEN....
Abstract Four poly(ADP-ribose) polymerase (PARP) inhibitors have now presented phase 3 monotherapy data showing compelling benefit of targeting tumours enriched with DNA damage response (DDR) pathway deficiencies, including BRCA gene mutations. Indirect treatment comparisons using the published clinical from these late stage trials suggest similar levels efficacy are observed in spite reported differences PARP trapping potency. However, there is greater diversity safety profiles. To try and...
PARP inhibitors (PARPi) are currently indicated for the treatment of ovarian, breast, pancreatic, and prostate cancers harboring mutations in tumor suppressor genes BRCA1 or BRCA2. In case ovarian cancers, their classification as homologous recombination repair (HRR) deficient (HRD) mutated also makes PARPi an available option beyond BRCA2 mutational status. However, identification most relevant genetic alterations driving HRD phenotype has proven difficult recent data have shown that other...
Abstract Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) are currently indicated for the treatment of ovarian, breast, pancreatic and prostate cancers harbouring mutations in tumour suppressor genes BRCA1 or BRCA2 . In case ovarian cancers, their classification as homologous recombination repair (HRR) deficient (HRD) mutated (HRRm) also makes PARPi an available option beyond mutational status. However, identification most relevant genetic alterations driving HRD phenotype has proven...
Abstract Treatments with PARPi in cancers impaired DNA repair mechanisms (i.e. Homologous Recombination Repair Deficiency, HRD) causes unsupportable genomic instability resulting tumor cell death. act via a dual mechanism: 1) they block PARylation activity that normally occurs response to damage; 2) trap PARP onto lesions creating potentially cytotoxic PARP-DNA complexes. The longer is inhibited and trapped the DNA, greater effect of preclinical models. However, differences trapping potency...
<p>Supplementary methods, figures, tables</p>
<div>AbstractPurpose:<p>We evaluated the properties and activity of AZD9574, a blood–brain barrier (BBB) penetrant selective inhibitor PARP1, assessed its efficacy safety alone in combination with temozolomide (TMZ) preclinical models.</p>Experimental Design:<p>AZD9574 was interrogated <i>in vitro</i> for selectivity, PARylation inhibition, PARP-DNA trapping, ability to cross BBB, potential inhibit cancer cell proliferation. <i>In vivo</i>...