A5050483295- DNA Repair Mechanisms
- Glioma Diagnosis and Treatment
- Cancer-related Molecular Pathways
- PARP inhibition in cancer therapy
- Peptidase Inhibition and Analysis
- Radiopharmaceutical Chemistry and Applications
- Brain Metastases and Treatment
- Pancreatic and Hepatic Oncology Research
- Cancer Immunotherapy and Biomarkers
- CRISPR and Genetic Engineering
- Carcinogens and Genotoxicity Assessment
- Cancer therapeutics and mechanisms
- Epigenetics and DNA Methylation
- Immune Cell Function and Interaction
- Lung Cancer Research Studies
- IgG4-Related and Inflammatory Diseases
- Immune cells in cancer
- Ferroptosis and cancer prognosis
- Cancer, Hypoxia, and Metabolism
- Colorectal Cancer Treatments and Studies
- Toxin Mechanisms and Immunotoxins
- Genomics and Chromatin Dynamics
- Cancer Genomics and Diagnostics
- Genetic factors in colorectal cancer
- Cancer-related gene regulation
AstraZeneca (United Kingdom)
2014-2024
Evotec (United Kingdom)
2022-2023
Bioscience (China)
2023
AstraZeneca (Canada)
2016
University of New Mexico
2005-2010
University of Oxford
2008-2009
Indiana University – Purdue University Indianapolis
2005
Indiana University School of Medicine
2005
Cancer Research UK
2003
University of Glasgow
2003
Poor survival rates of patients with tumors arising from or disseminating into the brain are attributed to an inability excise all tumor tissue (if operable), a lack blood-brain barrier (BBB) penetration chemotherapies/targeted agents, and intrinsic radio-/chemo-resistance. Ataxia-telangiectasia mutated (ATM) protein orchestrates cellular DNA damage response (DDR) cytotoxic double-strand breaks induced by ionizing radiation (IR). ATM genetic ablation pharmacological inhibition results in...
Mutations in the ATM tumor suppressor gene confer hypersensitivity to DNA-damaging chemotherapeutic agents. To explore genetic resistance mechanisms, we performed genome-wide CRISPR-Cas9 screens cells treated with DNA topoisomerase I inhibitor topotecan. Thus, here establish that inactivating terminal components of non-homologous end-joining (NHEJ) machinery or BRCA1-A complex specifically topotecan ATM-deficient cells. We show ATM-mutant poly-(ADP-ribose) polymerase (PARP) olaparib reflects...
ATM inhibitors, such as 7, have demonstrated the antitumor potential of inhibition when combined with DNA double-strand break-inducing agents in mouse xenograft models. However, properties 7 result a relatively high predicted clinically efficacious dose. In an attempt to minimize attrition during clinical development, we sought identify inhibitors low dose (<50 mg) and focused on strategies increase both potency human pharmacokinetic half-life (predominantly through volume distribution)....
Abstract Histone H2AX plays a key role in DNA damage signalling the surrounding regions of double-strand breaks (DSBs). In response to damage, becomes phosphorylated on serine residue 139 (known as γH2AX), resulting recruitment repair effectors 53BP1 and BRCA1. Here, by studying resistance poly(ADP-ribose) polymerase (PARP) inhibitors BRCA1/2-deficient mammary tumours, we identify function for γH2AX orchestrating drug-induced replication fork degradation. Mechanistically, γH2AX-driven...
Non-homologous DNA end-joining (NHEJ) is a major pathway of double strand break (DSB) repair in human cells. Here we show that vanillin (3-methoxy-4-hydroxybenzaldehyde)--a naturally occurring food component and an acknowledged antimutagen, anticlastogen anticarcinogen--is inhibitor NHEJ. Vanillin blocked by cell extracts directly inhibiting the activity DNA-PK, crucial NHEJ component. Inhibition was selective had no detectable effect on other steps process, unrelated protein kinase or...
The molecular mechanism by which foreign DNA integrates into the human genome is poorly understood yet critical to many disease processes, including retroviral infection and carcinogenesis, gene therapy. We hypothesized that of genomic integration may be similar transposition in lower organisms. identified a protein, termed Metnase, has SET domain transposase/nuclease domain. Metnase methylates histone H3 lysines 4 36, are associated with open chromatin. increases resistance ionizing...
Abstract Background Personalised medicine strategies may improve outcomes in pancreatic ductal adenocarcinoma (PDAC), but validation of predictive biomarkers is required. Having developed a clinical trial to assess the ATR inhibitor, AZD6738, combination with gemcitabine (ATRi/gem), we investigated ATM loss as biomarker response ATRi/gem PDAC. Methods Through kinase inhibition, siRNA depletion and CRISPR knockout ATM, assessed how targeting affected sensitivity PDAC cells ATRi/gem. Using...
ATM activation at telomeres confers chemoresistance in ALT neuroblastoma and is reversible preclinical models by knockdown or inhibition.
The inhibition of ataxia-telangiectasia mutated (ATM) has been shown to chemo- and radio-sensitize human glioma cells in vitro therefore might provide an exciting new paradigm the treatment glioblastoma multiforme (GBM). effective GBM will likely require a compound with potential efficiently cross blood–brain barrier (BBB). Starting from clinical candidate AZD0156, 4, we investigated imidazoquinolin-2-one scaffold goal improving CNS exposure humans. Strategies aimed at reducing hydrogen...
Inhibition of ataxia-telangiectasia mutated (ATM) during radiotherapy glioblastoma multiforme (GBM) may improve tumor control by short-circuiting the response to radiation-induced DNA damage. A major impediment for clinical implementation is that current inhibitors have limited central nervous system (CNS) bioavailability; thus, goal was identify ATM (ATMi) with improved CNS penetration. Drug screens and refinement lead compounds identified AZ31 AZ32. The were then tested
Metnase is a human protein with methylase (SET) and nuclease domains that widely expressed, especially in proliferating tissues. promotes non-homologous end-joining (NHEJ), knockdown causes mild hypersensitivity to ionizing radiation. also plasmid viral DNA integration, topoisomerase IIα (TopoIIα)-dependent chromosome decatenation. NHEJ factors have been implicated the replication stress response, TopoIIα has proposed relax positive supercoils front of forks. Here we show cell proliferation,...
Poly(ADP-ribose) glycohydrolase (PARG) is the only enzyme known to catalyse hydrolysis of O-glycosidic linkages ADP-ribose polymers, thereby reversing effects poly(ADP-ribose) polymerases. PARG deficiency leads cell death whilst depletion causes sensitisation certain DNA damaging agents, implicating as a potential therapeutic target in several disease areas. Efforts develop small molecule inhibitors activity have until recently been hampered by lack structural information on PARG. We used...
Flap endonuclease 1 (FEN1) is a structure selective required for proficient DNA replication and the repair of damage. Cellularly active inhibitors this enzyme have previously been shown to induce damage response and, ultimately, cell death. High-throughput screens human cancer cell-lines identify colorectal gastric with microsatellite instability (MSI) as enriched cellular sensitivity N-hydroxyurea series FEN1, but not PARP inhibitor olaparib or other response. This due synthetic lethal...
Abstract Myofibroblastic cancer-associated fibroblast (myoCAF)–rich tumors generally contain few T cells and respond poorly to immune-checkpoint blockade. Although myoCAFs are associated with poor outcome in most solid tumors, the molecular mechanisms regulating myoCAF accumulation remain unclear, limiting potential for therapeutic intervention. Here, we identify ataxia-telangiectasia mutated (ATM) as a central regulator of phenotype. Differentiating myofibroblasts vitro cultured ex vivo...
Cancer treatments targeting DNA repair deficiencies often encounter drug resistance, possibly due to alternative metabolic pathways that counteract the most damaging effects. To identify such pathways, we screened for exhibiting synthetic lethality with inhibition of damage response kinase Ataxia-telangiectasia-mutated (ATM) using a metabolism-centered Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 library. Our data revealed Kelch-like ECH-associated protein 1...
Abstract Purpose: Limited effective treatments are currently available for central nervous system (CNS) metastasis (CM). This is largely driven by the inability of current therapeutics to penetrate blood brain barrier (BBB) and lack preclinical models testing new therapies. Here we study efficacy AZD1390, a BBB penetrating ataxia-telangiectasia mutated inhibitor, as radiosensitizer breast cancer CM treatment. Experimental Design: Three patient-derived xenograft (PDX) tumors including 2 HER2+...
The vast majority of cancers commandeer the activity telomerase - remarkable enzyme responsible for prolonging cellular lifespan by maintaining length telomeres at ends chromosomes. Telomerase is only normally active in embryonic and highly proliferative somatic cells. Thus, targeting an attractive anti-cancer therapeutic rationale currently under investigation various phases clinical development. However, previous reports suggest that average 10-15% all lose functional most these turn to...
AZD0156 is an oral inhibitor of ATM, a serine threonine kinase that plays key role in DNA damage response (DDR) associated with double-strand breaks. Topoisomerase-I irinotecan used clinically to treat colorectal cancer (CRC), often combination 5-fluorouracil (5FU). and 5FU was evaluated preclinical models CRC determine whether low doses enhance the cytotoxicity chemotherapy regimens clinic.Anti-proliferative effects single-agent AZD0156, active metabolite (SN38), therapy were 12 cell lines....
We report the discovery of a novel series 3-cinnoline carboxamides as highly potent and selective ataxia telangiectasia mutated (ATM) kinase inhibitors. Optimization this focusing on potency physicochemical properties (especially permeability) led to identification compound 21, ATM inhibitor (ATM cell IC50 0.0028 μM) with excellent selectivity favorable pharmacokinetics properties. In vivo, 21 in combination irinotecan showed tumor regression SW620 colorectal xenograft model, superior...