A5055277039- DNA Repair Mechanisms
- PARP inhibition in cancer therapy
- CRISPR and Genetic Engineering
- Cancer therapeutics and mechanisms
- BRCA gene mutations in cancer
- Cancer-related Molecular Pathways
- Chronic Lymphocytic Leukemia Research
- Cancer Genomics and Diagnostics
- Cell death mechanisms and regulation
- Glioma Diagnosis and Treatment
- Advanced Breast Cancer Therapies
- Microtubule and mitosis dynamics
- Innovative Microfluidic and Catalytic Techniques Innovation
- Microfluidic and Capillary Electrophoresis Applications
- Genetic factors in colorectal cancer
- Carcinogens and Genotoxicity Assessment
- Radiation Therapy and Dosimetry
- Pancreatic and Hepatic Oncology Research
- Protein Degradation and Inhibitors
- Genetics and Neurodevelopmental Disorders
- Ovarian cancer diagnosis and treatment
- Ubiquitin and proteasome pathways
- Lung Cancer Research Studies
- Molecular Biology Techniques and Applications
- RNA modifications and cancer
AstraZeneca (United Kingdom)
2015-2024
AstraZeneca (Singapore)
2021
City University of Hong Kong
2014
The University of Texas Southwestern Medical Center
2013
Virginia Commonwealth University
2013
Newcastle University
2013
GW Pharmaceuticals (United Kingdom)
2004-2012
Molecular Oncology (United States)
2012
National Cancer Institute
2012
Rutgers Cancer Institute of New Jersey
2012
The inhibition of poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) is a potential synthetic lethal therapeutic strategy for the treatment cancers with specific DNA-repair defects, including those arising in carriers BRCA1 or BRCA2 mutation. We conducted clinical evaluation humans olaparib (AZD2281), novel, potent, orally active PARP inhibitor.This was phase 1 trial that included analysis pharmacokinetic and pharmacodynamic characteristics olaparib. Selection aimed at having study...
Whereas target-specific drugs are available for treating ERBB2-overexpressing and hormone receptor-positive breast cancers, no tailored therapy exists receptor- ERBB2-negative ("triple-negative") mammary carcinomas. Triple-negative tumors account 15% of all cancers frequently harbor defects in DNA double-strand break repair through homologous recombination (HR), such as BRCA1 dysfunction. The DNA-repair characteristic BRCA1-deficient cells confer sensitivity to poly(ADP-ribose) polymerase 1...
Poly(ADP-ribose) polymerase activation is an immediate cellular response to metabolic-, chemical-, or ionizing radiation-induced DNA damage and represents a new target for cancer therapy. In this article, we disclose novel series of substituted 4-benzyl-2 H-phthalazin-1-ones that possess high inhibitory enzyme potency both PARP-1 PARP-2. Optimized compounds from the also demonstrate good pharmacokinetic profiles, oral bioavailability, activity in vivo SW620 colorectal xenograft model....
Inhibition of PARP is a promising therapeutic strategy for homologous recombination-deficient tumors, such as BRCA1-associated cancers. We previously reported that BRCA1-deficient mouse mammary tumors may acquire resistance to the clinical inhibitor (PARPi) olaparib through activation P-glycoprotein drug efflux transporter. Here, we show tumor-specific genetic inactivation increases long-term response olaparib, but these eventually developed PARPi resistance. In fraction cases, this caused...
Abstract Purpose: To assess efficacy of the novel, selective poly(ADP-ribose) polymerase-1 (PARP-1) inhibitor AZD2281 against newly established BRCA2-deficient mouse mammary tumor cell lines and to determine potential synergy between cisplatin. Experimental Design: We thoroughly characterized a panel clonal from independent tumors BRCA2-proficient control tumors. Subsequently, we assessed sensitivity these conventional cytotoxic drugs novel PARP AZD2281. Finally, in vitro combination studies...
The kinase ataxia telangiectasia mutated and rad3 related (ATR) is a key regulator of the DNA-damage response apical which orchestrates cellular processes that repair stalled replication forks (replication stress) associated DNA double-strand breaks. Inhibition pathways mediated by ATR in context where alternative are less active expected to aid clinical increasing stress. Here we describe development candidate 2 (AZD6738), potent selective sulfoximine morpholinopyrimidine inhibitor with...
// Frank P. Vendetti 1 , Alan Lau 2 Sandra Schamus Thomas Conrads 3 Mark J. O’Connor Christopher Bakkenist 1, 4 Department of Radiation Oncology, University Pittsburgh School Medicine, Pittsburgh, PA, USA Cancer Bioscience, AstraZeneca, Macclesfield, United Kingdom Women's Health Integrated Research Center at Inova System, Defense Gynecologic Excellence, Annandale, VA, Pharmacology and Chemical Biology, Correspondence to: Bakkenist, e-mail: bakkenistcj@upmc.edu Keywords: ATM...
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 AZD6738 (ceralasertib) is a potent and selective orally bioavailable inhibitor of ataxia telangiectasia Rad3-related (ATR) kinase. ATR activated in response to stalled DNA replication forks promote G2–M cell-cycle checkpoints fork restart. Here, we found modulated CHK1 phosphorylation induced ATM-dependent signaling (pRAD50) the damage marker γH2AX. inhibited break-induced homologous recombination repair. In vitro sensitivity was elevated in, but not exclusive to, cells with defects...
Poly (ADP-ribose) polymerase 1 and 2 (PARP1/2) inhibitors (PARPi) are targeted therapies approved for homologous recombination repair (HRR)-deficient breast, ovarian, pancreatic, prostate cancers. Since inhibition of PARP1 is sufficient to cause synthetic lethality in tumors with deficiency (HRD), selective such as saruparib (AZD5305) being developed. It expected that leads a safer profile facilitates its combination other DNA damage inhibitors. Here, we aimed characterize the antitumor...
Abstract Purpose: Glioblastoma multiforme (GBM) is the most lethal form of brain cancer with a median survival only 12 to 15 months. Current standard treatment consists surgery followed by chemoradiation. The poor patients GBM due aggressive tumor invasiveness, an inability remove all tissue, and innate chemo- radioresistance. Ataxia–telangiectasia mutated (ATM) excellent target for radiosensitizing because its critical role in regulating DNA damage response p53, among other cellular...
Impaired DNA damage response pathways may create vulnerabilities of cancer cells that can be exploited therapeutically. One such selective vulnerability is the sensitivity BRCA1- or BRCA2-defective tumors (hence defective in repair by homologous recombination, HR) to inhibitors poly(ADP-ribose) polymerase-1 (PARP-1), an enzyme critical for alternative HR. While promising, treatment with PARP-1 (PARP-1i) faces some hurdles, including (1) acquired resistance, (2) search other sensitizing,...
Ataxia telangiectasia mutated (ATM) kinase signals DNA double-strand breaks (DSB) to cell-cycle arrest via p53 and repair. ATM-defective cells are sensitive DSB-inducing agents, making ATM an attractive target for anticancer chemo- radiosensitization. KU59403 is inhibitor with the potency, selectivity, solubility advanced preclinical evaluation. was not cytotoxic human cancer cell lines (SW620, LoVo, HCT116, MDA-MB-231) per se but significantly increased cytotoxicity of topoisomerase I II...
Recent literature has claimed that inhibition of the enzyme MTH1 can eradicate cancer. is one "housekeeping" enzymes are responsible for hydrolyzing damaged nucleotides in cells and thus prevent them from being incorporated into DNA. We have developed orthogonal chemically distinct tool compounds to those published allow us test hypothesis wide applicability treatment Here we present work led discovery three structurally different series inhibitors with excellent potency, selectivity, proven...
Abstract Ataxia telangiectasia and Rad3-related (ATR) can be considered an attractive target for cancer treatment due to its deleterious effect on cells harboring a homologous recombination defect. The aim of this study was investigate the potential use ATR inhibitor, AZD6738, treat gastric cancer. In SNU-601 with dysfunctional ATM, AZD6738 led accumulation DNA damage RAD51 foci formation, S phase arrest, caspase 3–dependent apoptosis. contrast, SNU-484 functional ATM were not sensitive...
Abstract Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest cancers, and overall survival rates have barely improved over past five decades. The antimetabolite gemcitabine remains part of standard care but shows very limited antitumor efficacy. Ataxia telangiectasia Rad3-related protein (ATR), apical kinase intra–S-phase DNA damage response, plays a central role in safeguarding cells from replication stress can therefore limit efficacy drug therapies. We investigated ability ATR...
This study reports the safety, tolerability, MTD, recommended phase II dose (RP2D), pharmacokinetic/pharmacodynamic profile, and preliminary antitumor activity of ceralasertib combined with carboplatin in patients advanced solid tumors. It also examined exploratory predictive pharmacodynamic biomarkers.Eligible (n = 36) received a fixed (AUC5) escalating doses (20 mg twice daily to 60 once daily) 21-day cycles. Sequential concurrent combination dosing schedules were assessed.Two MTD...
Abstract The Ataxia telangiectasia and Rad3-related (ATR) inhibitor ceralasertib in combination with the PD-L1 antibody durvalumab demonstrated encouraging clinical benefit melanoma lung cancer patients who progressed on immunotherapy. Here we show that modelling of intermittent treatment mouse tumor models reveals CD8 + T-cell dependent antitumor activity, which is separate from effects cells. Ceralasertib suppresses proliferating T-cells rapidly reversed off-treatment. causes up-regulation...
Abstract Germ-line heterozygosity of the BRCA2 gene in women predisposes to breast and ovarian cancers. Successful therapies targeted specifically at these neoplasms have thus far remained elusive. Recent studies mice shown that inhibition poly(ADP-ribose) polymerase-1 (PARP-1) targets cells lacking Brca2 xenografts derived from BRCA2-deficient ES or Chinese hamster ovary cells. We set out develop a more relevant preclinical model will inform accelerate translation into clinic. As such, we...
The PARP inhibitor AZD2461 was developed as a next-generation agent following olaparib, the first approved for cancer therapy. In BRCA1-deficient mouse models, olaparib resistance predominantly involves overexpression of P-glycoprotein, so poor substrate drug transporters. Here we demonstrate efficacy this compound against olaparib-resistant tumors that overexpress P-glycoprotein. addition, better tolerated in combination with chemotherapy than mice, which suggests could have significant...