A5033310499- PARP inhibition in cancer therapy
- Ovarian cancer diagnosis and treatment
- DNA Repair Mechanisms
- BRCA gene mutations in cancer
- Cancer therapeutics and mechanisms
- Cancer-related Molecular Pathways
- Cancer Genomics and Diagnostics
- Genomic variations and chromosomal abnormalities
- Acute Myeloid Leukemia Research
- Microtubule and mitosis dynamics
- Genetic factors in colorectal cancer
- Cancer Immunotherapy and Biomarkers
- Prostate Cancer Treatment and Research
- Lung Cancer Research Studies
- Colorectal Cancer Treatments and Studies
- Protein Degradation and Inhibitors
- Systemic Lupus Erythematosus Research
- Chronic Lymphocytic Leukemia Research
- Cell death mechanisms and regulation
- Immune Cell Function and Interaction
- Carcinogens and Genotoxicity Assessment
- Genomics and Chromatin Dynamics
- Sexual Differentiation and Disorders
- interferon and immune responses
- Mechanisms of cancer metastasis
AstraZeneca (United Kingdom)
2015-2024
AstraZeneca (Switzerland)
2021
AstraZeneca (United States)
2020
Defence Science and Technology Laboratory
2005-2019
Versus Arthritis
2016
Genomics (United Kingdom)
2016
Melbourn Science Park
2016
Prometheus (United States)
2009
University of Kentucky
1996-2002
Markey Cancer Center
1999
ObjectivePlatinum-resistant, high-grade serous ovarian cancer (HGSOC) has limited treatment options. Preclinical data suggest that poly(ADP-ribose) polymerase inhibitors (PARPi) and ataxia telangiectasia Rad3-related kinase (ATRi) are synergistic. CAPRI (NCT03462342) is an investigator-initiated study of olaparib plus ceralasertib in recurrent HGSOC. Herein, we present results from the platinum-resistant cohort.MethodsA Simon 2-stage design was utilized. Platinum-resistant HGSOC patients...
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 Purpose: Ceralasertib is a potent and selective oral inhibitor of the serine/threonine protein kinase ataxia telangiectasia Rad3-related (ATR) protein. Patients Methods: Eligible patients with solid tumors, enriched for melanoma, received ceralasertib in combination fixed dose paclitaxel (80 mg/m2 on D1, D8, D15) 28-day cycles. The was escalated to reach an MTD rolling 6 design. starting 40 mg QD. Fifty-seven (33 melanoma who failed prior PD1/L1 treatment) were enrolled 7 cohorts...
Background Despite therapeutic gains from immune checkpoint inhibitors (ICI) in many tumor types, new strategies are needed to extend treatment benefits, especially patients failing mount effective antitumor T-cell responses. Radiation and drug therapies can profoundly affect the microenvironment. Here, we aimed identify immunotherapies increase response conferred by combined ataxia telangiectasia Rad3-related kinase inhibition radiotherapy. Methods Using human papillomavirus (HPV)-negative...
Background Targeting the DNA damage repair (DDR) pathways is an attractive strategy for boosting cancer immunotherapy. Ceralasertib (AZD6738) oral kinase inhibitor of ataxia telangiectasia and Rad3 related protein, which a master regulator DDR. We conducted phase II trial ceralasertib plus durvalumab in patients with previously treated advanced gastric (AGC) to demonstrate safety, tolerability, clinical activity combination. Methods This II, open-label, single-center, non-randomized study...
Addition of ataxia telangiectasia and Rad3-related kinase inhibitors (ATRi) to PARP (PARPi) overcomes PARPi resistance in high-grade serous ovarian cancer (HGSOC) cell mouse models. We present the results an investigator-initiated study combination (olaparib) ATRi (ceralasertib) patients with acquired PARPi-resistant HGSOC.Eligible had recurrent, platinum-sensitive BRCA1/2 mutated or homologous recombination (HR)-deficient (HRD) HGSOC clinically benefited from (response by imaging/CA-125...
PATRIOT is a phase I study of the ATR inhibitor, AZD6738, as monotherapy, and in combination with palliative radiotherapy. Here, we describe protocol for this study, which opened 2014 currently recruiting comprises dose escalation both drug radiotherapy, expansion cohorts.
BACKGROUNDPhase 1 study of ATRinhibition alone or with radiation therapy (PATRIOT) was a first-in-human phase I the oral ATR (ataxia telangiectasia and Rad3-related) inhibitor ceralasertib (AZD6738) in advanced solid tumors.METHODSThe primary objective safety. Secondary objectives included assessment antitumor responses pharmacokinetic (PK) pharmacodynamic (PD) studies. Sixty-seven patients received 20-240 mg BD continuously intermittently (14 28-day cycle).RESULTSIntermittent dosing better...
We examined the toxicity of both single and multiple subcutaneous injections recombinant human ciliary neurotrophic factor (rhCNTF) in 72 patients with ALS, doses ranging from 2 to 100 micro gram/kg.Adverse events were generally dose related ranged mild severe. The tolerability daily rhCNTF was equivalent placebo at <or=to 5 gram/kg/day. At higher doses, anorexia, weight loss, reactivation herpes simplex virus (HSV1) labialis/stomatitis, cough, increased oral secretions occurred....
A high percentage of small cell lung cancer (SCLC) cases harbor cycle-related gene mutations and RICTOR amplification. Based on underlying somatic mutations, the authors have conducted a phase 2 biomarker-driven, multiarm umbrella study. The SCLC Umbrella Korea StudiES (SUKSES) is an adaptive platform trial that undergoes continual modification according to observed outcomes. This study included 286 patients with who failed platinum therapy had known genomic profiles based predesigned...
5516 Background: Following multiple blockbuster studies demonstrating long-term progression free and overall survival benefits with poly(ADP-ribose)polymerase inhibitors (PARPi), they have become an integral component of high grade serous ovarian cancer (HGSOC) treatment. Unfortunately, tumors ultimately acquire resistance thus therapies that overcome PARPi-resistance are urgently needed. Preclinical show the addition ataxia telangiectasia Rad3-related kinase (ATRi) to PARPi...
88 Background: Men with metastatic, castration resistant prostate cancer (mCRPC) harboring DNA repair defects (̃20%) achieve a radiographic progression free survival of 7.4 months PARP inhibitors (PARPi). Preclinical studies combining PARPi (olaparib) and damage checkpoint inhibitor (ATR inhibitor, ceralasertib) show synergy, providing the rationale to test this combination in men mCRPC, including where single agent olaparib has been shown be active. Methods: Two cohorts were accrued trial...
Abstract Linkage studies have indicated that a gene on chromosome arm 17q, designated BRCAI , confers susceptibility to familial breast and ovarian cancer. To investigate the possible involvement of in sporadic cancer we analysed loss heterozygosity (LOH) panel 100 primary tumours using 10 PCR‐based polymorphic markers from 17q12–21. Allele losses were detected 40 informative for at least one analysed. Of these deleted tumours, 27 showed partial or interstitial 17q. The pattern LOH with...
The dansyl fluorophore ligated to gold nanoparticles via imidazole and amine groups affords conjugates capable of detecting micromolar concentrations the chemical warfare agent sulfur mustard by a fluorescence switching 'ON' displacement assay.
Summary Marburg virus causes a highly infectious and lethal haemorrhagic fever in primates may be exploited as potential biothreat pathogen. To combat the infection threat of fever, there is need to develop license appropriate medical countermeasures. determine whether common marmoset ( C allithrix jacchus ) would an model assess therapies against initial susceptibility, lethality pathogenesis studies were performed. Low doses virus, between 4 28 TCID 50 , sufficient cause lethal,...
ABSTRACT We have used a GAL4 enhancer-trap line driving the expression of lacZ construct to examine reorganisation an identified group proprioceptive sensory neurons during metamorphosis in Drosophila. The results show that whilst most larval degenerate first 24 hours segmentally repeated array 6 per segment persists into adult stages become functional neurons. These retain their axonal projections central nervous system intact and unchanged throughout. neuron axons enter at around 44 after...
Abstract Background Based on a high incidence of genomic alteration in the cell cycle and DNA damage response (DDR)‐related pathways small lung cancer (SCLC), clinical efficacy DDR‐targeting agent olaparib (PARP inhibitor) as monotherapy combination with ceralasertib (ATR relapsed or refractory SCLC was evaluated. Methods As part phase 2 biomarker driven umbrella study, patients predefined DDR gene alterations who failed to benefit from prior platinum‐based regimens were allocated arm...