A5044721640- Head and Neck Cancer Studies
- DNA Repair Mechanisms
- interferon and immune responses
- Cancer Immunotherapy and Biomarkers
- Peptidase Inhibition and Analysis
- Virus-based gene therapy research
- Lung Cancer Treatments and Mutations
- Cell death mechanisms and regulation
- CAR-T cell therapy research
- Endoplasmic Reticulum Stress and Disease
- Cancer-related Molecular Pathways
- Cancer Diagnosis and Treatment
- Immunotherapy and Immune Responses
- PARP inhibition in cancer therapy
- Immune Cell Function and Interaction
- Cancer-related gene regulation
- Chemical Reactions and Isotopes
- Colorectal and Anal Carcinomas
- Protein Degradation and Inhibitors
- Circular RNAs in diseases
- Sarcoma Diagnosis and Treatment
- Radiopharmaceutical Chemistry and Applications
- Boron Compounds in Chemistry
- Asthma and respiratory diseases
- Cancer Research and Treatments
Institute of Cancer Research
2015-2024
Royal Marsden Hospital
2014-2023
Institute of Cancer Research
2022-2023
Regeneron (United States)
2022
Brimrose (United States)
2020
National Institute for Health Research
2018
Rabin Medical Center
2018
Royal Marsden NHS Foundation Trust
2018
Genome British Columbia
2016
Royal Victoria Hospital
2007
Abstract Purpose: ATR inhibitors (ATRi) are in early phase clinical trials and have been shown to sensitize chemotherapy radiotherapy preclinically. Limited data published about the effect of these drugs on tumor microenvironment. Experimental Design: We used an immunocompetent mouse model HPV-driven malignancies investigate inhibitor AZD6738 combination with fractionated radiation (RT). Gene expression analysis flow cytometry were performed posttherapy. Results: Significant...
AZD6738 is an orally active ATR inhibitor (ATRi) currently in phase I clinical trials. We found vitro growth inhibitory activity of this ATRi a panel human cancer cell lines. demonstrated radiosensitization by to single radiation fractions multiple lines independent both p53 and BRCA2 status the clonogenic assay. Radiosensitization clinically relevant doses fractionated was using 3D tumor spheroid model and, vivo, radiosensitized abrogating radiation-induced G
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...
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...
Head and neck squamous cell carcinoma (HNSCC) is a significant cause of cancer deaths. Cisplatin-based chemoradiotherapy standard-of-care for locally advanced disease. ATR DNA-PK inhibition are actively being investigated in clinical trials with preclinical data supporting translation as radiosensitizers. Here, we hypothesized that targeting both small molecule inhibitors would increase radiosensitization HNSCC lines. Radiosensitization was assessed by Bliss independence analysis colony...
Concurrent cisplatin radiotherapy (CCRT) is a current standard-of-care for locally advanced head and neck squamous cell carcinoma (HNSCC). However, CCRT frequently ineffective in patients with disease. It has previously been shown that HSP90 inhibitors act as radiosensitizers, but these studies have not focused on HNSCC. Here, we evaluated the inhibitor, AUY922, combined CCRT. The ability of AUY922 to sensitize was assessed p53 mutant lines by clonogenic assay. Modulation induced DNA damage...
Abstract Purpose: The prevention and treatment of metastatic sarcoma are areas significant unmet need. Immune checkpoint inhibitor monotherapy has shown little activity in there is great interest identifying novel combinations that may augment responses. In vitro vivo, we investigated the potential for an oncolytic vaccinia virus (GLV-1h68) delivered using isolated limb perfusion (ILP) to promote antitumor immune responses response PD-1 blockade sarcoma. Experimental Design: established...
Reovirus type 3 Dearing (reovirus) is a tumor-selective oncolytic virus currently under evaluation in clinical trials. Here, we report that the therapeutic efficacy of reovirus head and neck squamous cell cancer can be enhanced by targeting unfolded protein response (UPR) kinase, kinase R (PKR)-like endoplasmic reticulum (PERK). PERK inhibition GSK2606414 increased both 2D 3D models vitro, while perturbing normal host to reovirus-induced (ER) stress. UPR reporter constructs were used for...
Background Rectal cancers show a highly varied response to neoadjuvant radiotherapy/chemoradiation (RT/CRT) and the impact of tumor immune microenvironment on this is poorly understood. Current clinical regression grading systems attempt measure radiotherapy but are subject interobserver variation. An unbiased unique histopathological quantification method (change in cell density (ΔTCD)) may improve classification RT/CRT response. Furthermore, gene expression profiling (GEP) identify...
Chk1 inhibition increases cell sensitivity to both chemotherapy and radiotherapy in several tumour types is, therefore, a promising anti-cancer approach. Although inhibitors have been developed, their clinical progress has hampered by low bioavailability off-target toxicities.We characterized the radiosensitizing activity of CCT244747, first orally bioavailable inhibitor. We used panel bladder head neck cancer lines monitored effect combining CCT244747 with radiation vitro vivo...
Systemic relapse after radiotherapy and surgery is the major cause of disease-related mortality in sarcoma patients. Combining immunotherapy under investigation as a means to improve response rates. However, immune contexture understudied. Here, we use retrospective cohort patients, treated with neoadjuvant radiotherapy, TCGA data. We explore therapeutic targets relevance sarcoma, using genomics multispectral immunohistochemistry provide insights into tumor microenvironment across subtypes....
Abstract Purpose: Patritumab plus cetuximab with platinum as first-line therapy for patients recurrent and/or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN) was evaluated safety to determine recommended phase II combination dose. Patients Methods: aged ≥18 years confirmed R/M SCCHN received intravenous patritumab (18 mg/kg loading dose; 9 maintenance dose every 3 weeks) + (400 mg/m2 250 weekly) cisplatin (100 or carboplatin (AUC 5) six cycles until toxicity, disease...
Abstract Many cancers have high levels of replication stress and a poorly functional G1/S DNA damage checkpoint. This may render them more susceptible than normal tissues to inhibition ATR, an apical kinase in the response critical part stress. We report early results monotherapy dose-escalation phase PATRIOT study AZD6738, orally active ATR inhibitor patients (pts) with advanced solid tumors (NCT02223923), whose endpoints were MTD, safety, tolerability, pharmacokinetics (PK) preliminary...
TPS2603 Background: Tumour control rates from radiation therapy (RT) are limited by normal tissue toxicities. Novel strategies required to selectively sensitize tumour cells radiation-induced DNA damage. The G2 cell cycle checkpoint is an attractive target for this, as will be protected their intact G1 checkpoint, which lost in the majority of cancer cells. ATR important mediator checkpoint. Preclinical data suggest that inhibition sensitise damaging therapies, including RT. This multi-part...
TPS6104 Background: P is a fully human monoclonal antibody against epidermal growth factor receptor 3. blocks activation by the ligand, heregulin (HRG), inducing internalization. Evidence growing that HRG presence determines disease progression and survival; in phase 2 study non–small-cell lung cancer, + erlotinib increased progression-free survival (PFS) high mRNA expression (HRG-high) patients. A 1b SCCHN demonstrated safety, tolerability tumor response of C cisplatin or carboplatin...
Background: Advanced head and neck squamous cell carcinoma (HNSCC) is associated with a poor prognosis, biomarkers that predict response to treatment are highly desirable. The primary aim was progression-free survival (PFS) multivariate risk prediction model. Methods: Experimental covariates were derived from blood samples of 56 HNSCC patients which prospectively obtained within Phase 2 clinical trial (NCT02633800) at baseline after the first cycle combined platinum-based chemotherapy...
The combination of radiotherapy/chemoradiotherapy and immune checkpoint blockade can result in poor outcomes patients with locally advanced head neck squamous cell carcinoma (HNSCC). Here, we show that combining ATR inhibition (ATRi) radiotherapy (RT) increases the frequency activated NKG2A