A5066331764- Melanoma and MAPK Pathways
- Cancer Genomics and Diagnostics
- CAR-T cell therapy research
- Cutaneous Melanoma Detection and Management
- Cancer Immunotherapy and Biomarkers
- melanin and skin pigmentation
- Cancer, Hypoxia, and Metabolism
- Immunotherapy and Immune Responses
- Ocular Oncology and Treatments
- Cancer Cells and Metastasis
- Retinal Development and Disorders
- HER2/EGFR in Cancer Research
- RNA regulation and disease
- Microbial metabolism and enzyme function
- Cell Adhesion Molecules Research
- Histone Deacetylase Inhibitors Research
- Ubiquitin and proteasome pathways
- Immune cells in cancer
- Cytokine Signaling Pathways and Interactions
- Skin Protection and Aging
- Tryptophan and brain disorders
- Cancer Mechanisms and Therapy
- Gut microbiota and health
- Epigenetics and DNA Methylation
- Prostate Cancer Treatment and Research
University of Manchester
2015-2024
Cancer Research UK Manchester Institute
2015-2023
Institute of Cancer Research
2007-2014
Ludwig Cancer Research
2012
Institute of Cancer Research
2012
Cancer Research UK
2007-2009
University College London
2003-2008
Institute of Child Health
2004-2005
We describe a mechanism of tumorigenesis mediated by kinase-dead BRAF in the presence oncogenic RAS. show that drugs selectively inhibit drive RAS-dependent binding to CRAF, CRAF activation, and MEK-ERK signaling. This does not occur when is inhibited, demonstrating inhibition per se pathway activation; it only occurs inhibited Kinase-dead mimics effects BRAF-selective Braf Ras cooperate induce melanoma mice. Our data reveal another paradigm BRAF-mediated signaling promotes tumor...
Cutaneous squamous-cell carcinomas and keratoacanthomas are common findings in patients treated with BRAF inhibitors.
Targeted therapies and immunotherapies have transformed melanoma care, extending median survival from ∼9 to over 25 months, but nevertheless most patients still die of their disease. The aim precision medicine is tailor care for individual improve outcomes. To this end, we developed protocols facilitate individualized treatment decisions with advanced melanoma, analyzing 364 samples 214 patients. Whole exome sequencing (WES) targeted circulating tumor DNA (ctDNA) allowed us monitor responses...
Recently, the rationale for combining targeted therapy with immunotherapy has come to light, but our understanding of immune response during MAPK pathway inhibitor treatment is limited. We discovered that microenvironment can act as a source resistance pathway-targeted therapy, and moreover this becomes reinforced. In particular, we identified macrophage-derived TNFα crucial melanoma growth factor provides inhibitors through lineage transcription MITF (microphthalmia factor). Most...
The advent of effective adjuvant therapies for patients with resected melanoma has highlighted the need to stratify based on risk relapse given cost and toxicities associated treatment. Here we assessed circulating tumor DNA (ctDNA) predict monitor in stage III melanoma.
Abstract Multiple clinical trials targeting the gut microbiome are being conducted to optimize treatment outcomes for immune checkpoint blockade (ICB). To improve success of these interventions, understanding changes during ICB is urgently needed. Here through longitudinal profiling 175 patients treated with advanced melanoma, we show that several microbial species-level genome bins (SGBs) and pathways exhibit distinct patterns from baseline in achieving progression-free survival (PFS) 12...
IntroductionTumour burden is a prognostic biomarker in metastatic melanoma. However, tumour difficult to measure and there are currently no reliable surrogate biomarkers easily reliably determine it. The aim of this study was assess the potential plasma total cell free DNA as prognosis melanoma patients.Materials methodsA prospective cohort for circulating cell-free (cfDNA) concentration performed 43 patients. For 38 patients, paired blood collections scan assessments were available before...
BRAF inhibitors can extend progression‐free and overall survival in melanoma patients whose tumors harbor mutations BRAF. However, the majority of eventually develop resistance to these drugs. Here we show that mutant cells have developed acquired display increased oxidative metabolism dependency on mitochondria for survival. Intriguingly, is associated with a switch from glucose glutamine an dependence over proliferation. We resistant are more sensitive mitochondrial poisons glutaminolysis,...
Patients with high-risk stage II/III resected melanoma commonly develop distant metastases. At present, we cannot differentiate between patients who will recur or those are cured by surgery. We investigated if circulating tumor DNA (ctDNA) can predict relapse and survival in melanoma.
Abstract Lysyl oxidase (LOX) remodels the tumour microenvironment by cross-linking extracellular matrix. LOX overexpression is associated with poor cancer outcomes. Here, we find that regulates epidermal growth factor receptor (EGFR) to drive progression. We show EGFR suppressing TGFβ1 signalling through secreted protease HTRA1. This increases expression of Matrilin2 (MATN2), an EGF-like domain-containing protein traps at cell surface facilitate its activation EGF. describe a pharmacological...
The small G-protein NRAS is mutated in 22% of human melanomas, whereas the related proteins KRAS and HRAS are only 2% 1% respectively. We have developed a mouse model melanoma which Cre recombinase/LoxP technology used to drive inducible expression (G12V)KRAS melanocytic lineage. mice develop skin hyperpigmentation, nevi, tumors that bear many cardinal histopathology features molecular characteristics melanoma. These invade destroy underlying muscles cells derived from them can grow as...
BackgroundThe application of precision medicine in oncology requires in-depth characterisation a patient's tumours and the dynamics their responses to treatment.Patients methodsWe used next-generation sequencing circulating cell-free DNA (cfDNA) monitor response KIT p.L576P-mutant metastatic vaginal mucosal melanoma sequential targeted, immuno- chemotherapy.ResultsDespite mutation, imatinib was mixed. Unfortunately, were not accessible for molecular analysis. To study mechanism underlying...
Abstract B-cell acute lymphoblastic leukemia (B-ALL) is an aggressive hematological disease that kills ~50% of adult patients. With the exception some BCR-ABL1 + patients who benefit from tyrosine kinase inhibitors, there are no effective targeted therapies for B-ALL and chemotherapy remains first-line therapy despite adverse side effects poor efficacy. We show that, although MEK/ERK pathway activated in cells driven by different oncogenes, MEK inhibition does not suppress cell growth....
The prostate cancer (PCa) diagnostic pathway is undergoing a radical change with the introduction of multiparametric magnetic resonance imaging (mpMRI), genomic testing, and different biopsy techniques. It has been proposed that these tests should be used in sequential manner to optimise risk stratification.
Abstract Although immune checkpoint inhibitors (ICIs) have achieved unprecedented results in melanoma, the biological features of durable responses initiated by these drugs remain unknown. Here we show genetic and phenotypic changes induced treatment with programmed cell death-1 (PD-1) blockade a genetically engineered mouse model melanoma driven oncogenic BRAF. In this controlled system anti-PD-1 yields ~35% tumors, prolongs survival ~27% animals. We identify increased stroma remodeling...
We recently demonstrated that expression of (V600E)Braf in mature mouse melanocytes induces melanoma. Here, we show using the tyrosinase promoter leads to an unexpected embryonic lethality, with animals dying before, at, or shortly after birth. The mice suffer from a range developmental defects skin, brain, eyes and heart, tissues are normally colonized by melanocytes. expressing cells potential melanocytic precursors fully transformed, suggesting stimulates proliferation blocks...
Mutation of the Chx10 homeobox gene in mice and humans causes congenital blindness microphthalmia (small eyes). This study used Chx10-/- (ocular retardation) to investigate how lack affects progenitor/stem cell behavior retina ciliary epithelium (CE).The distribution mitotic retinal progenitor cells (RPCs) during embryonic development was analyzed using phosphohistone 3 (H3)-labeling. DNA flow cytometry measure content. The phenotype dividing postnatal CE by incorporation thymidine analogue...
KRAS is mutated in ∼90% of pancreatic ductal adenocarcinomas, ∼35% colorectal cancers and ∼20% non-small-cell lung cancers. There has been recent progress targeting