A5006108612- Melanoma and MAPK Pathways
- Virus-based gene therapy research
- Cancer Research and Treatments
- Monoclonal and Polyclonal Antibodies Research
- Synthesis and biological activity
- Click Chemistry and Applications
- Cancer Mechanisms and Therapy
- RNA Interference and Gene Delivery
- CRISPR and Genetic Engineering
- Computational Drug Discovery Methods
- HER2/EGFR in Cancer Research
- Protein Degradation and Inhibitors
- Brain Metastases and Treatment
- Biochemical and Molecular Research
- Advanced Breast Cancer Therapies
- Protein Kinase Regulation and GTPase Signaling
- Glycosylation and Glycoproteins Research
- Glioma Diagnosis and Treatment
- CAR-T cell therapy research
- Pancreatic and Hepatic Oncology Research
- Viral Infectious Diseases and Gene Expression in Insects
- Microbial metabolism and enzyme function
- Peptidase Inhibition and Analysis
- Cytokine Signaling Pathways and Interactions
- Cancer, Hypoxia, and Metabolism
Gettysburg College
2025
Medicines Discovery Catapult
2025
Cancer Research UK Manchester Institute
2012-2024
Institute of Cancer Research
2011-2023
Cancer Research UK
2009-2023
University of Manchester
2012-2021
Institute of Cancer Research
2010-2015
Advanced Cancer Therapeutics
2015
Surrey Memorial Hospital
2015
Transnational Press London
2015
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.
We generated cell lines resistant to BRAF inhibitors and show that the EGF receptor (EGFR)-SRC family kinase (SFK)-STAT3 signaling pathway was upregulated in these cells. In addition driving proliferation of cells, this also stimulated invasion metastasis. EGFR cooperated with block growth cells vitro vivo, monotherapy broad specificity tyrosine inhibitor dasatinib blocked metastasis vivo. analyzed tumors from patients intrinsic or acquired resistance vemurafenib observed increased SFK...
Research Article15 June 2015Open Access Source Data Targeting the LOX/hypoxia axis reverses many of features that make pancreatic cancer deadly: inhibition LOX abrogates metastasis and enhances drug efficacy Bryan W Miller Cancer UK Beatson Institute, Garscube Estate, Glasgow, Search for more papers by this author Jennifer P Morton Mark Pinese The Garvan Institute Medical Research, Sydney, NSW, Australia Grazia Saturno Manchester Withington, Manchester, Nigel B Jamieson West Scotland...
Fibroblasts display extensive transcriptional heterogeneity, yet functional annotation and characterization of their heterocellular relationships remains incomplete. Using mass cytometry, we chart the stromal composition 18 murine tissues 5 spontaneous tumor models, with an emphasis on mesenchymal phenotypes. This analysis reveals heterogeneity across tumors, identifies coordinated between immune cell subsets in pancreatic ductal adenocarcinoma. Expression CD105 demarks two stable...
BRAF and MEK inhibitors are effective in mutant melanoma, but most patients eventually relapse with acquired resistance, others present intrinsic resistance to these drugs. Resistance is often mediated by pathway reactivation through receptor tyrosine kinase (RTK)/SRC-family (SFK) signaling or NRAS, which drive paradoxical of the pathway. We describe pan-RAF (CCT196969, CCT241161) that also inhibit SFKs. These compounds do not activation MEK/ERK NRAS melanoma. They melanoma cells...
Abstract The oncogenic version of B-RAF, V599EB-RAF, is found in approximately 70% human melanomas. However, the role that this oncogene plays melanoma unclear because V559EB-RAF also 80% benign nevi. We have examined B-RAF early stages by expressing V599EB-RAF cultured melanocytes. In these cells, induced constitutive mitogen activated ERK-activating kinase (MEK) and extracellular signal-regulated (ERK) signaling, 12-O-tetradecanoylphorbol-13-acetate-independent growth, tumorigenicity nude...
Abstract Melanocytes require the RAS/RAF/MEK/ERK and cyclic AMP (cAMP) signaling pathways to maintain fine balance between proliferation differentiation. We have investigated how cross-talk these affects melanoma progression. show that cAMP suppresses CRAF activity in melanocytes this is essential suppress oncogenic potential of cells. As a consequence, BRAF alone responsible for MEK. However, when RAS mutated melanoma, cells switch their from CRAF. This accompanied by dysregulated...
Abstract Hsp90 is a ubiquitously expressed molecular chaperone that folds, stabilizes, and functionally regulates many cellular proteins. The benzoquinone ansamysin 17-allylamino-17-demethoxygeldanamycin (17-AAG) an anticancer drug disrupts binding to its clients, causing their degradation through the ubiquitin-dependent proteasomal pathway. protein kinase B-RAF mutated in ∼7% of human cancers. most common mutation (∼90%) V600EB-RAF, which has constitutively elevated activity, stimulates...
BRAF is a serine-threonine-specific protein kinase that mutated in 2% of human cancers. Oncogenic validated therapeutic target constitutively activates mitogen-activated (MEK)-extracellular signal-regulated (ERK) signaling, driving tumor cell proliferation and survival. Drugs designed to have been developed, but it difficult prove they mediate their antitumor effects by inhibiting rather than working through off-target effects. We generated drug-resistant versions oncogenic mutating the...
When therapy leads to cancer metastasis, knowing where else target in the pathway may be key successful treatment.
Antibody-directed enzyme prodrug therapy is a targeted in which activated selectively at the tumour site by an enzyme, has been to antibody (antibody-enzyme conjugate). Previous clinical trials have shown evidence of response, however, drug had long half-life, resulted dose-limiting myelosuppression. Also, targeting system, although giving high blood ratios antibody-enzyme conjugate (10 000:1) required administration clearing addition conjugate. The purpose this current study therefore was...
A series of novel cationic lipids was designed and synthesized in an effort to understand the importance various structural features with respect transfection efficiency. Particular attention has been paid hydrophobic domain headgroup. An efficient method synthesizing asymmetric diether is described, using alkyl chains ranging from C12 C18 unsaturated oleyl group. The ternary formulations including lipid 3β-[N-(N',N'-dimethylaminoethyl)carbamoyl]cholesterol (DC-Chol) dioleoyl...
The bystander effect is an important part of tumor kill using gene-directed enzyme prodrug therapy (GDEPT). Recently, we have described a novel system bacterial nitroreductase and the CB1954 (NTR/CB1954). We demonstrate here presence cell-permeable cytotoxic activity in conditioned growth medium (NTR)-transduced cells treated with show that its appearance corresponds to two metabolites previously identified (Friedlos et al., 1992). degree transferred cytotoxicity correlates level NTR...
The synthesis of three novel prodrugs, 4-[bis[2-(mesyloxy)ethyl]amino]benzoyl-L-glutamic acid (7), 4-[(2-chloroethyl)[2-(mesyloxy)ethyl]amino]benzoyl-L-glutamic (8), and 4-[bis(2-chloroethyl)amino]benzoyl-L-glutamic (9), for use as anticancer agents, is described here. Each a bifunctional alkylating agent in which the activating effect ionized carboxyl function masked through an amide bond to glutamic residue. These relatively inactive prodrugs are designed be activated their corresponding...
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...