A5079480111- Cancer, Lipids, and Metabolism
- Molecular Biology Techniques and Applications
- Cancer Research and Treatments
- Cholesterol and Lipid Metabolism
- Eicosanoids and Hypertension Pharmacology
- Prostate Cancer Treatment and Research
- Endoplasmic Reticulum Stress and Disease
- Cancer-related gene regulation
- Mass Spectrometry Techniques and Applications
- Protein Degradation and Inhibitors
- Heat shock proteins research
- Cancer Genomics and Diagnostics
- Fibroblast Growth Factor Research
- Immunotherapy and Immune Responses
- Advanced Proteomics Techniques and Applications
- Advanced Radiotherapy Techniques
- Metabolomics and Mass Spectrometry Studies
- Hormonal Regulation and Hypertension
- Ubiquitin and proteasome pathways
- Hepatocellular Carcinoma Treatment and Prognosis
- FOXO transcription factor regulation
- Kruppel-like factors research
- Sarcoma Diagnosis and Treatment
- PARP inhibition in cancer therapy
- CAR-T cell therapy research
Institute of Cancer Research
2016-2025
University of Bristol
2011
Bristol Institute for Transfusion Sciences
2011
NHS Blood and Transplant
2011
Chinese People's Armed Police General Hospital
2009
FGFR1 and FGFR2 are amplified in many tumor types, yet what determines response to FGFR inhibition cancers is unknown. In a translational clinical trial, we show that gastric with high-level clonal amplification have high rate the selective inhibitor AZD4547, whereas subclonal or low-level did not respond. Using cell lines patient-derived xenograft models, initiates distinct oncogene addiction phenotype, characterized by FGFR2-mediated transactivation of alternative receptor kinases,...
Resistance to androgen receptor (AR) blockade in castration-resistant prostate cancer (CRPC) is associated with sustained AR signaling, including through alternative splicing of (AR-SV). Inhibitors transcriptional coactivators that regulate activity, the paralog histone acetyltransferase proteins p300 and CBP, are attractive therapeutic targets for lethal cancer. Herein, we validate targeting p300/CBP as a strategy describe CCS1477, novel small-molecule inhibitor conserved bromodomain. We...
Abstract Purpose: Persistent androgen receptor (AR) signaling drives castration-resistant prostate cancer (CRPC) and confers resistance to AR-targeting therapies. Novel therapeutic strategies overcome this are urgently required. We evaluated how bromodomain extra-terminal (BET) protein inhibitors (BETi) abrogate aberrant AR in CRPC. Experimental Design: determined associations between BET expression, AR-driven transcription, patient outcome; the effect mechanism by which chemical BETi (JQ1...
Deleterious ATM alterations are found in metastatic prostate cancer (PC); PARP inhibition has antitumour activity against this subset, but only some loss PCs respond. To characterise ATM-deficient lethal PC and to study synthetic therapeutic strategies for subset. We studied advanced biopsies using validated immunohistochemical (IHC) next-generation sequencing (NGS) assays. In vitro cell line models modified CRISPR-Cas9 impair function were generated used drug-sensitivity functional assays,...
Androgen receptor (AR) signalling is a key prostate cancer (PC) driver, even in advanced 'castrate-resistant' disease (CRPC). To systematically identify microRNAs (miRs) modulating AR activity lethal disease, hormone-responsive and -resistant PC cells expressing luciferase-based reporter were transfected with miR inhibitor library; 78 inhibitors significantly altered activity. Upon validation, miR-346, miR-361-3p miR-197 markedly reduced transcriptional activity, mRNA protein levels,...
Abstract It has been recognized for decades that ERBB signaling is important in prostate cancer, but targeting receptors as a therapeutic strategy cancer ineffective clinically. However, we show here membranous HER3 protein commonly highly expressed lethal associating with reduced time to castration resistance (CR) and survival. Multiplex immunofluorescence indicated the ligand NRG1 detectable primarily tumor-infiltrating myelomonocytic cells human cancer; this observation was confirmed...
CDK4/6 inhibition in combination with endocrine therapy is the standard of care for estrogen receptor (ER+) breast cancer, and although cytostasis frequently observed, new treatment strategies that enhance efficacy are required. Here, we perform two independent genome-wide CRISPR screens to identify genetic determinants sensitivity. Genes involved oxidative stress ferroptosis modulate sensitivity, GPX4 as top sensitiser both screens. Depletion or increases sensitivity palbociclib...
Abstract Purpose: Advanced prostate cancer (PCa) is invariably fatal with the androgen receptor (AR) being a major therapeutic target. AR signaling inhibitors have improved overall survival for men advanced PCa, but treatment resistance inevitable and includes reactivation of signaling. Novel approaches targeting these mechanisms to block tumor growth an urgent unmet clinical need. One attractive strategy target heat shock proteins critical functional activity. Experimental Design: We first...
<p>NXP800-resistant 22Rv1 prostate cancer cell sublines demonstrate the reversal of NXP800-mediated phenotype. <b>A,</b> Long-term treatment cells with increasing concentrations (up to 2.5 μmol/L) DMSO (vehicle-C, white), CCT365248 (inactive-C, blue), and NXP800 (NXP800-R, red) led generation cell–derived sublines. Mean growth was determined after 5 days by CellTiter-Glo Luminescent Cell Viability Assay compared day 0 vehicle-C SD for each subline developed is shown....
<p>Supplementary figure 6: Inhibition of the unfolded protein response with ISRIB rescues NXP800-mediated suppression AR signaling and PCa model growth</p>
<p>GO cellular response to heat gene expression signature associates with AR signaling and poorer prognosis in men suffering from CRPC. <b>A</b> <b>G,</b> Two independent (PCF-SU2C ICR-RMH) transcriptome cohorts of patients Quantification GO each cohort CRPC the PCF-SU2C (<b>A</b>) ICR-RMH (<b>G</b>) cohorts. Biopsies (red dots) >80th percentile (dotted line) are shown. <b>B</b> <b>H,</b> Kaplan–Meier curves for...
<p>Supplementary figure 2: AR and AR-V7 bind members of the 70KDa heat shock protein family mediated cellular stress increases HSP72 expression, associates with GO Cellular Response to Heat gene expression signature, in PCa cells</p>
<p>NXP800 inhibits the growth of AR-dependent and AR-independent prostate cancer models with activation UPR inhibition key signaling pathways. <b>A</b> <b>B,</b> PDX-O [CP50, CP89, CP129, CP142 (<b>A</b>)], AR-positive (VCaP, LNCaP, LNCaP95, 22Rv1), AR-negative (PC3 DU145) cell lines (<b>B</b>) were treated vehicle (DMSO 0.1%) or various concentrations (5, 10, 50, 100, 250 nmol/L) NXP800 (active, red line), CCT365248 (inactive, blue in...
<p>Supplementary figure 1: Chemical structures of NXP800 and CCT365248</p>
<p>Supplementary figure 3: GO Cellular Response to Heat gene expression signature associates with AR signaling in CRPC transcriptomes</p>
<p>NXP800 activates the UPR and inhibits key signaling pathways identifying a novel mechanism of action in prostate cancer models. <b>A,</b> VCaP, LNCaP95, 22Rv1 cells were treated with 250 nmol/L CCT365248 (inactive) or NXP800 (active) for 24 hours prior to addition puromycin 30 minutes. PERK, phospho-eIF2α, ATF4 (PERK arm); ATF6 (ATF6 IRE1 (IRE1 arm) protein; E2F1; (incorporation surrogate protein synthesis); GAPDH (housekeeping) expression was determined by Western blot...
<p>Supplementary figure 4: NXP800 decreases basal HSP72 protein levels and blocks induction in response to HSP90 inhibition PCa cell lines</p>
<div>AbstractPurpose:<p>Advanced prostate cancer is invariably fatal, with the androgen receptor (AR) being a major therapeutic target. AR signaling inhibitors have improved overall survival for men advanced cancer, but treatment resistance inevitable and includes reactivation of signaling. Novel approaches targeting these mechanisms to block tumor growth an urgent unmet clinical need. One attractive strategy target heat shock proteins (HSP) critical functional...
<p>Supplementary figure 9: NXP800 demonstrates tolerability in a castration-resistant VCaP PCa cell line-derived mouse xenograft</p>
<p>Supplementary figure 7: NXP800 does not decrease basal HSP72 protein levels and HSP90 inhibitor-induced induction in NXP800-resistant 22Rv1 PCa cell sub-lines</p>
<p>NXP800 inhibits AR transactivation and signaling to inhibit the growth of aberrant prostate cancer models. <b>A–C,</b> VCaP (<b>A</b>), LNCaP95 (<b>B</b>), 22Rv1 (<b>C</b>) cells were treated with vehicle (DMSO 0.1%) or various concentrations (5, 10, 50, 100, 250 nmol/L) NXP800 (active, red line) CCT365248 (inactive, blue line), was determined after 5 days by CellTiter-Glo Luminescent Cell Viability Assay. Mean (compared vehicle;...
<p>Supplementary figure 10: NXP800 demonstrates limited impact on AR and AR-V7 protein levels associated signaling in-vivo but does induce apoptosis reduce cellular proliferation</p>
<p>NXP800 activates the UPR and inhibits E2F-mediated transcription to drive antitumor activity against castration-resistant VCaP prostate cancer cell line–derived mouse xenograft. <b>A</b> <b>B,</b> Castration-resistant emergent xenografts were treated with vehicle (<i>n</i> = 7, gray) or 35 mg/kg NXP800 (active, <i>n</i> 8, red) after tumors had established growth a defined dosing schedule for 38 days. Mean tumor volume (normalized...
<p>Supplementary figure 5: Enzalutamide inhibits AR signaling in enzalutamide responsive VCaP PCa cells but not resistant LNCaP95 and 22Rv1 cells.</p>