A5054502156- Melanoma and MAPK Pathways
- Synthesis and biological activity
- Cancer-related Molecular Pathways
- Computational Drug Discovery Methods
- Cytokine Signaling Pathways and Interactions
- Protein Kinase Regulation and GTPase Signaling
- Cancer therapeutics and mechanisms
- interferon and immune responses
- Cancer Cells and Metastasis
- Cancer, Hypoxia, and Metabolism
- Cancer Research and Treatments
- Gene expression and cancer classification
- Heat shock proteins research
- PI3K/AKT/mTOR signaling in cancer
- Cancer Mechanisms and Therapy
- Bioinformatics and Genomic Networks
- Advanced Breast Cancer Therapies
University of Cambridge
2016-2017
Copy-number gain of the oncostatin-M receptor (OSMR) occurs frequently in cervical squamous cell carcinoma (SCC) and is associated with adverse clinical outcome. We previously showed that OSMR overexpression renders SCC cells more sensitive to major ligand (OSM), which increases migration invasion vitro. hypothesised a contribution this phenotype would come from epithelial-mesenchymal transition (EMT).We performed comprehensive integrated study, involving vitro line studies, vivo animal...
The MAPK signaling pathway is commonly upregulated in human cancers. As the primary downstream effector of pathway, ERK an attractive therapeutic target for treatment MAPK-activated cancers and overcoming resistance to upstream inhibition. ASTX029 a highly potent selective dual-mechanism inhibitor, discovered using fragment-based drug design. Because its distinctive ERK-binding mode, inhibits both catalytic activity phosphorylation itself by MEK, despite not directly inhibiting MEK activity....
The oncostatin M (OSM) receptor (OSMR) shows frequent gene copy number gains and overexpression in cervical squamous cell carcinomas (SCCs), associated with adverse clinical outcomes. In SCC cells that overexpress OSMR, the major ligand OSM induces multiple pro-malignant effects, including invasion, secretion of angiogenic factors, metastasis. Here, we demonstrate, for first time, OSMR activates cell-autonomous feed-forward signalling, via further expression sustained STAT3 activation,...
Aberrant activation of the mitogen-activated protein kinase pathway frequently drives tumor growth, and ERK1/2 kinases are positioned at a key node in this pathway, making them important targets for therapeutic intervention. Recently, number inhibitors have been advanced to investigational clinical trials patients with activating mutations B-Raf proto-oncogene or Ras. Here, we describe discovery candidate ASTX029 (15) through structure-guided optimization our previously published...
Abstract In response to cellular stress, the tumor suppressor p53 is activated modulate cell cycle progression, DNA repair, and apoptosis. Inhibition of MDM2-p53 interaction in tumors carrying wild-type prevents its degradation can reactivate elicit an anti-cancer effect. Targeting p53-MDM2 therefore remains a promising strategy for cancer therapy. However, development first generation MDM2 antagonists has been challenged by dose-limiting, on-target bone marrow toxicities. Understanding...
Abstract Aim We aimed to design an MDM2-p53 antagonist with a differentiated tolerability profile that could be used treat patients wild-type TP53 malignancies. As part of alliance between Newcastle University, Astex Pharmaceuticals, and Cancer Research Horizons, we discovered ASTX295, potent inhibitor the interaction is currently under clinical investigation in solid tumors (NCT03975387). selected ASTX295 as compound predicted short plasma half-life, which hypothesised would help mitigate...
Abstract Background High-throughput drug screening and computational methods to associate genomic features of cell lines sensitivity are valuable tools for predicting biomarkers sensitivity. In addition, integrating expression-based patterns could improve biomarker prediction patient stratification. Particularly weighted gene co-expression networks represent an effective approach identify key modules possible biological mechanisms Using a combination panel networks, we predicted markers...
<p>Table listing details of antibodies used</p>
<p>Supplementary figures 1-7 show the effects of AST029 on ERK signalling in RAS-mutant cell lines (1) and tumour xenograft tissue (3), ASTX029 plasma PK linearity (2), activity a line panel showing MAPK mutation status (4) mouse body weight (5), PKPD following b.i.d dosing to Colo205 tumour-bearing mice (6) PD qd A375R (7).</p>
<p>Supplementary figures 1-7 show the effects of AST029 on ERK signalling in RAS-mutant cell lines (1) and tumour xenograft tissue (3), ASTX029 plasma PK linearity (2), activity a line panel showing MAPK mutation status (4) mouse body weight (5), PKPD following b.i.d dosing to Colo205 tumour-bearing mice (6) PD qd A375R (7).</p>
<p>Table listing details of antibodies used</p>
<div>Abstract<p>The MAPK signaling pathway is commonly upregulated in human cancers. As the primary downstream effector of pathway, ERK an attractive therapeutic target for treatment MAPK-activated cancers and overcoming resistance to upstream inhibition. ASTX029 a highly potent selective dual-mechanism inhibitor, discovered using fragment-based drug design. Because its distinctive ERK-binding mode, inhibits both catalytic activity phosphorylation itself by MEK, despite not...
<div>Abstract<p>The MAPK signaling pathway is commonly upregulated in human cancers. As the primary downstream effector of pathway, ERK an attractive therapeutic target for treatment MAPK-activated cancers and overcoming resistance to upstream inhibition. ASTX029 a highly potent selective dual-mechanism inhibitor, discovered using fragment-based drug design. Because its distinctive ERK-binding mode, inhibits both catalytic activity phosphorylation itself by MEK, despite not...
Abstract Background Dysregulation of cell cycle and transcriptional processes promote tumorigenesis tumor growth. Due to its dual role in regulating both cellular processes, CDK7 is an attractive therapeutic target, with several inhibitors clinical trials. Preclinical data suggests that such agents could have utility across a range types particularly those driven by defects the regulation processes. Consequently, potential patient populations are broad often lack well-defined stratification....
Abstract The MAPK pathway is commonly hyper-activated in human cancers due to the occurrence of oncogenic mutations RAF, RAS and upregulation RTKs. therapeutic potential inhibition has been demonstrated by clinical efficacy RAF MEK1/2 (MEK) inhibitors treatment BRAF-mutant melanoma. However, response such agents short-lived onset resistance mechanisms, which majority cases result reactivation ERK1/2 (ERK) signalling. Therefore, direct targeting ERK an attractive approach overcoming...
Abstract Non-small cell lung cancer (NSCLC) molecular profiling is a key factor in treatment selection. Although, patients with NSCLC tumors harboring EGFR or ALK mutations can benefit from personalized therapies, there are currently no approved targeted therapies for KRAS mutant which occur 25% to 30% of NSCLC. The constitutive activation the MAPK pathway these provides rationale targeting effectors such as MEK1/2 (MEK) ERK1/2 (ERK). Inhibitor MEK kinase have been tested clinically...