A5090563561- Neuroblastoma Research and Treatments
- Cancer, Hypoxia, and Metabolism
- Advanced MRI Techniques and Applications
- MRI in cancer diagnosis
- Ubiquitin and proteasome pathways
- ATP Synthase and ATPases Research
- Neuroendocrine Tumor Research Advances
- Elasticity and Material Modeling
- Radiomics and Machine Learning in Medical Imaging
- Medical Imaging Techniques and Applications
- Ultrasound Imaging and Elastography
- Protein Degradation and Inhibitors
- Cellular Mechanics and Interactions
- Cancer therapeutics and mechanisms
- DNA Repair Mechanisms
- Lung Cancer Research Studies
- Ultrasound and Hyperthermia Applications
- Microtubule and mitosis dynamics
- Cancer-related Molecular Pathways
- Virus-based gene therapy research
- Colorectal Cancer Treatments and Studies
- Lanthanide and Transition Metal Complexes
- Computational Drug Discovery Methods
- Glioma Diagnosis and Treatment
- AI in cancer detection
Institute of Cancer Research
2016-2025
Royal Marsden NHS Foundation Trust
2012-2025
Cancer Research UK
2009-2023
Engineering and Physical Sciences Research Council
2009-2023
Royal Marsden Hospital
2017-2018
University College London
2016
Medical Research Council
2016
AstraZeneca (United Kingdom)
2016
University of Manchester
2015
Cancer Imaging Centre
2012
Cancer organoids to model therapy response are miniature, three-dimensional cell culture models that can be made from primary patient tumors and studied in the laboratory. Vlachogiannis et al. asked whether such “tumor-in-a-dish” approaches used predict drug responses clinic. They generated a live organoid biobank patients with metastatic gastrointestinal cancer who had previously been enrolled phase I or II clinical trials. This allowed authors compare how actually responded Encouragingly,...
Real-time detection of the rates metabolic flux, or exchange endogenous enzymatic reactions, is now feasible in biological systems using Dynamic Nuclear Polarization Magnetic Resonance. Derivation reaction rate kinetics from this technique typically requires multi-compartmental modeling dynamic data, and results are therefore model-dependent prone to misinterpretation. We present a model-free formulism based on ratio total areas under curve (AUC) injected product metabolite, for example...
There is a clinical need for noninvasive biomarkers of tumor hypoxia prognostic and predictive studies, radiotherapy planning, therapy monitoring. Oxygen-enhanced MRI (OE-MRI) an emerging imaging technique quantifying the spatial distribution extent oxygen delivery in vivo. In OE-MRI, longitudinal relaxation rate protons (ΔR1) changes proportion to concentration molecular dissolved plasma or interstitial tissue fluid. Therefore, well-oxygenated tissues show positive ΔR1. We hypothesized that...
Malignant tumors are typically associated with altered rigidity relative to normal host tissue. Magnetic resonance elastography (MRE) enables the noninvasive quantitation of mechanical properties deep-seated tissue following application an external vibrational stress that In this preclinical study, we used MRE quantify (kPa) elasticity modulus Gd and viscosity Gl three intracranially implanted glioma breast metastatic tumor models. all these brain tumors, found a notable softness...
Abstract Neuroblastoma is the most common paediatric solid tumour and prognosis remains poor for high-risk cases despite use of multimodal treatment. Analysis public drug sensitivity data showed neuroblastoma lines to be sensitive indisulam, a molecular glue that selectively targets RNA splicing factor RBM39 proteosomal degradation via DCAF15-E3-ubiquitin ligase. In models, indisulam induces rapid loss RBM39, accumulation errors growth inhibition in DCAF15-dependent manner. Integrative...
Abstract Purpose: Many tumors exhibit defective cell-cycle checkpoint control and increased replicative stress. CHK1 is critically involved in the DNA damage response maintenance of replication fork stability. We have therefore discovered a novel potent, highly selective, orally active ATP-competitive inhibitor, CCT244747, present its preclinical pharmacology therapeutic activity. Experimental Design: Cellular activity was assessed using an ELISA assay, cytotoxicity SRB assay. Biomarker...
ABSTRACT The first-in-class inhibitor of ALK, c-MET and ROS1, crizotinib (Xalkori), has shown remarkable clinical efficacy in treatment ALK-positive non-small cell lung cancer. However, neuroblastoma, activating mutations the ALK kinase domain are typically refractory to treatment, highlighting need for more potent inhibitors. next-generation PF-06463922 is predicted exhibit increased affinity mutants prevalent neuroblastoma. We examined activity ALK-driven neuroblastoma models vitro vivo....
The undruggable nature of oncogenic Myc transcription factors poses a therapeutic challenge in neuroblastoma, pediatric cancer which MYCN amplification is strongly associated with unfavorable outcome. Here, we show that CYC065 (fadraciclib), clinical inhibitor CDK9 and CDK2, selectively targeted MYCN-amplified neuroblastoma via multiple mechanisms. — component the elongation complex P-TEFb bound to MYCN-amplicon superenhancer, its inhibition resulted selective loss nascent transcription. led...
ALK-activating mutations are identified in approximately 10% of newly diagnosed neuroblastomas and ALK amplifications a further 1%-2% cases. Lorlatinib, third-generation anaplastic lymphoma kinase (ALK) inhibitor, will soon be given alongside induction chemotherapy for children with ALK-aberrant neuroblastoma. However, resistance to single-agent treatment has been reported therapies that improve the response duration urgently required. We studied preclinical combination lorlatinib...
Neuroblastoma is the most common extracranial solid tumor in infants, arising from developmentally stalled neural crest-derived cells. Driving differentiation a promising therapeutic approach for this devastating disease. Here, we show that CDK4/6 inhibitor palbociclib not only inhibits proliferation but induces extensive neuronal of adrenergic neuroblastoma Palbociclib-mediated manifested by phenotypic and transcriptional changes accompanied establishment an epigenetic program driving...
Aurora kinases regulate key stages of mitosis including centrosome maturation, spindle assembly, chromosome segregation, and cytokinesis. A B kinase overexpression has also been associated with various human cancers, as such, they have extensively studied novel antimitotic drug targets. Here, we characterize the inhibitor CCT137690, a highly selective, orally bioavailable imidazo[4,5-b]pyridine derivative that inhibits low nanomolar IC(50) values in both biochemical cellular assays exhibits...
Abstract Purpose: MYCN-dependent neuroblastomas have low cure rates with current multimodal treatment regimens and novel therapeutic drugs are therefore urgently needed. In previous preclinical studies, we shown that targeted inhibition of cyclin-dependent kinase 2 (CDK2) resulted in specific killing MYCN-amplified neuroblastoma cells. This study describes the vivo evaluation CDK inhibitor AT7519. Experimental Design: Preclinical drug testing was performed using a panel MYCN single copy cell...
Non-invasive serial imaging is desirable to detect processes such as necrotic and apoptotic cell death in cancer patients undergoing treatment. This study investigated the use of diffusion-weighted (DW-) magnetic resonance (MRI) for induced by either a cytotoxic drug (irinotecan), or apoptosis-inducing agent birinapant, human tumour xenografts vivo. Nude mice bearing SW620 colon carcinoma were treated with vehicle, irinotecan (50 mg kg−1) birinapant (30 up 5 days. DW-MRI was performed prior...
// Lynsey Vaughan 1,9 , Paul A. Clarke 2 Karen Barker 1 Yvan Chanthery 3 Clay W. Gustafson Elizabeth Tucker Jane Renshaw Florence Raynaud 4 Xiaodun Li 1,11 Rosemary Burke 5 Yann Jamin 6 Simon P. Robinson Andrew Pearson Michel Maira 7,10 William Weiss Workman and Louis Chesler 1,2,8 Division of Clinical Studies, The Institute Cancer Research, Sutton, Surrey, UK Research Therapeutics Unit, Signal Transduction Molecular Pharmacology Team, Department Neurology, Pediatrics, Neurosurgery, Brain...
Increased stiffness in the extracellular matrix (ECM) contributes to tumor progression and metastasis. Therefore, stromal modulating therapies accompanying biomarkers are being developed target ECM stiffness. Magnetic resonance (MR) elastography can noninvasively quantitatively map viscoelastic properties of tumors
Neuroblastoma is a pediatric cancer that frequently metastatic and resistant to conventional treatment. In part, lack of natively metastatic, chemoresistant
Magnetic resonance elastography (MRE) is an emerging imaging technique that affords non-invasive quantitative assessment and visualization of tissue mechanical properties in vivo. In this study, MRE was used to quantify (kPa) the absolute value complex shear modulus |G*|, elasticity Gd viscosity Gl SW620 human colorectal cancer xenografts before 24 h after treatment with either 200 mg kg−1 vascular disrupting agent ZD6126 (N-acetylcolchinol-O-phosphate) or vehicle control, data were compared...
Purpose To investigate the combined use of hyperoxia‐induced ΔR 2 * and 1 as a noninvasive imaging biomarker tumor hypoxia. Materials Methods MRI was performed on rat GH3 prolactinomas (n = 6) human PC3 prostate xenografts propagated in nude mice. multiple gradient echo inversion recovery truefisp images were acquired from identical transverse slices to quantify R before during carbogen (95% O /5% CO ) challenge, correlates assessed. Results Mean baseline 119 ± 7 s −1 0.6 0.03 for 77 12 0.7...
Neuroblastoma is the most common childhood extracranial solid tumor. In high-risk cases, many of which are characterized by amplification MYCN, outcome remains poor. Mutations in p53 (TP53) tumor suppressor rare at diagnosis, but evidence suggests that function often impaired relapsed, treatment-resistant disease. To address role loss development and pathogenesis neuroblastoma, we generated a MYCN-driven genetically engineered mouse model tamoxifen-inducible p53ER(TAM) fusion protein was...
Purpose To cross-validate T1-weighted oxygen-enhanced (OE) MRI measurements of tumor hypoxia with intrinsic susceptibility and to demonstrate the feasibility translation technique for patients. Materials Methods Preclinical studies in nine 786–0-R renal cell carcinoma (RCC) xenografts prospective clinical eight patients RCC were performed. Longitudinal relaxation rate changes (∆R1) after 100% oxygen inhalation quantified, reflecting paramagnetic effect on tissue protons because presence...