A5059545579- PI3K/AKT/mTOR signaling in cancer
- Cancer-related gene regulation
- Ovarian cancer diagnosis and treatment
- Computational Drug Discovery Methods
- Lung Cancer Treatments and Mutations
- Advanced Breast Cancer Therapies
- Cancer, Hypoxia, and Metabolism
- Biochemical and Molecular Research
- Colorectal Cancer Treatments and Studies
- Glioma Diagnosis and Treatment
- RNA modifications and cancer
- Neuroblastoma Research and Treatments
- Growth Hormone and Insulin-like Growth Factors
- Protein Degradation and Inhibitors
- Pancreatic and Hepatic Oncology Research
- Gastric Cancer Management and Outcomes
- PARP inhibition in cancer therapy
- Sarcoma Diagnosis and Treatment
- Cancer Genomics and Diagnostics
- Cancer-related Molecular Pathways
- HER2/EGFR in Cancer Research
- BRCA gene mutations in cancer
- Cancer Mechanisms and Therapy
- Enzyme function and inhibition
- ATP Synthase and ATPases Research
Institute of Cancer Research
2015-2024
Institute of Cancer Research
2024
Cancer Research UK
2008-2023
Royal Marsden NHS Foundation Trust
2013-2023
University of Bonn
2013
Royal Marsden Hospital
2013
University College London
2010
Cardiff University
2010
Moredun Research Institute
2010
BTG International (United Kingdom)
2007
Abstract Inflammation is a hallmark of cancer 1 . In patients with cancer, peripheral blood myeloid expansion, indicated by high neutrophil-to-lymphocyte ratio, associates shorter survival and treatment resistance across malignancies therapeutic modalities 2–5 Whether inflammation drives progression prostate in humans remain unclear. Here we show that inhibition chemotaxis can reduce tumour-elicited reverse therapy subset metastatic castration-resistant (CRPC). We higher ratio reflects...
We undertook a comprehensive clinical and biological investigation of serial medulloblastoma biopsies obtained at diagnosis relapse. Combined MYC family amplifications P53 pathway defects commonly emerged relapse, all patients in this group died rapidly progressive disease postrelapse. To study interaction, we investigated transgenic model MYCN-driven found spontaneous development Trp53 inactivating mutations. Abrogation p53 function produced aggressive tumors that mimicked characteristics...
To provide rationale for using phosphoinositide 3-kinase (PI3K) and/or mitogen-activated protein kinase (MAPK) pathway inhibitors to treat rhabdomyosarcomas, a major cause of pediatric and adolescent cancer deaths.The prevalence PI3K/MAPK activation in rhabdomyosarcoma clinical samples was assessed immunohistochemistry. Compensatory signaling cross-talk between pathways determined cell lines following p110α short hairpin RNA-mediated depletion. Pharmacologic inhibition reprogrammed stable...
Abstract Diffuse intrinsic pontine glioma (DIPG) is a lethal childhood brainstem tumour, with quarter of patients harbouring somatic mutations in ACVR1 , encoding the serine/threonine kinase ALK2. Despite being an amenable drug target, little has been done to-date to systematically evaluate role DIPG, nor screen currently available inhibitors patient-derived tumour models. Here we show dependence DIPG cells on mutant receptor, and preclinical efficacy two distinct chemotypes ALK2 inhibitor...
Abstract Preclinical studies have demonstrated synergy between PARP and PI3K/AKT pathway inhibitors in BRCA1 BRCA2 (BRCA1/2)–deficient BRCA1/2-proficient tumors. We conducted an investigator-initiated phase I trial utilizing a prospective intrapatient dose- escalation design to assess two schedules of capivasertib (AKT inhibitor) with olaparib (PARP 64 patients advanced solid Dose expansions enrolled germline BRCA1/2-mutant tumors, or BRCA1/2 wild-type cancers harboring somatic DNA damage...
Activation of the PI3K/AKT/mTOR pathway through loss phosphatase and tensin homolog (PTEN) occurs in approximately 50% patients with metastatic castration-resistant prostate cancer (mCRPC). Recent evidence suggests that combined inhibition androgen receptor (AR) AKT may be beneficial mCRPC PTEN loss.
Diffuse hemispheric gliomas, H3G34R/V-mutant (DHG-H3G34), are lethal brain tumors lacking targeted therapies. They originate from interneuronal precursors; however, leveraging this origin for therapeutic insights remains unexplored. Here, we delineate a cellular hierarchy along the interneuron lineage development continuum, revealing that DHG-H3G34 mirror spatial patterns of progenitor streams surrounding nests, as seen during human development. Integrating these findings with genome-wide...
Abstract The Wnt signaling pathway is frequently deregulated in cancer due to mutations genes encoding APC, β-catenin, and axin. To identify small-molecule inhibitors of as potential therapeutics, a diverse chemical library was screened using transcription factor reporter cell line which the activity induced at level Disheveled protein. A series deconvolution studies used focus on three compound that selectively killed lines with constitutive signaling. Activities compounds included ability...
AT13148 is an oral AGC kinase inhibitor, which potently inhibits ROCK and AKT kinases. In preclinical models, has been shown to have antimetastatic antiproliferative activity.
Fragment-based screening identified 7-azaindole as a protein kinase B inhibitor scaffold. Fragment elaboration using iterative crystallography of inhibitor−PKA−PKB chimera complexes efficiently guided improvements in the potency and selectivity compounds, resulting identification nanomolar 6-(piperidin-1-yl)purine, 4-(piperidin-1-yl)-7-azaindole, 4-(piperidin-1-yl)pyrrolo[2,3-d]pyrimidine inhibitors PKBβ with antiproliferative activity showing pathway inhibition cells. A divergence binding...
Protein kinase B (PKB or Akt) is an important component of intracellular signaling pathways regulating growth and survival. Signaling through PKB frequently deregulated in cancer, inhibitors therefore have potential as antitumor agents. The optimization lipophilic substitution within a series 4-benzyl-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-amines provided ATP-competitive, nanomolar with up to 150-fold selectivity for inhibition over the closely related PKA. Although active cellular...
Abstract AKT is frequently deregulated in cancer, making it an attractive anticancer drug target. CCT128930 a novel ATP-competitive inhibitor discovered using fragment- and structure-based approaches. It potent, advanced lead pyrrolopyrimidine compound exhibiting selectivity for over PKA, achieved by targeting single amino acid difference. exhibited marked antiproliferative activity inhibited the phosphorylation of range substrates multiple tumor cell lines vitro, consistent with inhibition....
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...
BackgroundWe have previously shown that raised p-S6K levels correlate with resistance to chemotherapy in ovarian cancer. We hypothesised inhibiting signalling the dual m-TORC1/2 inhibitor patients receiving weekly paclitaxel could improve outcomes such patients.Patients and methodsIn dose escalation, (80 mg/m2) was given 6/7 weeks combination two intermittent schedules of vistusertib (dosing starting on day paclitaxel): schedule A, dosed bd for 3 consecutive days per week (3/7 days) B, 2...
SR4554 is a fluorine-containing 2-nitroimidazole, designed as hypoxia marker detectable with 19F magnetic resonance spectroscopy (MRS). In an initial phase I study of SR4554, nausea/vomiting was found to be dose-limiting, and 1400 mg m−2 established MTD. Preliminary MRS studies demonstrated some evidence retention in tumour. this we investigated higher doses intratumoral localisation the signal. Patients had tumours ⩾3 cm diameter ⩽4 deep. Measurements were performed using 1H/19F surface...
Somatic mutations in ACVR1 are found a quarter of children with diffuse intrinsic pontine glioma (DIPG), but there no inhibitors licensed for the disease. Using an artificial intelligence-based platform to search approved compounds ACVR1-mutant DIPG, combination vandetanib and everolimus was identified as possible therapeutic approach. Vandetanib, inhibitor VEGFR/RET/EGFR, target (K d = 150 nmol/L) reduce DIPG cell viability vitro has limited ability cross blood-brain barrier. In addition...
Phosphoinositide-specific phospholipase C (PLC) is a key enzyme in the regulation of Ca(2+) release from inositol 1,4,5-triphosphate-sensitive stores. U73122 (1-(6-((17beta-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione) has been extensively used as pharmacological inhibitor PLC to elucidate importance this family signal transduction pathways. an electrophilic maleimide group, which readily reacts with nucleophiles such thiols and amines. In current study conjugation...
Abstract Background: Preclinical experiments in-vitro show MEK inhibitors can cause upregulation of p-FAK in KRASM cells. The combination a and FAK inhibitor could overcome this in-vivo. Methods: We are conducting an open label phase I dose escalation with expansion study (NCT03875820). Dose evaluated twice week schedule (Mon/Thurs) CH5126766/VS-6766 (CH) 3 weeks out 4 day dosing defactinib (Def) administered 4. levels explored were cohort 1 (CH 3.2 mg, 200 mg Def), 2a Def mg) 2b 400 mg)....
Abstract Background: There is an urgent need for better trial designs to assess targeted drug combinations. We proposed a novel intrapatient (intrapt) dose escalation design optimize exposures, minimize pharmacokinetic (PK) variability and reduce patient (pt) numbers needed (Yap et al, JCO 2013). In vivo synergy between PARP PI3K pathway inhibition was seen in BRCA1-related sporadic cancers (Juvekar al; Ibrahim Cancer Discov 2012), providing rationale this study. Methods: Two-stage...
2503 Background: ONX-0801 is a first-in-class alpha folate receptor (AFR) targeted thymidylate synthase inhibitor, engineered to differentially accumulate 6000-fold in AFR overexpressing cancer cells. Methods: A 3+3 dose escalation design was used and two IV schedules were explored. Schedule A, weekly dosing (QW) schedule B, once every 2 weeks (Q2W). cycle consisted of 4 treatment stopped after 6 cycles both schedules. An expansion cohort evaluate clinical activity patients with high grade...