Browsing Clinical Studies by author "Raynaud, Florence"
Now showing items 1-16 of 16
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A phase I dose-escalation study of enzalutamide in combination with the AKT inhibitor AZD5363 (capivasertib) in patients with metastatic castration-resistant prostate cancer.
Kolinsky, MP; Rescigno, P; Bianchini, D; Zafeiriou, Z; Mehra, N; et al. (ELSEVIER, 2020-02-21)BACKGROUND: Activation of the PI3K/AKT/mTOR pathway through loss of phosphatase and tensin homolog (PTEN) occurs in approximately 50% of patients with metastatic castration-resistant prostate cancer (mCRPC). Recent evidence ... -
Combined MYC and P53 defects emerge at medulloblastoma relapse and define rapidly progressive, therapeutically targetable disease.
Hill, RM; Kuijper, S; Lindsey, JC; Petrie, K; Schwalbe, EC; et al. (CELL PRESS, 2015-01-12)We undertook a comprehensive clinical and biological investigation of serial medulloblastoma biopsies obtained at diagnosis and relapse. Combined MYC family amplifications and P53 pathway defects commonly emerged at relapse, ... -
Development and validation of a LC-MS/MS method for the quantification of the checkpoint kinase 1 inhibitor SRA737 in human plasma.
Zangarini, M; Berry, P; Sludden, J; Raynaud, FI; Banerji, U; et al. (FUTURE SCI LTD, 2017-07-01)AIM: SRA737 is an orally active small-molecule inhibitor of checkpoint kinase 1 being investigated in an oncology setting. A HPLC-MS/MS method for quantifying plasma concentrations of SRA737 was validated. METHODS & RESULTS: ... -
Differences in Signaling Patterns on PI3K Inhibition Reveal Context Specificity in KRAS-Mutant Cancers.
Stewart, A; Coker, EA; Pölsterl, S; Georgiou, A; Minchom, AR; et al. (AMER ASSOC CANCER RESEARCH, 2019-08-01)It is increasingly appreciated that drug response to different cancers driven by the same oncogene is different and may relate to differences in rewiring of signal transduction. We aimed to study differences in dynamic ... -
Dual blockade of the PI3K/AKT/mTOR (AZD8055) and RAS/MEK/ERK (AZD6244) pathways synergistically inhibits rhabdomyosarcoma cell growth in vitro and in vivo.
Renshaw, J; Taylor, KR; Bishop, R; Valenti, M; De Haven Brandon, A; et al. (AMER ASSOC CANCER RESEARCH, 2013-08-05)PURPOSE: 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. ... -
First-in-Human Study of AT13148, a Dual ROCK-AKT Inhibitor in Patients with Solid Tumors.
McLeod, R; Kumar, R; Papadatos-Pastos, D; Mateo, J; Brown, JS; et al. (AMER ASSOC CANCER RESEARCH, 2020-09-15)PURPOSE: AT13148 is an oral AGC kinase inhibitor, which potently inhibits ROCK and AKT kinases. In preclinical models, AT13148 has been shown to have antimetastatic and antiproliferative activity. PATIENTS AND METHODS: The ... -
Individualized Prediction of Drug Response and Rational Combination Therapy in NSCLC Using Artificial Intelligence-Enabled Studies of Acute Phosphoproteomic Changes.
Coker, EA; Stewart, A; Ozer, B; Minchom, A; Pickard, L; et al. (AMER ASSOC CANCER RESEARCH, 2022-06-01)We hypothesize that the study of acute protein perturbation in signal transduction by targeted anticancer drugs can predict drug sensitivity of these agents used as single agents and rational combination therapy. We assayed ... -
Inhibition of mTOR-kinase destabilizes MYCN and is a potential therapy for MYCN-dependent tumors.
Vaughan, L; Clarke, PA; Barker, K; Chanthery, Y; Gustafson, CW; et al. (IMPACT JOURNALS LLC, 2016-09-06)MYC oncoproteins deliver a potent oncogenic stimulus in several human cancers, making them major targets for drug development, but efforts to deliver clinically practical therapeutics have not yet been realized. In childhood ... -
Metabolomic changes of the multi (-AGC-) kinase inhibitor AT13148 in cells, mice and patients are associated with NOS regulation.
Pal, A; Asad, Y; Ruddle, R; Henley, AT; Swales, K; et al. (SPRINGER, 2020-04-13)INTRODUCTION: To generate biomarkers of target engagement or predictive response for multi-target drugs is challenging. One such compound is the multi-AGC kinase inhibitor AT13148. Metabolic signatures of selective signal ... -
Modulation of Plasma Metabolite Biomarkers of the MAPK Pathway with MEK Inhibitor RO4987655: Pharmacodynamic and Predictive Potential in Metastatic Melanoma.
Ang, JE; Pal, A; Asad, YJ; Henley, AT; Valenti, M; et al. (AMER ASSOC CANCER RESEARCH, 2017-10-01)MAPK pathway activation is frequently observed in human malignancies, including melanoma, and is associated with sensitivity to MEK inhibition and changes in cellular metabolism. Using quantitative mass spectrometry-based ... -
p53 Loss in MYC-Driven Neuroblastoma Leads to Metabolic Adaptations Supporting Radioresistance.
Yogev, O; Barker, K; Sikka, A; Almeida, GS; Hallsworth, A; et al. (AMER ASSOC CANCER RESEARCH, 2016-09-29)Neuroblastoma is the most common childhood extracranial solid tumor. In high-risk cases, many of which are characterized by amplification of MYCN, outcome remains poor. Mutations in the p53 (TP53) tumor suppressor are rare ... -
Phase I Trial of the PARP Inhibitor Olaparib and AKT Inhibitor Capivasertib in Patients with BRCA1/2- and Non-BRCA1/2-Mutant Cancers.
Yap, TA; Kristeleit, R; Michalarea, V; Pettitt, SJ; Lim, JSJ; et al. (AMER ASSOC CANCER RESEARCH, 2020-10-01)Preclinical studies have demonstrated synergy between PARP and PI3K/AKT pathway inhibitors in BRCA1 and BRCA2 (BRCA1/2)-deficient and BRCA1/2-proficient tumors. We conducted an investigator-initiated phase I trial utilizing ... -
Plasma Metabolomic Changes following PI3K Inhibition as Pharmacodynamic Biomarkers: Preclinical Discovery to Phase I Trial Evaluation.
Ang, JE; Pandher, R; Ang, JC; Asad, YJ; Henley, AT; et al. (AMER ASSOC CANCER RESEARCH, 2016-06-01)PI3K plays a key role in cellular metabolism and cancer. Using a mass spectrometry-based metabolomics platform, we discovered that plasma concentrations of 26 metabolites, including amino acids, acylcarnitines, and ... -
The clinical development candidate CCT245737 is an orally active CHK1 inhibitor with preclinical activity in RAS mutant NSCLC and Eµ-MYC driven B-cell lymphoma.
Walton, MI; Eve, PD; Hayes, A; Henley, AT; Valenti, MR; et al. (IMPACT JOURNALS LLC, 2016-01-19)CCT245737 is the first orally active, clinical development candidate CHK1 inhibitor to be described. The IC50 was 1.4 nM against CHK1 enzyme and it exhibited>1,000-fold selectivity against CHK2 and CDK1. CCT245737 potently ... -
Triplet Therapy with Palbociclib, Taselisib, and Fulvestrant in PIK3CA-Mutant Breast Cancer and Doublet Palbociclib and Taselisib in Pathway-Mutant Solid Cancers.
Pascual, J; Lim, JSJ; Macpherson, IR; Armstrong, AC; Ring, A; et al. (AMER ASSOC CANCER RESEARCH, 2021-01-01)Cyclin-dependent kinase 4/6 (CDK4/6) and PI3K inhibitors synergize in PIK3CA-mutant ER-positive HER2-negative breast cancer models. We conducted a phase Ib trial investigating the safety and efficacy of doublet CDK4/6 ... -
Vistusertib (dual m-TORC1/2 inhibitor) in combination with paclitaxel in patients with high-grade serous ovarian and squamous non-small-cell lung cancer.
Basu, B; Krebs, MG; Sundar, R; Wilson, RH; Spicer, J; et al. (OXFORD UNIV PRESS, 2018-07-17)BACKGROUND: We have previously shown that raised p-S6K levels correlate with resistance to chemotherapy in ovarian cancer. We hypothesised that inhibiting p-S6K signalling with the dual m-TORC1/2 inhibitor in patients ...