A5019036811- Lung Cancer Treatments and Mutations
- Heat shock proteins research
- Cannabis and Cannabinoid Research
- Glutathione Transferases and Polymorphisms
- Biochemical effects in animals
- Liver physiology and pathology
- Neuroscience and Neuropharmacology Research
- RNA modifications and cancer
- Cancer Genomics and Diagnostics
- Radiopharmaceutical Chemistry and Applications
- HER2/EGFR in Cancer Research
- Synthesis and biological activity
- Lung Cancer Research Studies
- Computational Drug Discovery Methods
- PI3K/AKT/mTOR signaling in cancer
- Cancer Treatment and Pharmacology
- Eicosanoids and Hypertension Pharmacology
- Galectins and Cancer Biology
- PARP inhibition in cancer therapy
- Medical Imaging Techniques and Applications
- Toxin Mechanisms and Immunotoxins
- Peptidase Inhibition and Analysis
- Cholangiocarcinoma and Gallbladder Cancer Studies
- MicroRNA in disease regulation
- Colorectal Cancer Treatments and Studies
Institute of Bioorganic Chemistry
2016-2025
Institute of Bioorganic Chemistry
2024
S.P.E.C.I.E.S.
2022
Novartis (Switzerland)
2011-2021
Chinese Academy of Medical Sciences & Peking Union Medical College
2018
Guangdong General Hospital
2018
Guangdong Academy of Medical Sciences
2018
Academy of Military Medical Sciences
2018
Russian Academy of Sciences
2007-2015
Yandex (Russia)
2015
Among patients with non–small-cell lung cancer (NSCLC), MET exon 14 skipping mutations occur in 3 to 4% and amplifications 1 6%. Capmatinib, a selective inhibitor of the receptor, has shown activity models various types activation.
Focal amplification and activating point mutation of the MET gene are well-characterized oncogenic drivers that confer susceptibility to targeted inhibitors. Recurrent somatic splice site alterations at exon 14 (METex14) result in skipping activation have been characterized, but their full diversity prevalence across tumor types unknown. Here, we report analysis genomic profiles from 38,028 patients identify 221 cases with METex14 mutations (0.6%), including 126 distinct sequence variants....
MET dysregulation occurs in up to 26% of non-small-cell lung cancers (NSCLCs) after epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) treatment. Capmatinib (INC280) is a potent and selective with preclinical activity combination gefitinib EGFR-mutant, MET-amplified/overexpressing models acquired EGFR-TKI resistance. This phase Ib/II study investigated the safety efficacy capmatinib plus patients EGFR-mutated, MET-dysregulated (amplified/overexpressing) NSCLC who...
A phase I study was conducted with the primary objective of determining maximum tolerated dose (MTD) AUY922 in patients advanced solid tumors. Secondary objectives included characterization safety, pharmacokinetic, and pharmacodynamic profiles.Patients tumors received 1-hour i.v. infusions once a week 28-day cycle. An adaptive Bayesian logistic regression model that employed observed dose-limiting toxicities (DLT) first treatment cycle used to guide dose-escalation decisions, established MTD...
Abstract Purpose: HSP90 chaperones have key client proteins that are involved in all hallmarks of breast cancer growth and progression. The primary aim this clinical trial was to evaluate the feasibility using 89Zr-trastuzumab PET (for HER2-positive cancer) or 89Zr-bevacizumab [for estrogen receptor (ER)–positive cancer] determine vivo degradation caused by novel inhibitor NVP-AUY922. Experimental Design: Of note, 70 mg/m2 NVP-AUY922 administered intravenously a weekly schedule patients with...
•This study provides first evidence of clinically meaningful antitumor activity capmatinib in MET-dysregulated NSCLC.•Accurate biomarker selection the patients is needed to identify expected respond better capmatinib.•MET amplification GCN ≥6 and/or METex14 skipping are strong predictive biomarkers for response capmatinib.•Overexpression alone cannot be considered as a reliable predict efficacy capmatinib.•Capmatinib well tolerated with majority AEs grade 1 and 2. BackgroundDysregulation...
Abstract HSP90 enables the activation of many client proteins which most clinically validated is HER2. NVP-AUY922, a potent inhibitor, currently in phase II clinical trials. To explore its potential use HER2-amplified breast and gastric cancers, we evaluated effect AUY922 alone combination with trastuzumab both trastuzumab-sensitive -resistant models. A panel 16 human 45 cancer cell lines, including (3 13, respectively) cells, was treated over various concentrations. In cancer, used lines...
BACKGROUND NVP‐AUY922 (AUY; Luminespib) with or without bortezomib showed preclinical activity against multiple myeloma (MM) cells. This phase 1/1B study assessed alone and in patients relapsed refractory MM. METHODS Dose escalation was guided by an adaptive Bayesian logistic regression model. In 1, who progressed after 2 to 4 prior therapies received intravenously once weekly. 1B, fewer plus bortezomib. The primary objective determine the maximum tolerated dose (MTD) of NVP‐AUY922. RESULTS...
9067 Background: cMET dysregulation occurs in 3–10% of NSCLC and is a negative prognostic factor. INC280 highly selective inhibitor with preclinical clinical antitumor activity. The dose-escalation part this ongoing Ph I study (NCT01324479) included cMET-dysregulated expansion group. Preliminary efficacy was seen pts high expression, prompting the addition second group EGFRwt, cMET-expressing NSCLC. We report here on both groups. Methods: primary objective met; RP2D established at 400 mg BID...
Capmatinib is an oral, ATP-competitive, and highly potent, type 1b MET inhibitor. Herein, we report phase 1 dose-escalation results for capmatinib in advanced MET-positive solid tumor patients dose expansion non-lung tumors. was well tolerated with a manageable safety profile across all explored doses. Dose-limiting toxicities (DLT) occurred at 200 mg twice daily (bid), 250 bid, 450 bid capsules; however, no DLT were reported 600 (capsules). tablets 400 had comparable tolerability exposure...
8017 Background: Despite high response rates to EGFR tyrosine kinase inhibitors (TKIs), most patients (pts) with EGFR-mut NSCLC ultimately relapse. Dysregulation of the MET pathway is implicated as a therapeutically tractable resistance mechanism, occurring in 15–20% cases. INC280 highly selective, oral inhibitor preclinical activity EGFR-mut/MET-activated when combined TKIs. Methods: This Ph Ib/II, open-label, dose-escalation study plus gef was performed pts (age ≥18 yrs, ECOG PS ≤2) who...
2520^ Background: Aberrations in the MET receptor tyrosine kinase pathway occur various human malignancies (via amplification, mutation, or overexpression) driving cell proliferation, survival and metastasis. INC280 is a highly selective, oral small molecule inhibitor with preclinical activity tumor models. This dose escalation study evaluated patients (pts) dependent advanced solid tumors. Methods: In this Phase (Ph) I study, primary objective was to determine MTD recommended Ph II (RP2D),...
9020 Background: Most pts withEGFR-mut NSCLC progress on EGFR tyrosine kinase inhibitor (TKI) therapy despite high initial response rates. cMET is dysregulated in 15−25% of with acquired TKI resistance. INC280 a highly selective preclinical and preliminary clinical activity EGFR-mut, cMET+ when combined TKIs. This Ph Ib/II study evaluates the safety efficacy + gefitinib who have progressed gefitinib, erlotinib, or afatinib (NCT01610336). We report here II expansion part. Methods: The primary...
2-arachnadoyl glycerol (2-AG) is one of the most common endocannabinoid molecules with anti-proliferative, cytotoxic, and pro-proliferative effects on different types tumors. Typically, it induces cell death via cannabinoid receptor 1/2 (CB1/CB2)-linked ceramide production. In breast cancer, counterbalanced by sphingosine-1-phosphate, thus mechanisms 2-AG influence proliferation are poorly understood. We evaluated mechanism anti-proliferative action lysophaosphatidylinositol (LPI) in six...
Background/Objectives: Natural cytokinins are a promising group of anti-tumor agents. In this work, we hypothesized that modification the ethylenediurea moiety with alkyl and oxygen-containing groups could be way to enhance anti-proliferative properties molecule. Methods: Ten new analogs these substitutions were tested for activity in human cancer cell lines MDA-MB-231 (breast cancer), A-375 (melanoma), U-87 MG (glioblastoma) during 72 h incubation using resazurin test evaluated substances...
7543 Background: AUY922 is a highly potent, non-geldanamycin, HSP90 inhibitor. A Phase I study in advanced solid tumors provided recommended II dose of 70 mg/m 2 . acts as chaperone client proteins, including those relevant NSCLC pathogenesis. This assessed pts with previously treated stratified by molecular status. Methods: Pts who progressed following ≥2 prior lines chemotherapy, received 1-hr infusion once-weekly. were assigned to 4 strata: EGFR activating mutations (EGFR mut), KRAS mut,...
// Anthony Kong 1, 2 , Daniel Rea Samreen Ahmed 3 J. Thaddeus Beck 4 Rafael López 5 Laura Biganzoli 6 Anne C. Armstrong 7 Massimo Aglietta 8 Emilio Alba 9 Mario Campone 10 Shu-Fang Hsu Schmitz 11 Caroline Lefebvre 12 Mikhail Akimov 13 Soo-Chin Lee 14 1 Previous address: Churchill Hospital, Oxford University Hospitals NHS Trust and of Oxford, United Kingdom School Cancer Sciences, Birmingham, Department Oncology, Leicester, Leicester Royal Infirmary, Highlands Oncology Group, Fayetteville,...
Heat-shock protein 990 (HSP990) is a potent and selective synthetic small-molecule HSP90 inhibitor. The primary objectives of this phase I first-in-human study were to determine dose-limiting toxicities (DLTs), maximum-tolerated dose (MTD) recommended II (RP2D). Secondary included characterisation the safety profile, pharmacokinetics (PKs) pharmacodynamics (PDs). was administered orally once or two times weekly on 28-day cycle schedule in patients with advanced solid tumours. Dose escalation...
The aims of this study were to develop co-delivery systems paclitaxel (PTX) and etoposide prodrug (4'-O-benzyloxycarbonyl-etoposide, ETP-cbz) based on non-cross-linked human serum albumin (HSA) poly(lactide-co-glycolide) nanoparticles evaluate the synergistic potential these drugs in vitro. nanoformulations prepared by high-pressure homogenisation technique characterised using DLS, TEM, SEM, AFM, HPLC, CZE, in-vitro release, cytotoxicity murine glioma cells. All had 90-150 nm size negative...
Endocannabinoid anandamide (AEA) and paracannabinoid lysophosphatidylinositol (LPI) play a significant role in cancer cell proliferation regulation. While inhibits the of cells, LPI is known as stimulant. Despite endocannabinoid receptor crosstalk simultaneous presence microenvironment both molecules, their combined activity has never been studied. We evaluated effect on AEA six human breast lines different carcinogenicity (MCF-10A, MCF-7, BT-474, BT-20, SK-BR-3, MDA-MB-231) using resazurin...
BackgroundIdentification of appropriate markers for predicting clinical benefit with erlotinib in non-small-cell lung cancer (NSCLC) may be able to guide patient selection treatment. This open-label, multicentre, phase II trial aimed identify genes potential use as biomarkers from therapy.MethodsAdults stage IIIb/IV NSCLC whom one or more chemotherapy regimen had failed were treated (150 mg/day). Tumour biopsies analysed using gene expression profiling Affymetrix GeneChip® microarrays....
AUY922 is a potent non-geldanamycin inhibitor of heat-shock protein 90. This study was carried out in Japanese patients to determine the maximum tolerated dose (MTD), and characterize safety, tolerability pharmacokinetics single-agent AUY922.Japanese with advanced solid tumors whose disease had progressed on at least one line standard therapy, or for whom no therapy existed, were treated (intravenous, once-weekly, 28-day cycle, starting 8 mg/m(2)).Thirty-one treated. Two DLTs reported...