Michel Vidal

Paris Descartes, CPSC | Paris 5

High interindividual variability (IIV) of the clinical response to epidermal growth factor receptor (EGFR) inhibitors such as osimertinib in non-small-cell lung cancer (NSCLC) might be related to the IIV in plasma exposure. The aim of this study was to evaluate the exposure–response relationship for toxicity and efficacy of osimertinib in unselecte...

Conclusion and discussion • Lasso based peptides showed good Fap7 binding affinity and cell activity while conjugated to CPP. Our efforts will focus on peptide optimization to improve affinity, stability and cell permeability. • Oxime and triazole click ligation in solution are very rapid and clean. We will try in situ ligation in the presence of F...

In our research project of protein-protein interaction inhibition (PPI), we need to synthesize a series of peptides consisted of a cyclic 17-mer peptide and a 16-mer cell penetration peptide (CPP). The synthetic efficiency of long peptides is sequence dependent that may sometimes become tedious. Thus, we decide to synthesize the cyclic peptides and...

The vascular endothelial growth factor (VEGF) family of cytokines plays a key role in vasculogenesis, angiogenesis, and lymphangiogenesis. VEGF-A is the main member of this family, alongside placental growth factor (PlGF), VEGF-B/C/D in mammals, and VEGF-E/F in other organisms. To study the activities of these growth factors under physiological and...

Background The risk of drug–drug interactions (DDI) has become a major issue in cancer patients. However, data in sarcoma patients are scarce. We aimed to evaluate the frequency and the factors associated with DDI with antitumor treatments, and to evaluate the impact of a pharmacist evaluation before anticancer treatment.Patients and methodsWe perf...

Pathological angiogenesis is mainly initiated by the binding of abnormal expressed vascular endothelial growth factors (VEGFs) to their receptors (VEGFRs). Blocking the VEGF/VEGFR interaction is a clinically proven treatment in cancer. Our previous work by epitope scan had identified cyclic peptides, mimicking the loop 1 of VEGF-A, VEGF-B and place...

Background: The risk of drug drug interactions (DDI) has become a major issue in cancer patient care. However, data in sarcoma patients are scarce. We aimed to evaluate the frequency of DDI with antitumor treatments, identify the risk factors for DDI and evaluate the impact of a pharmacist evaluation before anticancer treatment. Patients and Method...

A new liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous quantification of dabrafenib (DAB), its main metabolite hydroxy-dabrafenib (OHD) and trametinib (TRA) in human plasma has been developed and validated. After addition of internal standard (dabrafenib-d9), extraction was achieved after protein precipitation w...

Purpose Erlotinib is an oral first-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor approved for non–small cell lung cancers (NSCLC) with EGFR-activating mutations. Older patients experience more toxicities compared with younger patients at the standard recommended dose of 150 mg once daily. The aims of this study were t...

Supporting information related to the paper "One-pot oxime ligation from peptides bearing thiazolidine and aminooxyacetyl groups"

One-pot oxime ligation under mild conditions using Pd(II) as a shared catalyst from an aldehyde precursor (Thz) and a protected aminooxyacetyl group (Proc-Aoa) is reported. Two complementary metal-free protocols using unmasked Aoa-peptide are also described. Acetoxime-peptide can proceed to the desired oxime through an additional transoximation ste...

Patients treated with dabrafenib/trametinib (DAB/TRA) exhibit a large interindividual variability in clinical outcomes. The aims of this study were to characterize the pharmacokinetics of DAB, hydroxy-dabrafenib (OHD), and TRA in BRAF-mutated patients and to investigate the exposure–response relationship for toxicity and efficacy in metastatic mela...

A large interindividual variability has been observed in anti Programmed cell Death 1 (anti-PD1) therapies efficacy. The aim of this study is to assess the correlation of soluble PD-1 (sPD-1), soluble Programmed cell Death Ligand 1 (sPD-L1), Vascular Endothelial Growth Factor A (VEGFA), soluble CD40 ligand (sCD40L) and soluble CD44 (sCD44), with su...

Context Anti-PD1 therapy nivolumab has been approved for the treatment of advanced non-small cell lung cancer (NSCLC). However, a large inter-individual variability in its efficacy has been observed. Thus, the search for reliable factors to predict anti-PD1 efficacy represents a major challenge, particularly in NSCLC patients. The aim of this prosp...

Context Anti-PD1 therapy nivolumab has been approved for the treatment of advanced non-small cell lung cancer (NSCLC). However, a large inter-individual variability in its efficacy has been observed. Thus, the search for reliable factors to predict anti-PD1 efficacy represents a major challenge, particularly in NSCLC patients. The aim of this prosp...

Introduction: Enzalutamide (ENZA) is an oral androgen receptor inhibitor approved by the Food and Drug Administration and the European Medicines Agency for the treatment of metastatic and nonmetastatic castration-resistant prostate cancer (CRPC). ENZA is extensively metabolized by cytochrome P450 3A4 into N-desmethyl ENZA (NDE), an active metaboli...

Preeclampsia is a hypertensive pregnancy disease associated with a massive increase in sFlt-1 (soluble form of the vascular endothelial growth factor 1) in the maternal circulation, responsible for angiogenic imbalance and endothelial dysfunction. Pilot studies suggest that extracorporeal apheresis may reduce circulating sFlt-1 and prolong pregnanc...

Purpose: Limited published data are available regarding the pharmacokinetic (PK) and pharmacodynamic (PD) variables of prolonged-release tacrolimus (PRT) after liver transplantations. The goal of this study was to compare the PK and PD profiles of PRT in early and stable liver transplant recipients by developing a population PK model of PRT and in...

Physiological and pathological angiogenesis is mainly regulated by the binding of the vascular endothelial growth factor (VEGF) to its receptors (VEGFRs). Antagonists of VEGFR are very attractive for the treatment of diseases related to excessive angiogenesis. Our previously designed C-terminal alkylated cyclic peptides [YKDEGLEE]-NHR (R = alkyl, a...

Aims: Cytidine deaminase (CDA) activity in cancer patients' serum has been proposed as a predictive biomarker for efficacy and toxicity of nucleoside analogues. However, discrepant results about its predictive value have been reported due to the high interindividual variability in CDA activity. This study aimed at identifying determinants of this...

Targeted protein quantification using tandem mass spectrometry coupled to high performance chromatography (LC–MS/MS) has been used to quantify proteins involved in the absorption, distribution, metabolism and excretion (ADME) of xenobiotics to better understand these processes. At the blood-brain barrier (BBB), these proteins are particularly impor...

Dabrafenib is a potent and selective inhibitor of BRAF-mutant kinase that is approved, as monotherapy or in combination with trametinib (mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitor), for unresectable or metastatic BRAF-mutated melanoma, advanced non-small cell lung cancer and anaplastic thyroid cancer harbouring the BRAFV600E mut...

Δ⁴-abiraterone (Δ4A) is an activemetabolite of abiraterone (ABI), which is approved in the treatment of metastatic castration resistant prostate cancer (mCRPC). The contribution of Δ4A to the clinical antitumor activity of ABI remains unknown. The aim of this study was to explore the relationship between plasma Δ4A concentration and survival in 36...

The use of anticoagulants in patients with cancer is challenging as several co-morbidities modifying pharmacokinetic (PK) parameters and significant drug-drug interactions with concomitant anti-neoplastic therapies may lead to PK variability resulting in increased risk of thrombosis or bleeding. Data on the management of patients with cancer-associ...

Background : Abiraterone (ABI), a steroidal CYP17A1 inhibitor, blocks the DHT synthesis from adrenal precursor steroids in castration resistant prostate cancer (mCRPC) patients. ABI is converted by 3β-hydroxysteroid dehydrogenase (HSD3B) into D4-abiraterone (D4-ABI). In a previous preclinical study, D4-ABI was shown to block multiple steroidogenic...

Short peptides composed of naturally occurring amino acids are usually unstructured in aqueous media. The installation of covalent constraints within their side chains or backbones, resulting in the formation of macrocyclic peptides, is an appealing approach to stabilize them in defined secondary structures. Therefore, with the objective to stabili...

Tyrosine kinase inhibitors (TKIs) used in the treatment of metastatic renal cell carcinoma present high interindividual variability in clinical response and toxicity. In addition, high interindividual variability in pharmacokinetics (PK) of TKIs is observed which could explain therapeutic failure or elevated toxicity in some patients. Monitoring of...

This work describes the isolation and characterization of the hydrolysable tannin punicalagin, obtained from the yellow peel of pomegranate (Punica granatum, belonging to the family Lythraceae). The natural product was present as a mixture of α and β anomers, rapidly interconverting under acidic pH conditions. A fast and efficient purification meth...

The interaction between vascular endothelial growth factor (VEGF) and its receptors (VEGFR) has important implications in angiogenesis and cancer, which moved us to search for peptide derivatives able to block this protein–protein interaction. In a previous work we had described a collection of linear 13-mer peptides specially designed to adopt hel...

Therapeutic drug monitoring (TDM) could be helpful in oral targeted therapies. Data are sparse to evaluate its impact on treatment management. This study aimed to determine a threshold value of plasma drug exposure associated with the occurrence of grade 3-4 toxicity, then the potential impact of TDM on clinical decision. Consecutive outpatients tr...

Cancer angiogenesis is mainly initiated by the vascular endothelial growth factors (VEGFs). Based on the reported crystal structures of three natural ligands (VEGF-A, -B and PlGF) with the major receptors VEGFR-1 and VEGFR-2, we scanned receptor-binding epitopes of these ligands by designing linear and cyclic peptides in aim to disrupt the VEGF-A/V...

LC-MS/MS-based targeted absolute protein quantification (in fmol of the analyte protein per μg of total protein) is employed for the molecular characterization of the blood brain barrier (BBB) using isolated brain microvessels. Nevertheless, the heterogeneity of the sample regarding the levels of different cells co-isolated within the microvessels...

Background: Circulating tumor DNA (ctDNA) has been reported as a prognostic marker in melanoma. In BRAF V600-mutant melanoma, a plasma under-exposure to vemurafenib could favor emerging resistance but no biological data are available to support this hypothesis. Objective: We aimed to investigate the relationship between vemurafenib plasma concen...

The VEGFR1 has been shown to play a role in the regulation of angiogenesis, and has therefore been associated to several pathologies. In order to extend our toolbox of screening methods for the identification of compounds disrupting the VEGF receptor 1/VEGF interaction, we developed a fast and accurate displacement assay, in which VEGF receptor 1 d...

Background Older non-small cell lung cancer (NSCLC) patients under erlotinib are reported to experience more acute toxicity. We hypothesized that modifications in erlotinib pharmacokinetics might explain this observation. Methods A monocentric prospective clinico-pharmacological study included stage IIIb/IV NSCLC consecutive pts. treated with erlot...

Enzalutamide is currently approved for the treatment of men with metastatic castration-resistant prostate cancer (mCRPC). To date, a single liquid chromatographic–tandem mass spectroscopy method is available to measure plasma enzalutamide concentration in mCRPC patients. In this work, an accurate and sensitive HPLC-UV method has been developed for...

Purpose: Abiraterone acetate combined with prednisone improves survival in metastatic castration-resistant prostate cancer (mCRPC) patients. This oral anticancer agent may result in drug-drug interactions (DDI). We aimed to evaluate the prevalence of DDI with abiraterone and the possible determinants for the occurrence of these DDI. Methods: We...

Nivolumab, an anti PD-1 monoclonal antibody, has been approved for the treatment of previously treated advanced or metastatic non-small-cell lung cancer (NSCLC). The aim of this study was to develop and validate an ELISA method for the quantification of nivolumab in plasma from patients with NSCLC in order to perform future pharmacokinetic/pharmaco...

Background: Abiraterone (ABI) is a major oral agent for the treatment of metastatic castration-resistant prostate cancer (mCRPC) patients but its systemic exposure is subject to a large inter-individual variability. We aimed to explore the relationship between ABI trough plasma concentration and prostate-specific antigen (PSA) response in mCRPC pa...

Angiogenesis is tightly regulated through the binding of vascular endothelial growth factors (VEGFs) to their receptors (VEGFRs). In this context, we showed that human VEGFR1 domain 2 crystallizes in the presence of Zn²⁺, Co²⁺ or Cu²⁺ as a dimer that forms via metal-ion interactions and interlocked hydrophobic surfaces. SAXS, NMR and size exclusion...

Sequence alignment for the VEGFR1d2 (flt1) in the class Mammalia. The residues encompassing the dimerization site are in green boxes and the His147 and His223 homologous are in red boxes. (TIF)

Mapping of the perturbed resonances volumes onto the homodimeric crystal structure of hVEGFR1d2. Amino acids with drastic volume decrease after addition of cadmium have been colored in red on the structure. The cadmium ion is represented as a space filling model and colored in purple. The cadmium bridges the two monomers of hVEGFR1d2 by binding his...

X-ray fluorescence spectra of hVEGFR1d2 crystals. (A) hVEGFR1d2 crystallized in C2221 space group in the presence of 4 mM Laxaphycin B. (B) hVEGFR1d2 crystallized in P1 space group in the presence of 10 mM CoCl2. The spectra revealed a unique anomalous signal for each crystal form that corresponds to zinc K-edge (A) or to cobalt K-edge (B). (TIF)

Natural products guttiferone A, hyperforin, and aristoforin were able to inhibit or increase SIRT1 catalytic activity, depending on protein concentration and presence of detergent. On the basis of NMR data for guttiferone A, we demonstrated that the aggregation state of the natural product played a crucial role for its interaction with the enzyme....

Introduction: In the past decade, treatment options for metastatic renal cell carcinoma and soft-tissue sarcoma have expanded. Pazopanib was discovered during the screening of compounds that suppressed vascular endothelial growth factor receptor-2 (VEGFR-2). As other tyrosine kinase inhibitors (TKI), pazopanib is not totally specific for one targe...

Introduction: Melanoma is a highly malignant cutaneous tumor of melanin-producing cells. MEL050 is a synthetic benzamide-derived molecule that specifically binds to melanin with high affinity. Our aim was to implement a fully automated radiosynthesis of [(18)F]MEL050, using for the first time, the AllInOne™ synthesis module (Trasis), and to evalua...

Introduction: Sunitinib, a potent multi-tyrosine kinase (TK) inhibitor, is a standard first-line treatment for metastatic renal cell carcinoma (mRCC). In addition to its antiangiogenic activity, sunitinib is known to have immune-modulating properties especially on regulatory T-cells and tumor-infiltrating lymphocytes. However, data is sparse about...

Theileria-infected macrophages display many features of cancer cells such as heightened invasive capacity; however, the tumor-like phenotype is reversible by killing the parasite. Moreover, virulent macrophages can be attenuated by multiple in vitro passages and so provide a powerful model to elucidate mechanisms related to transformed macrophage v...

The v114* cyclic peptide has been identified as a tight Vascular Endothelial Growth Factor (VEGF) ligand. Here we report on the use of Isothermal Titration Calorimetry, 96-well plate competition assay and Circular Dichroism (CD) to explore the binding determinants of a new set of related peptides. Anti-VEGF antibodies are currently used in the clin...

Vemurafenib is a BRAF kinase inhibitor approved for first-line treatment of metastatic BRAF V600 -mutant melanoma. However, data on the pharmacokinetic/pharmacodynamic (PK/PD) relationship are lacking. The aim of this prospective, multicenter study was to explore the PK/PD relationship for vemurafenib in outpatients with advanced BRAF-mutated melan...

Background: Sunitinib is a protein tyrosine kinase (PTK) inhibitor that has immune-modulating properties. In this context, peripheral blood mononuclear cells (PBMC), mainly constituted by lymphocytes, could be a perfect surrogate tissue for identifying and assaying pharmacodynamic biomarkers of sunitinib. In this study, we investigated the changes...

Background Therapeutic drug monitoring for hydroxychloroquine (HCQ) has been suggested to assess nonadherence and optimize treatment efficacy in systemic lupus erythematosus patients. Materials & methods After protein precipitation, HCQ and its metabolites, desethylhydroxychloroquine and desethylchloroquine were separated on a phenyl column and mo...

In a recent issue of the Journal of Clinical Pharmacology, we read with interest the paper by Thomeas et al [1] which evaluated the biological reproducibility and estimated relevant covariates for candidate circulating biomarkers of angiogenesis. The study examined VEGF-A, soluble VEGFR2 and angiopoietin 2 after exposure to sorafenib (Nexavar®, a p...

Introduction: The platelet-derived growth factor receptor (PDGFR) pathway has important functions in cell growth and, by overexpression or mutation, could also be a driver for tumor development. Moreover, PDGFR is expressed in a tumoral microenvironment and could promote tumorigenesis. With these biological considerations, the PDGFR pathway could...

Introduction: Sunitinib is a multikinase inhibitor active in various cancers types including renal cancers and endocrine tumors. The study analyzed the influence of the lean body mass (LBM) and of pharmacogenetic variants on the exposure to sunitinib and its active metabolite, SU12662, and on sunitinib toxicity and clinical activity. Materials an...

Previously designed cyclic peptide antagonist c[YYDEGLEE]-NH2 disrupts the interaction between vascular endothelial growth factor (VEGF) and its receptors (VEGFRs). It represents a promising tool in the fight against cancer and age-related macular degeneration. We described in this paper the optimization of the lead peptide by C-terminal modificati...

Depending on the substituents adjacent to the triple bond the intramolecular cyclization of propargyl ureas provide imidazolinones (II) or methylene-imidazolidinones (IV) in good yields.