Background Tumor resistance is a frequent cause of therapy failure and remains a major challenge ... more Background Tumor resistance is a frequent cause of therapy failure and remains a major challenge for the long-term management of colorectal cancer (CRC). The aim of this study was to determine the implication of the tight junctional protein claudin 1 (CLDN1) in the acquired resistance to chemotherapy. Methods Immunohistochemistry was used to determine CLDN1 expression in post-chemotherapy liver metastases from 58 CRC patients. The effects of oxaliplatin on membrane CLDN1 expression were evaluated by flow cytometry, immunofluorescence and western blotting experiments in vitro and in vivo. Phosphoproteome analyses, proximity ligation and luciferase reporter assays were used to unravel the mechanism of CLDN1 induction. RNAseq experiments were performed on oxaliplatin-resistant cell lines to investigate the role of CLDN1 in chemoresistance. The “one-two punch” sequential combination of oxaliplatin followed by an anti-CLDN1 antibody-drug conjugate (ADC) was tested in both CRC cell lines ...
Journal of Pharmaceutical and Biomedical Analysis, Sep 1, 2020
HAL is a multidisciplinary open access archive for the deposit and dissemination of scientific re... more HAL is a multidisciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L'archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.
The human pregnane X receptor (hPXR) is activated by a large set of endogenous and exogenous comp... more The human pregnane X receptor (hPXR) is activated by a large set of endogenous and exogenous compounds and plays a critical role in the control of detoxifying enzymes and transporters regulating liver and gastrointestinal drug metabolism and clearance. hPXR is also involved in both the development of multidrug resistance and enhanced cancer cells aggressiveness. Moreover, its unintentional activation by pharmaceutical drugs can mediate drug-drug interactions and cause severe adverse events. In that context, the potential of the anticancer BRAF inhibitor dabrafenib suspected to activate hPXR and the human constitutive androstane receptor (hCAR) has not been thoroughly investigated yet. Using different reporter cellular assays, we demonstrate that dabrafenib can activate hPXR as efficiently as its reference agonist SR12813, whereas it does not activate mouse or zebrafish PXR nor hCAR. We also showed that dabrafenib binds to recombinant hPXR, induces the expression of hPXR responsive genes in colon LS174T-hPXR cancer cells and human hepatocytes and finally increases the proliferation in LS174T-hPXR cells. Our study reveals that by using a panel of different cellular techniques it is possible to improve the assessment of hPXR agonist activity for new developed drugs.
International Journal of Molecular Sciences, May 20, 2022
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
Intratumour heterogeneity due to cancer cell clonal evolution and microenvironment composition an... more Intratumour heterogeneity due to cancer cell clonal evolution and microenvironment composition and tumor differences due to genetic variations between patients suffering of the same cancer pathology play a crucial role in patient response to therapies. This study is oriented to show that matrix-assisted laser-desorption ionization-Mass spectrometry imaging (MALDI-MSI), combined with an advanced multivariate data processing pipeline can be used to discriminate subtle variations between highly similar colorectal tumors. To this aim, experimental tumors reproducing the emergence of drug-resistant clones were generated in athymic mice using subcutaneous injection of different mixes of two isogenic cell lines, the irinotecan-resistant HCT116-SN50 (R) and its sibling human colon adenocarcinoma sensitive cell line HCT116 (S). Because irinotecan-resistant and irinotecan-sensitive are derived from the same original parental HCT116 cell line, their genetic characteristics and molecular compositions are closely related. The multivariate data processing pipeline proposed relies on three steps: (a) multiset multivariate curve resolution (MCR) to separate biological contributions from background; (b) multiset K-means segmentation using MCR scores of the biological contributions to separate between tumor and necrotic parts of the tissues; and (c) partial-least squares discriminant analysis (PLS-DA) applied to tumor pixel spectra to discriminate between R and S tumor populations. High levels of correct classification rates (0.85), sensitivity (0.92) and specificity (0.77) for the PLS-DA classification model were obtained. If previously labeled tissue is available, the multistep modeling strategy proposed constitutes a good approach for the identification and characterization of highly similar phenotypic tumor subpopulations that could be potentially applicable to any kind of cancer tissue that exhibits substantial heterogeneity.
ICSBP (IRF-8) is a transcription factor of the IRF family expressed only in the immune system. It... more ICSBP (IRF-8) is a transcription factor of the IRF family expressed only in the immune system. It is induced in macrophages by gamma interferon (IFN-␥) and contributes to macrophage functions. By interacting with Ets family protein PU.1, ICSBP binds to the IRF/Ets composite element and stimulates transcription. ICSBP binds to another DNA element, the IFN-stimulated response element (ISRE), a common target of the IRF family. Limited knowledge as to how ICSBP and other IRF proteins regulate ISRE-dependent transcription in IFN-␥-activated macrophages is available. By mass-spectrometric analysis of ISRE-bound proteins in macrophages, we identified TEL, another Ets member, as a factor recruited to the element in an IFN-␥-dependent manner. In vitro analysis with recombinant proteins indicated that this recruitment is due to a direct interaction between ICSBP and TEL, which is enhanced by the presence of ISRE. Significantly, the interaction with TEL in turn resulted in the recruitment of the histone deacetytase HDAC3 to the ISRE, causing increased repression of IFN-␥-mediated reporter activity through the ISRE. This repression may provide a negativefeedback mechanism operating after the initial transcriptional activation by IFN-␥. By associating with two different Ets family proteins, ICSBP exerts a dual function in IFN-␥-dependent gene regulation in an immune system-specific manner.
Background: The irinotecan-induced phosphokinome changes in colorectal cancer (CRC) cells were us... more Background: The irinotecan-induced phosphokinome changes in colorectal cancer (CRC) cells were used to guide the selection of targeted agents to be tested in combination with irinotecan. Methods: Phosphokinome profiling with peptide arrays of tumour samples from nude mice xenografted with HT29 cells and treated or not with an effective dose of irinotecan was used to identify signalling pathways activated by irinotecan treatment. Then, drugs targeting these pathways were combined in vitro with irinotecan to test potential synergistic effect. The interactions between these drug combinations were assessed by a dose matrix approach. Confirmation of the most potential combination has been confirmed in vivo in xenografted mice. Results: Irinotecan induced in vivo the activation of AKT and MEK1 phosphorylation. The dose matrix approach showed that BKM120 (PI3K inhibitor) and MEK162 (MEK inhibitor) are synergistic in vitro and in vivo with a cytostatic and cytotoxic effect, while combination of BKM120 and irinotecan or MEK162 and irinotecan are only additive or even antagonistic. However, the triple combination of SN38, BKM120 and MEK162 showed a better synergistic effect that BKM120 and MEK162, indicating that the cells need to inhibit both AKT and ERK pathways to become more sensitive to irinotecan-based chemotherapies. Conclusion: Analysis of chemotherapy-induced phosphokinome changes helps to elucidate the mechanisms of drug resistance and to guide the selection of targets for combination therapies with synergistic activity.
Background: Topoisomerase I (TOP1) is a nuclear enzyme that catalyzes the relaxation of supercoil... more Background: Topoisomerase I (TOP1) is a nuclear enzyme that catalyzes the relaxation of supercoiled DNA during DNA replication and transcription. TOP1 is the molecular target of camptothecin and related drugs such as irinotecan and SN38 (irinotecan's active metabolite). Irinotecan is widely used as an anti-cancer agent in the treatment of metastatic colon cancer. However, its efficacy is often limited by the development of resistance. Methods: We previously established several SN38 resistant HCT116-derived clones to study the mechanisms underlying resistance to SN38. Here, we investigated whether resistance to SN38 in these cell lines could be linked to the presence of TOP1 mutations and changes in its expression and activity. Functional analyses were performed on these cell lines challenged with SN38 and we specifically monitored the double strands breaks with γH2AX staining and replication activity with molecular combing. Results: In SN38 resistant HCT116 clones we identified three new TOP1 mutations, which are located in the core subdomain III (p.R621H and p.L617I) and in the linker domain (p.E710G) and are packed together at the interface between these two domains. The presence of these TOP1 mutations in SN38 resistant HCT116 cells did not modify TOP1 expression or intrinsic activity. Conversely, following challenge with SN38, we observed a decrease of TOP1-DNA cleavage complexes and a reduction in double-stranded break formation). In addition, we showed that SN38 resistant HCT116 cells present a strong decrease in the SN38-dependent asymmetry of replication forks that is characteristic of SN38 sensitive HCT116 cells. Conclusions: These results indicate that the TOP1 mutations are involved in the development of SN38 resistance. We hypothesize that p.L617, p.R621 and p.E710 TOP1 residues are important for the functionality of the linker and that mutation of one of these residues is sufficient to alter or modulate its flexibility. Consequently, linker fluctuations could have an impact on SN38 binding by reducing the enzyme affinity for the drug.
Aim: Most of targeted cancer drugs are developed in the clinical setting as single agent or as ad... more Aim: Most of targeted cancer drugs are developed in the clinical setting as single agent or as add-on of a standard treatment. Indeed, scarce data are available about the interaction effect in terms of synergism or antagonism for combinations of targeted agent or of targeted agents and cytotoxics at different doses. We studied the interaction effects of combinations of BKM120, MEK162 and SN38 (the active metabolite of irinotecan) on CRC cell lines. Materials and methods: A combination drug screening was performed on 7 CRC cell lines, 2 of which previously made resistant to irinotecan. For each cell line the combinations of BKM120 and MEK162, of BKM120 and SN38, and of MEK162 and SN38 were tested. Cell survival was assessed by sulforhodamine B cytotoxic assay in matrices of full-range dose combinations for both drugs. We compiled an R script to perform a synergy analysis according to a modified version of the method proposed by Léhar and al. (Nat Biotechnol 2009;27:659-666). Our version of the Léhar method allows quantification of synergism or antagonism for each dose combination point in dose matrices of two or more drugs, and yields a synthetic interaction parameter, the combination index (CI). A CI of > 0 indicating synergy, a CI of < 0 antagonism, and a CI of 0 additivity. Results: We could detect a pronounced synergism between BKM120 and MEK162, with a mean combination index of 1.82 for the 7 cell lines tested. Drug combinations including chemotherapy showed less positive interactions. A moderate synergistic interaction was detected between SN38 and MEK162, with a mean CI of 1.16. Combinations of SN38 and BKM120 were mainly additive, with a mean CI of 0.17. Interestingly, the distribution of synergistic effect was not homogeneous over the dose matrices. Analysis of matrices for the BKM120/MEK162 combination showed focal areas high synergy, which were quite constantly located in dose regions corresponding to IC10-IC30 for BKM120 and IC20-IC35 for MEK162. On the contrary, analysis of matrices for the BKM/SN38 combination showed focal areas of intense antagonism located in dose regions corresponding to IC15-IC30 for BKM120 and IC5-IC30 for SN38. No clear correlation was detected between, on the one side, the type of pharmacological interaction for all drug combinations tested and, on the other side, the mutational status of KRAS and p53, or sensitivity to irinotecan. Conclusions: Our data show the importance of an extensive preclinical testing of the interaction effects of drug combinations at different doses. We are now performing synergism analysis of three dimension matrices for three-drug combinations. Phosphoproteomic analysis of drug combination effect on this high synergism areas compared to other dose matrix areas is ongoing, with the aim to elucidate the underlying molecular mechanism(s). Citation Format: Diego Tosi, Salima Atis, Caroline Mollevi, Nadia Vie, Pierre Martineau, Celine Gongora. Synergism analysis of dose matrices for combinations of BKM120 (a PI3K inhibitor), MEK162 (a MEK1/2 inhibitor) and chemotherapy in colorectal cancer (CRC) cell lines. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr A40.
Background: The CDK4/6 inhibitors palbociclib is prescribed in association with hormonal therapy ... more Background: The CDK4/6 inhibitors palbociclib is prescribed in association with hormonal therapy for the management of metastatic breast cancer patients. Like most oral targeted drug, therapeutic drug monitoring may be used for personalize their dosage. Using a recently published dosing technique (LC-MS/MS), we aimed at evaluating the correlation between first-cycle palbociclib plasma exposition and co-medications in order to evaluate drug-drug interaction (DDI) impact under palbociclib treatment.Methods: This is an open-label phase 4 study conducted in female subjects with first-line metastatic breast cancer (NCT04025541) treated with a palbociclib-aromatase inhibitor association. Plasma concentration of palbociclib was assessed at 24 hours postdose (plasma trough concentration Ctrough) at day 15 of first cycle of treatment. A dedicated pharmacist consultation allowed the determination of clinical covariates of interest, such as weight, body surface area, ethnicity, food intake, co-medications use and DDI before Palbociclib initiation and retrospectively at the end of clinical trial. Patients were classified then according to their risk of DDI potentially leading to inhibition of CYP3A4 and/or P-glycoprotein and gastric pH increase by gastric acid-suppressive (GAS) agents (such as proton pump inhibitors, histamine H2-receptor blockers or alginic acid). Relevant drug known to have an inhibition of CYP3A4 and/or P-glycoprotein or pH-modification activity were checked in databases (e.g. DDI predictor®, Drugs.com®, Pubmed®). Results: To date, after Ctrough analysis of the 35 first cases, the geometric mean (± standard deviation [min-max]) of palbociclib plasma Ctrough was 79.5 ng/ml (± 26.1% [43.6 ng/mL - 133 ng/mL]) at day 15, similar to what reported in the PALOMA trials. No correlation between plasma concentration and body weight, body area or also age of the patients was found in our cohort. Regarding ethnicity, all the included patients were from Caucasian origin. 31% of patients (11/35) were identified of taking drugs that could cause DDI CYP3A4 and P-glycoprotein inhibition mediated (amlodipine n=3, simvastatin n=3, losartan n=2, fluconazole n=1, atorvastatin n=1, ivabradine n=1). These potential DDI interactions were associated with a significantly higher palbociclib concentration DDI subgroup (102 ng/mL vs 69 ng/mL) (p=0.000272) (Table 1). No CYP3A4 and/or P-glycoprotein inductor were reported in cohort. 1.4% of patients (5/35) were identified of taking GAS agents (pantoprazole n=2, ranitidine n=2, alginic acid n=1). We found a significantly reduction of palbociclib concentration (59.2 ng/mL vs 79.8 ng/mL) (p=0.048) in patients taking GAS medications (Table 1). Conclusion : These preliminary results, in real-life settings, obtained with our recently-published HPLC-MS/MS method, give important information on palbociclib monitoring and pharmacokinetic variability. DDI appear to have a significant impact on palbociclib plasma exposure, GAS agents are already know to modified palbociclib absorption. Additional studies are needed to characterize palbociclib plasma concentration variations between patients, and their clinical impact on efficacy and safety. The study is ongoing and will evaluate additional potential clinical and biological impact of DDI on neutropenia occurrence, on a larger population of patients. Table 1: Patients’ plasma palbociclib concentration (day 15 of cycle 1 of treatment).Plasma palbociclib concentrations (ng/ml), global cohort (n=35)Geometric mean (CV%) (min;max)79.5 (26.1%) (43.6;133)Plasma palbociclib concentrations (ng/ml), cohort with DDI CYP3A4 and P-gp mediated (n=11)Geometric mean (CV%)102 (24.3%)Plasma palbociclib concentrations (ng/ml), cohort without DDI CYP3A4 and P-gp mediated (n=24)Geometric mean (CV%)69 (19.8%)Plasma palbociclib concentrations (ng/ml), cohort with GAS treatment (n=5)Geometric mean (CV%)59.2 (15.9%)Plasma palbociclib concentrations (ng/ml), cohort without GAS treatment (n=30)Geometric mean (CV%)82.9 (26.1%) Citation Format: Fanny Leenhardt, Matthieu Gracia, Catherine Perrin, Claudia Muracciole-Bich, Bénédicte Marion, Celine Roques, Marie Alexandre, Nelly Firmin, Stephane Pouderoux, Litaty Mbatchi, Celine Gongora, William Jacot, Alexandre Evrard. Impact of drug-drug interaction on palbociclib serum levels: Interest of therapeutic drug monitoring [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS5-16.
Background and Aims: Gastric cancer is the fourth most common malignancy and the second leading c... more Background and Aims: Gastric cancer is the fourth most common malignancy and the second leading cause of cancer death in both sexes worldwide. Despite a global decrease in incidence, gastric cancer remains a disease of prominent morbidity and mortality, especially in Eastern Asia. The clinical outcome of gastric cancer has gradually improved, but the survival rate of patients with advanced gastric cancer is still disappointing. Achieving a better understanding of molecular aberrations associated with gastric carcinogenesis might identify new diagnostic and therapeutic strategies for this disease.MicroRNAs (miRNAs) recently emerged as prominent regulators of cancer processes. MicroRNAs are small, 18-to 24-nucleotide noncoding RNAs, with profound impact on many processes that are frequently disrupted during malignant transformation, including cell proliferation, apoptosis, stress responses, maintenance of stem cell potency and metabolism. Here we aim to identify miRs whose deregulated expression leads to the activation of oncogenic pathways in human gastric cancers. Methods: 39 out of 123 tumoral and matched peritumoral gastric specimens from three independent Europian subsets of patients were analyzed for the expression of 851 human miRs using Agilent Platform. The remaining 84 samples were used to validate miRs differentially expressed between tumoral and matched peritumoral specimens by qPCR. In vitro and in vivo experimental assays were employed to test the tumor suppressor activities of miR-204 and to functionally validate its mRNAs targets. Results: miR-204 falls into a cluster of 8 miRs differentially expressed between tumoral and peritumoral samples in all three analyzed subsets. Its downregulation has prognostic value and correlates with T status. Ectopic expression of miR-204 inhibited colony forming ability, migration and tumor engraftment of gastric cancer cells. Conclusions: microRNAs are differentially expressed in gastric tumors and underline specific genetic alterations. MiR 204 is significantly down-regulated in gastric tumor specimens compared to matched peritumoral tissues. These findings strongly indicate that down-regulation of miR-204 in gastric tumors might coincide with loss of tumor suppressor activity and consequently favor gastric transformation.
Bioorganic & Medicinal Chemistry Letters, Nov 1, 2020
Naturally occurring styryl lactone, crassalactone D (1), unnatural 4-epi-crassalactone D (2), and... more Naturally occurring styryl lactone, crassalactone D (1), unnatural 4-epi-crassalactone D (2), and the corresponding 7-epimers (3 and 4) have been synthesized starting from D-glucose. The key step of the synthesis is a new one-pot sequence that commenced with a Z-selective Wittig olefination of suitably functionalized sugar lactols with a stabilized ylide, (methoxycarbonylmethylene)-triphenylphosphorane, in dry methanol, to afford 1 or 3, in the mixtures with the corresponding 4-epimers (2 or 4, respectively). A number of 6-O-cinnamoyl derivatives of styryl lactones 1e4 have been prepared, bearing electron donating or electron withdrawing functionalities in the C-4 position of cinnamic acid residue. The synthesized products were evaluated for their in vitro antiproliferative activity against selected human tumour cell lines, whereupon very potent cytotoxicities have been recorded in many cases. SAR analysis indicated some important structural features responsible for biological activity, such as stereochemistry at the C-4 and C-7 positions, as well as the nature of a substituent at the C-4 position in the aromatic ring of cinnamoate moiety. Flow cytometry and Western blot analysis data gave insight in the mechanism underlying antiproliferative effects of the synthesized compounds.
HAL (Le Centre pour la Communication Scientifique Directe), Nov 1, 1999
Interferons (IFNs) encode a large family of multifonctional secreted proteins that are involved i... more Interferons (IFNs) encode a large family of multifonctional secreted proteins that are involved in antiviral defense, the regulation of cell growth and modulation of the immune response. They are subdivided into two types that activate transduction pathways via different cell surface receptors. Binding of both IFN type I and II results in the differential activation of JAK (Janus kinases) that phosphorylate latent cytoplasmic transcription factors termed STATs (signal transducer and activator of transcription). Phosphorylated STATs translocate to the nucleus, bind specific DNA elements and direct transcription. Type I IFN induces the phosphorylation of STAT1 and STAT2 proteins by tyrosine phosphorylation involving the type I IFN receptor-associated tyrosine kinases TYK2 and JAK1. Following phosphorylation, STAT1 and STAT2 form the transcriptionally active IFN-stimulated gene factor 3 (ISGF3) by association with a protein of the IFN regulatory factor (IRF) family, p48. The specificity of the transcriptional activation by ISGF3 is mediated by specific elements termed IFN-stimulatory response element (ISRE) located in the promoter region of IFN-inducible genes. ISREs drive the expression of most IFN type I-regulated genes and a few IFN type II-regulated genes. Gene induction by type II IFN involves the phosphorylation of only STAT1 by JAK1 and Jak2 kinases. This phosphorylation generates a homodimer of STAT1 which is able to bind the IFNgamma-activated site (GAS) to activate transcription. This signaling is rapid and direct. Molecules involved in the IFN signaling pathways have been shown to be used by other polypeptide ligands in their own signal transduction pathways. Pathways other than JAK/STAT are also involved in IFN signaling, but their mechanisms are less clear. The best documented are the mitogen-activated protein kinase (MAPK) cascade, the components of the TCR (T cell receptor) signaling cascade and the Pi3 kinase pathway.
Cannabinoid receptors are known to be expressed in microglia; however, their involvement in speci... more Cannabinoid receptors are known to be expressed in microglia; however, their involvement in specific aspects of microglial immune function has not been demonstrated. Many effects of cannabinoids are mediated by two G-protein coupled receptors, designated CB1 and CB2. We have shown that the CB1 receptor is expressed in microglia that also express MHC class II antigen (J. Neuroimmunol. 82 (1998) 13-21). In our present study, we have analyzed the effect of cannabinoid agonist CP55,940 on MHC class II expression on the surface of IFN-gamma induced microglial cells by flow cytometry. CP55,940 blocked the class II MHC expression induced by IFN-gamma. It has been shown that the regulation of class II MHC genes occurs primarily at the transcriptional level, and a non-DNA binding protein, class II transactivator (CIITA), has been shown to be the master activator for class II transcription. We find that mRNA levels of CIITA are increased in IFN-gamma induced EOC 20 microglial cells and that this increase is almost entirely eliminated by the cannabinoid agonist CP55,940. These data suggests that cannabinoids affect MHC class II expression through actions on CIITA at the transcriptional level.
e14661 Background: Colorectal cancer (CRC) is the second cause of cancer-related death worldwide.... more e14661 Background: Colorectal cancer (CRC) is the second cause of cancer-related death worldwide. Recent tremendous progresses have installed immunotherapy as a treatment option and opened multiple ways to address therapeutic challenges for MSI or MSS CRC patients. Accordingly, Brenus-Pharma developed a therapeutic cancer vaccine, the STC-1010, basing on the technology by stimulating tumor cells (STC) with physical (irradiation and heat shock) and chemical (via standard-of-care (SoC) chemotherapy) stress, coupled with the haptenization for overexpressing tumor-related antigens. Methods: The mouse version of STC-1010 (mSTC-1010) vaccine prepared using two CRC mouse cell lines (CT26 and CMT93) and one pancreatic cancer mouse cell line (LTPA), previously showed encouraging results in pre-clinical studies on MSS CT26 ‘cold-tumor’ and anti-PD1 resistant MSI MC38 ‘hot-tumor’ murine models. mSTC-1010 associated with immunostimulant (cyclophosphamide and GM-CSF at low doses), combined or no...
Background: The survival rate for patients with Pancreatic Ductal Adenocarcinoma (PDAC) is dramat... more Background: The survival rate for patients with Pancreatic Ductal Adenocarcinoma (PDAC) is dramatically poor with a five-year survival rate less than 10%. The research of new treatments, which could complement the current therapeutic arsenal constituted by Gemcitabine, FOLFIRINOX (fluorouracile, leucovorin, irinotecan, oxaliplatin) and nab-paclitaxel, is a major challenge. Imiqualines are new original small heterocyclic chemical molecules based on the quinoxalinic moiety. Among these first in class compounds, the lead EAPB02303 (1) displays outstanding nanomolar activities comparable to those of the current best anticancer agents on a panel of human cancer cell lines, notably on poorly sensitive cancer like PDAC and melanoma. We tested here if EAPB02303 could be an attractive first in class molecule in PDAC and we conducted in-deep molecular characterization and bioinformatics studies to decipher its mechanism of action. Methods: We characterized EAPB02303 effect on tumor growth in-...
Background Tumor resistance is a frequent cause of therapy failure and remains a major challenge ... more Background Tumor resistance is a frequent cause of therapy failure and remains a major challenge for the long-term management of colorectal cancer (CRC). The aim of this study was to determine the implication of the tight junctional protein claudin 1 (CLDN1) in the acquired resistance to chemotherapy. Methods Immunohistochemistry was used to determine CLDN1 expression in post-chemotherapy liver metastases from 58 CRC patients. The effects of oxaliplatin on membrane CLDN1 expression were evaluated by flow cytometry, immunofluorescence and western blotting experiments in vitro and in vivo. Phosphoproteome analyses, proximity ligation and luciferase reporter assays were used to unravel the mechanism of CLDN1 induction. RNAseq experiments were performed on oxaliplatin-resistant cell lines to investigate the role of CLDN1 in chemoresistance. The “one-two punch” sequential combination of oxaliplatin followed by an anti-CLDN1 antibody-drug conjugate (ADC) was tested in both CRC cell lines ...
Journal of Pharmaceutical and Biomedical Analysis, Sep 1, 2020
HAL is a multidisciplinary open access archive for the deposit and dissemination of scientific re... more HAL is a multidisciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L'archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.
The human pregnane X receptor (hPXR) is activated by a large set of endogenous and exogenous comp... more The human pregnane X receptor (hPXR) is activated by a large set of endogenous and exogenous compounds and plays a critical role in the control of detoxifying enzymes and transporters regulating liver and gastrointestinal drug metabolism and clearance. hPXR is also involved in both the development of multidrug resistance and enhanced cancer cells aggressiveness. Moreover, its unintentional activation by pharmaceutical drugs can mediate drug-drug interactions and cause severe adverse events. In that context, the potential of the anticancer BRAF inhibitor dabrafenib suspected to activate hPXR and the human constitutive androstane receptor (hCAR) has not been thoroughly investigated yet. Using different reporter cellular assays, we demonstrate that dabrafenib can activate hPXR as efficiently as its reference agonist SR12813, whereas it does not activate mouse or zebrafish PXR nor hCAR. We also showed that dabrafenib binds to recombinant hPXR, induces the expression of hPXR responsive genes in colon LS174T-hPXR cancer cells and human hepatocytes and finally increases the proliferation in LS174T-hPXR cells. Our study reveals that by using a panel of different cellular techniques it is possible to improve the assessment of hPXR agonist activity for new developed drugs.
International Journal of Molecular Sciences, May 20, 2022
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
Intratumour heterogeneity due to cancer cell clonal evolution and microenvironment composition an... more Intratumour heterogeneity due to cancer cell clonal evolution and microenvironment composition and tumor differences due to genetic variations between patients suffering of the same cancer pathology play a crucial role in patient response to therapies. This study is oriented to show that matrix-assisted laser-desorption ionization-Mass spectrometry imaging (MALDI-MSI), combined with an advanced multivariate data processing pipeline can be used to discriminate subtle variations between highly similar colorectal tumors. To this aim, experimental tumors reproducing the emergence of drug-resistant clones were generated in athymic mice using subcutaneous injection of different mixes of two isogenic cell lines, the irinotecan-resistant HCT116-SN50 (R) and its sibling human colon adenocarcinoma sensitive cell line HCT116 (S). Because irinotecan-resistant and irinotecan-sensitive are derived from the same original parental HCT116 cell line, their genetic characteristics and molecular compositions are closely related. The multivariate data processing pipeline proposed relies on three steps: (a) multiset multivariate curve resolution (MCR) to separate biological contributions from background; (b) multiset K-means segmentation using MCR scores of the biological contributions to separate between tumor and necrotic parts of the tissues; and (c) partial-least squares discriminant analysis (PLS-DA) applied to tumor pixel spectra to discriminate between R and S tumor populations. High levels of correct classification rates (0.85), sensitivity (0.92) and specificity (0.77) for the PLS-DA classification model were obtained. If previously labeled tissue is available, the multistep modeling strategy proposed constitutes a good approach for the identification and characterization of highly similar phenotypic tumor subpopulations that could be potentially applicable to any kind of cancer tissue that exhibits substantial heterogeneity.
ICSBP (IRF-8) is a transcription factor of the IRF family expressed only in the immune system. It... more ICSBP (IRF-8) is a transcription factor of the IRF family expressed only in the immune system. It is induced in macrophages by gamma interferon (IFN-␥) and contributes to macrophage functions. By interacting with Ets family protein PU.1, ICSBP binds to the IRF/Ets composite element and stimulates transcription. ICSBP binds to another DNA element, the IFN-stimulated response element (ISRE), a common target of the IRF family. Limited knowledge as to how ICSBP and other IRF proteins regulate ISRE-dependent transcription in IFN-␥-activated macrophages is available. By mass-spectrometric analysis of ISRE-bound proteins in macrophages, we identified TEL, another Ets member, as a factor recruited to the element in an IFN-␥-dependent manner. In vitro analysis with recombinant proteins indicated that this recruitment is due to a direct interaction between ICSBP and TEL, which is enhanced by the presence of ISRE. Significantly, the interaction with TEL in turn resulted in the recruitment of the histone deacetytase HDAC3 to the ISRE, causing increased repression of IFN-␥-mediated reporter activity through the ISRE. This repression may provide a negativefeedback mechanism operating after the initial transcriptional activation by IFN-␥. By associating with two different Ets family proteins, ICSBP exerts a dual function in IFN-␥-dependent gene regulation in an immune system-specific manner.
Background: The irinotecan-induced phosphokinome changes in colorectal cancer (CRC) cells were us... more Background: The irinotecan-induced phosphokinome changes in colorectal cancer (CRC) cells were used to guide the selection of targeted agents to be tested in combination with irinotecan. Methods: Phosphokinome profiling with peptide arrays of tumour samples from nude mice xenografted with HT29 cells and treated or not with an effective dose of irinotecan was used to identify signalling pathways activated by irinotecan treatment. Then, drugs targeting these pathways were combined in vitro with irinotecan to test potential synergistic effect. The interactions between these drug combinations were assessed by a dose matrix approach. Confirmation of the most potential combination has been confirmed in vivo in xenografted mice. Results: Irinotecan induced in vivo the activation of AKT and MEK1 phosphorylation. The dose matrix approach showed that BKM120 (PI3K inhibitor) and MEK162 (MEK inhibitor) are synergistic in vitro and in vivo with a cytostatic and cytotoxic effect, while combination of BKM120 and irinotecan or MEK162 and irinotecan are only additive or even antagonistic. However, the triple combination of SN38, BKM120 and MEK162 showed a better synergistic effect that BKM120 and MEK162, indicating that the cells need to inhibit both AKT and ERK pathways to become more sensitive to irinotecan-based chemotherapies. Conclusion: Analysis of chemotherapy-induced phosphokinome changes helps to elucidate the mechanisms of drug resistance and to guide the selection of targets for combination therapies with synergistic activity.
Background: Topoisomerase I (TOP1) is a nuclear enzyme that catalyzes the relaxation of supercoil... more Background: Topoisomerase I (TOP1) is a nuclear enzyme that catalyzes the relaxation of supercoiled DNA during DNA replication and transcription. TOP1 is the molecular target of camptothecin and related drugs such as irinotecan and SN38 (irinotecan's active metabolite). Irinotecan is widely used as an anti-cancer agent in the treatment of metastatic colon cancer. However, its efficacy is often limited by the development of resistance. Methods: We previously established several SN38 resistant HCT116-derived clones to study the mechanisms underlying resistance to SN38. Here, we investigated whether resistance to SN38 in these cell lines could be linked to the presence of TOP1 mutations and changes in its expression and activity. Functional analyses were performed on these cell lines challenged with SN38 and we specifically monitored the double strands breaks with γH2AX staining and replication activity with molecular combing. Results: In SN38 resistant HCT116 clones we identified three new TOP1 mutations, which are located in the core subdomain III (p.R621H and p.L617I) and in the linker domain (p.E710G) and are packed together at the interface between these two domains. The presence of these TOP1 mutations in SN38 resistant HCT116 cells did not modify TOP1 expression or intrinsic activity. Conversely, following challenge with SN38, we observed a decrease of TOP1-DNA cleavage complexes and a reduction in double-stranded break formation). In addition, we showed that SN38 resistant HCT116 cells present a strong decrease in the SN38-dependent asymmetry of replication forks that is characteristic of SN38 sensitive HCT116 cells. Conclusions: These results indicate that the TOP1 mutations are involved in the development of SN38 resistance. We hypothesize that p.L617, p.R621 and p.E710 TOP1 residues are important for the functionality of the linker and that mutation of one of these residues is sufficient to alter or modulate its flexibility. Consequently, linker fluctuations could have an impact on SN38 binding by reducing the enzyme affinity for the drug.
Aim: Most of targeted cancer drugs are developed in the clinical setting as single agent or as ad... more Aim: Most of targeted cancer drugs are developed in the clinical setting as single agent or as add-on of a standard treatment. Indeed, scarce data are available about the interaction effect in terms of synergism or antagonism for combinations of targeted agent or of targeted agents and cytotoxics at different doses. We studied the interaction effects of combinations of BKM120, MEK162 and SN38 (the active metabolite of irinotecan) on CRC cell lines. Materials and methods: A combination drug screening was performed on 7 CRC cell lines, 2 of which previously made resistant to irinotecan. For each cell line the combinations of BKM120 and MEK162, of BKM120 and SN38, and of MEK162 and SN38 were tested. Cell survival was assessed by sulforhodamine B cytotoxic assay in matrices of full-range dose combinations for both drugs. We compiled an R script to perform a synergy analysis according to a modified version of the method proposed by Léhar and al. (Nat Biotechnol 2009;27:659-666). Our version of the Léhar method allows quantification of synergism or antagonism for each dose combination point in dose matrices of two or more drugs, and yields a synthetic interaction parameter, the combination index (CI). A CI of > 0 indicating synergy, a CI of < 0 antagonism, and a CI of 0 additivity. Results: We could detect a pronounced synergism between BKM120 and MEK162, with a mean combination index of 1.82 for the 7 cell lines tested. Drug combinations including chemotherapy showed less positive interactions. A moderate synergistic interaction was detected between SN38 and MEK162, with a mean CI of 1.16. Combinations of SN38 and BKM120 were mainly additive, with a mean CI of 0.17. Interestingly, the distribution of synergistic effect was not homogeneous over the dose matrices. Analysis of matrices for the BKM120/MEK162 combination showed focal areas high synergy, which were quite constantly located in dose regions corresponding to IC10-IC30 for BKM120 and IC20-IC35 for MEK162. On the contrary, analysis of matrices for the BKM/SN38 combination showed focal areas of intense antagonism located in dose regions corresponding to IC15-IC30 for BKM120 and IC5-IC30 for SN38. No clear correlation was detected between, on the one side, the type of pharmacological interaction for all drug combinations tested and, on the other side, the mutational status of KRAS and p53, or sensitivity to irinotecan. Conclusions: Our data show the importance of an extensive preclinical testing of the interaction effects of drug combinations at different doses. We are now performing synergism analysis of three dimension matrices for three-drug combinations. Phosphoproteomic analysis of drug combination effect on this high synergism areas compared to other dose matrix areas is ongoing, with the aim to elucidate the underlying molecular mechanism(s). Citation Format: Diego Tosi, Salima Atis, Caroline Mollevi, Nadia Vie, Pierre Martineau, Celine Gongora. Synergism analysis of dose matrices for combinations of BKM120 (a PI3K inhibitor), MEK162 (a MEK1/2 inhibitor) and chemotherapy in colorectal cancer (CRC) cell lines. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr A40.
Background: The CDK4/6 inhibitors palbociclib is prescribed in association with hormonal therapy ... more Background: The CDK4/6 inhibitors palbociclib is prescribed in association with hormonal therapy for the management of metastatic breast cancer patients. Like most oral targeted drug, therapeutic drug monitoring may be used for personalize their dosage. Using a recently published dosing technique (LC-MS/MS), we aimed at evaluating the correlation between first-cycle palbociclib plasma exposition and co-medications in order to evaluate drug-drug interaction (DDI) impact under palbociclib treatment.Methods: This is an open-label phase 4 study conducted in female subjects with first-line metastatic breast cancer (NCT04025541) treated with a palbociclib-aromatase inhibitor association. Plasma concentration of palbociclib was assessed at 24 hours postdose (plasma trough concentration Ctrough) at day 15 of first cycle of treatment. A dedicated pharmacist consultation allowed the determination of clinical covariates of interest, such as weight, body surface area, ethnicity, food intake, co-medications use and DDI before Palbociclib initiation and retrospectively at the end of clinical trial. Patients were classified then according to their risk of DDI potentially leading to inhibition of CYP3A4 and/or P-glycoprotein and gastric pH increase by gastric acid-suppressive (GAS) agents (such as proton pump inhibitors, histamine H2-receptor blockers or alginic acid). Relevant drug known to have an inhibition of CYP3A4 and/or P-glycoprotein or pH-modification activity were checked in databases (e.g. DDI predictor®, Drugs.com®, Pubmed®). Results: To date, after Ctrough analysis of the 35 first cases, the geometric mean (± standard deviation [min-max]) of palbociclib plasma Ctrough was 79.5 ng/ml (± 26.1% [43.6 ng/mL - 133 ng/mL]) at day 15, similar to what reported in the PALOMA trials. No correlation between plasma concentration and body weight, body area or also age of the patients was found in our cohort. Regarding ethnicity, all the included patients were from Caucasian origin. 31% of patients (11/35) were identified of taking drugs that could cause DDI CYP3A4 and P-glycoprotein inhibition mediated (amlodipine n=3, simvastatin n=3, losartan n=2, fluconazole n=1, atorvastatin n=1, ivabradine n=1). These potential DDI interactions were associated with a significantly higher palbociclib concentration DDI subgroup (102 ng/mL vs 69 ng/mL) (p=0.000272) (Table 1). No CYP3A4 and/or P-glycoprotein inductor were reported in cohort. 1.4% of patients (5/35) were identified of taking GAS agents (pantoprazole n=2, ranitidine n=2, alginic acid n=1). We found a significantly reduction of palbociclib concentration (59.2 ng/mL vs 79.8 ng/mL) (p=0.048) in patients taking GAS medications (Table 1). Conclusion : These preliminary results, in real-life settings, obtained with our recently-published HPLC-MS/MS method, give important information on palbociclib monitoring and pharmacokinetic variability. DDI appear to have a significant impact on palbociclib plasma exposure, GAS agents are already know to modified palbociclib absorption. Additional studies are needed to characterize palbociclib plasma concentration variations between patients, and their clinical impact on efficacy and safety. The study is ongoing and will evaluate additional potential clinical and biological impact of DDI on neutropenia occurrence, on a larger population of patients. Table 1: Patients’ plasma palbociclib concentration (day 15 of cycle 1 of treatment).Plasma palbociclib concentrations (ng/ml), global cohort (n=35)Geometric mean (CV%) (min;max)79.5 (26.1%) (43.6;133)Plasma palbociclib concentrations (ng/ml), cohort with DDI CYP3A4 and P-gp mediated (n=11)Geometric mean (CV%)102 (24.3%)Plasma palbociclib concentrations (ng/ml), cohort without DDI CYP3A4 and P-gp mediated (n=24)Geometric mean (CV%)69 (19.8%)Plasma palbociclib concentrations (ng/ml), cohort with GAS treatment (n=5)Geometric mean (CV%)59.2 (15.9%)Plasma palbociclib concentrations (ng/ml), cohort without GAS treatment (n=30)Geometric mean (CV%)82.9 (26.1%) Citation Format: Fanny Leenhardt, Matthieu Gracia, Catherine Perrin, Claudia Muracciole-Bich, Bénédicte Marion, Celine Roques, Marie Alexandre, Nelly Firmin, Stephane Pouderoux, Litaty Mbatchi, Celine Gongora, William Jacot, Alexandre Evrard. Impact of drug-drug interaction on palbociclib serum levels: Interest of therapeutic drug monitoring [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS5-16.
Background and Aims: Gastric cancer is the fourth most common malignancy and the second leading c... more Background and Aims: Gastric cancer is the fourth most common malignancy and the second leading cause of cancer death in both sexes worldwide. Despite a global decrease in incidence, gastric cancer remains a disease of prominent morbidity and mortality, especially in Eastern Asia. The clinical outcome of gastric cancer has gradually improved, but the survival rate of patients with advanced gastric cancer is still disappointing. Achieving a better understanding of molecular aberrations associated with gastric carcinogenesis might identify new diagnostic and therapeutic strategies for this disease.MicroRNAs (miRNAs) recently emerged as prominent regulators of cancer processes. MicroRNAs are small, 18-to 24-nucleotide noncoding RNAs, with profound impact on many processes that are frequently disrupted during malignant transformation, including cell proliferation, apoptosis, stress responses, maintenance of stem cell potency and metabolism. Here we aim to identify miRs whose deregulated expression leads to the activation of oncogenic pathways in human gastric cancers. Methods: 39 out of 123 tumoral and matched peritumoral gastric specimens from three independent Europian subsets of patients were analyzed for the expression of 851 human miRs using Agilent Platform. The remaining 84 samples were used to validate miRs differentially expressed between tumoral and matched peritumoral specimens by qPCR. In vitro and in vivo experimental assays were employed to test the tumor suppressor activities of miR-204 and to functionally validate its mRNAs targets. Results: miR-204 falls into a cluster of 8 miRs differentially expressed between tumoral and peritumoral samples in all three analyzed subsets. Its downregulation has prognostic value and correlates with T status. Ectopic expression of miR-204 inhibited colony forming ability, migration and tumor engraftment of gastric cancer cells. Conclusions: microRNAs are differentially expressed in gastric tumors and underline specific genetic alterations. MiR 204 is significantly down-regulated in gastric tumor specimens compared to matched peritumoral tissues. These findings strongly indicate that down-regulation of miR-204 in gastric tumors might coincide with loss of tumor suppressor activity and consequently favor gastric transformation.
Bioorganic & Medicinal Chemistry Letters, Nov 1, 2020
Naturally occurring styryl lactone, crassalactone D (1), unnatural 4-epi-crassalactone D (2), and... more Naturally occurring styryl lactone, crassalactone D (1), unnatural 4-epi-crassalactone D (2), and the corresponding 7-epimers (3 and 4) have been synthesized starting from D-glucose. The key step of the synthesis is a new one-pot sequence that commenced with a Z-selective Wittig olefination of suitably functionalized sugar lactols with a stabilized ylide, (methoxycarbonylmethylene)-triphenylphosphorane, in dry methanol, to afford 1 or 3, in the mixtures with the corresponding 4-epimers (2 or 4, respectively). A number of 6-O-cinnamoyl derivatives of styryl lactones 1e4 have been prepared, bearing electron donating or electron withdrawing functionalities in the C-4 position of cinnamic acid residue. The synthesized products were evaluated for their in vitro antiproliferative activity against selected human tumour cell lines, whereupon very potent cytotoxicities have been recorded in many cases. SAR analysis indicated some important structural features responsible for biological activity, such as stereochemistry at the C-4 and C-7 positions, as well as the nature of a substituent at the C-4 position in the aromatic ring of cinnamoate moiety. Flow cytometry and Western blot analysis data gave insight in the mechanism underlying antiproliferative effects of the synthesized compounds.
HAL (Le Centre pour la Communication Scientifique Directe), Nov 1, 1999
Interferons (IFNs) encode a large family of multifonctional secreted proteins that are involved i... more Interferons (IFNs) encode a large family of multifonctional secreted proteins that are involved in antiviral defense, the regulation of cell growth and modulation of the immune response. They are subdivided into two types that activate transduction pathways via different cell surface receptors. Binding of both IFN type I and II results in the differential activation of JAK (Janus kinases) that phosphorylate latent cytoplasmic transcription factors termed STATs (signal transducer and activator of transcription). Phosphorylated STATs translocate to the nucleus, bind specific DNA elements and direct transcription. Type I IFN induces the phosphorylation of STAT1 and STAT2 proteins by tyrosine phosphorylation involving the type I IFN receptor-associated tyrosine kinases TYK2 and JAK1. Following phosphorylation, STAT1 and STAT2 form the transcriptionally active IFN-stimulated gene factor 3 (ISGF3) by association with a protein of the IFN regulatory factor (IRF) family, p48. The specificity of the transcriptional activation by ISGF3 is mediated by specific elements termed IFN-stimulatory response element (ISRE) located in the promoter region of IFN-inducible genes. ISREs drive the expression of most IFN type I-regulated genes and a few IFN type II-regulated genes. Gene induction by type II IFN involves the phosphorylation of only STAT1 by JAK1 and Jak2 kinases. This phosphorylation generates a homodimer of STAT1 which is able to bind the IFNgamma-activated site (GAS) to activate transcription. This signaling is rapid and direct. Molecules involved in the IFN signaling pathways have been shown to be used by other polypeptide ligands in their own signal transduction pathways. Pathways other than JAK/STAT are also involved in IFN signaling, but their mechanisms are less clear. The best documented are the mitogen-activated protein kinase (MAPK) cascade, the components of the TCR (T cell receptor) signaling cascade and the Pi3 kinase pathway.
Cannabinoid receptors are known to be expressed in microglia; however, their involvement in speci... more Cannabinoid receptors are known to be expressed in microglia; however, their involvement in specific aspects of microglial immune function has not been demonstrated. Many effects of cannabinoids are mediated by two G-protein coupled receptors, designated CB1 and CB2. We have shown that the CB1 receptor is expressed in microglia that also express MHC class II antigen (J. Neuroimmunol. 82 (1998) 13-21). In our present study, we have analyzed the effect of cannabinoid agonist CP55,940 on MHC class II expression on the surface of IFN-gamma induced microglial cells by flow cytometry. CP55,940 blocked the class II MHC expression induced by IFN-gamma. It has been shown that the regulation of class II MHC genes occurs primarily at the transcriptional level, and a non-DNA binding protein, class II transactivator (CIITA), has been shown to be the master activator for class II transcription. We find that mRNA levels of CIITA are increased in IFN-gamma induced EOC 20 microglial cells and that this increase is almost entirely eliminated by the cannabinoid agonist CP55,940. These data suggests that cannabinoids affect MHC class II expression through actions on CIITA at the transcriptional level.
e14661 Background: Colorectal cancer (CRC) is the second cause of cancer-related death worldwide.... more e14661 Background: Colorectal cancer (CRC) is the second cause of cancer-related death worldwide. Recent tremendous progresses have installed immunotherapy as a treatment option and opened multiple ways to address therapeutic challenges for MSI or MSS CRC patients. Accordingly, Brenus-Pharma developed a therapeutic cancer vaccine, the STC-1010, basing on the technology by stimulating tumor cells (STC) with physical (irradiation and heat shock) and chemical (via standard-of-care (SoC) chemotherapy) stress, coupled with the haptenization for overexpressing tumor-related antigens. Methods: The mouse version of STC-1010 (mSTC-1010) vaccine prepared using two CRC mouse cell lines (CT26 and CMT93) and one pancreatic cancer mouse cell line (LTPA), previously showed encouraging results in pre-clinical studies on MSS CT26 ‘cold-tumor’ and anti-PD1 resistant MSI MC38 ‘hot-tumor’ murine models. mSTC-1010 associated with immunostimulant (cyclophosphamide and GM-CSF at low doses), combined or no...
Background: The survival rate for patients with Pancreatic Ductal Adenocarcinoma (PDAC) is dramat... more Background: The survival rate for patients with Pancreatic Ductal Adenocarcinoma (PDAC) is dramatically poor with a five-year survival rate less than 10%. The research of new treatments, which could complement the current therapeutic arsenal constituted by Gemcitabine, FOLFIRINOX (fluorouracile, leucovorin, irinotecan, oxaliplatin) and nab-paclitaxel, is a major challenge. Imiqualines are new original small heterocyclic chemical molecules based on the quinoxalinic moiety. Among these first in class compounds, the lead EAPB02303 (1) displays outstanding nanomolar activities comparable to those of the current best anticancer agents on a panel of human cancer cell lines, notably on poorly sensitive cancer like PDAC and melanoma. We tested here if EAPB02303 could be an attractive first in class molecule in PDAC and we conducted in-deep molecular characterization and bioinformatics studies to decipher its mechanism of action. Methods: We characterized EAPB02303 effect on tumor growth in-...
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Papers by Celine Gongora