Pharmacology of EAPB0203, a novel imidazo[1,2-a]quinoxaline derivative with anti-tumoral activity on melanoma

International audienceIn spite of the development of new anticancer drugs by the pharmaceutical industry, melanoma and T lymphomas are diseases for which medical advances remain limited. Thus, there was an urgent need of new therapeutics with an original mechanism of action. Since several years, our group develops quinox-alinic compounds. In this paper, the first preclinical results concerning one lead compound, EAPB0203, are presented. This compound exhibits in vitro cytotoxic activity on A375 and M4Be human melanoma cell lines superior to that of imiquimod and fotemustine. A liquid chromatography-mass spectrometry method was first validated to simultaneously quantify EAPB0203 and its metabolite, EAPB0202, in rat plasma. Thereafter, the pharmacokinetic profiles of EAPB0203 were studied in rat after intravenous and intraperitoneal administrations. After intraperitoneal administration the absolute bioavailability remains limited (22.7%). In xenografted mouse, after intraperitoneal administration of 5 and 20 mg/kg, EAPB0203 is more potent than fotemustine. The survival time was increased up to 4 and 2 weeks compared to control mice and mice treated by fotemustine, respectively. The results of this study demonstrate the relationship between the dose of EAPB0203 and its effects on tumor growth. Thus, promising efficacy, tolerance and pharmacokinetic data of EAPB0203 encourage the development towards patient benefit

EGFR-dependent mechanisms of resistance to osimertinib determined by ctDNA NGS analysis identify patients with better outcome

International audienceBackground: Osimertinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that is highly selective for EGFR T790M subclones in patients with EGFR sensitizing non-small cell lung cancer (NSCLC). Unfortunately, all patients develop resistance through EGFR-dependent or EGFR-independent pathways. Recently, circulating tumoral DNA (ctDNA) analysis has highlighted the usefulness of plasma genotyping for exploring patient survival outcomes after disease progression under osimertinib.Methods: Plasma samples from patients treated with osimertinib as a second-line therapy were collected and the presence of molecular alterations of acquired resistance was evaluated after relapse under osimertinib using ctDNA molecular profiling by next-generation sequencing (NGS) assays. The clinical implications of these genomic alterations for the efficiency of the third-generation TKI were further assessed.Results: Our ctDNA molecular profiling of plasma samples highlighted large number of actionable genomic alterations. According to ctDNA NGS results, patients were classified as having developed an EGFR-dependent or EGFR-independent mechanism of resistance. Thus, patients who developed an EGFR-dependent mechanism of resistance responded longer to osimertinib (13.8 vs. 4.6 months; P<10-4) and have a better post-osimertinib clinical outcome than EGFR-independent resistant patients. Moreover, the development of an EGFR-dependent mechanism of osimertinib resistance was identified as the best fit to determine patients' clinical outcome compared with EGFR T790M status alone (P=0.003).Conclusions: Our study highlights the potential of ctDNA NGS to rapidly select the appropriate drug after osimertinib failure and to determine clinical outcomes of patients. We suggest that ctDNA NGS should be more intensively used in clinical practice to follow patients under third-generation TKIs

Protein interactions study through proximity-labeling

International audienc

Analyse de deux antigènes associés aux tumeurs solides, l'antigène carcinoembryonnaire (ACE) et l'antigène erbB-2 (étude des épitopes continus de l'ACE)

MONTPELLIER-BU Médecine (341722104) / SudocMONTPELLIER-BU Médecine UPM (341722108) / SudocPARIS-BIUM (751062103) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

FDA- and EMA-Approved Tyrosine Kinase Inhibitors in Advanced EGFR-Mutated Non-Small Cell Lung Cancer: Safety, Tolerability, Plasma Concentration Monitoring, and Management

Non-small-cell lung cancer (NSCLC) is the most common form of primary lung cancer. The discovery of several oncogenic driver mutations in patients with NSCLC has allowed the development of personalized treatments based on these specific molecular alterations, in particular in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR) gene. Gefitinib, erlotinib, afatinib, and osimertinib are TK inhibitors (TKIs) that specifically target EGFR and are currently approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) as first line treatment for sensitive EGFR-mutant patients. However, these four drugs are associated with severe adverse events (AEs) that can significantly impact patient health-related quality of life and patient monitoring. EGFR-TKIs are commonly used together with other types of medication that can substantially interact. Here, we review approaches used for the management of TKI-AEs in patients with advanced NSCLC to promote the benefits of treatments and minimize the risk of TKI treatment discontinuation. We also consider potential TKI&ndash;drug interactions and discuss the usefulness of plasma concentration monitoring TKIs based on chromatographic and mass spectrometry approaches to guide clinical decision-making. Adjusting the most appropriate therapeutic strategies and drug doses may improve the performance therapy and prognosis of patients with advanced EGFR-mutated NSCLC

Combination of tissue and liquid biopsy molecular profiling to detect transformation to small cell lung carcinoma during osimertinib treatment

International audienceBackground: Histological transformation of advanced non-small cell lung cancer (NSCLC) to small cell lung cancer (SCLC) is one of the mechanisms of resistance to third-generation tyrosine kinase inhibitors (TKIs), such as osimertinib. This acquired TKI resistance is linked to the high degree of tumor heterogeneity and adaptive cellular signaling pathways, including epidermal growth factor receptor (EGFR)-dependent pathways, observed in NSCLC.Methods: Here, we investigated a series of paired pre- and post-histological transformation biopsies obtained from three patients initially having a NSCLC with an EGFR activating mutation treated with first-generation TKI, who then received osimertinib as second-line after EGFR T790M resistance and, lastly, developed a histological transformation to SCLC. Both tissue and liquid biopsies were analyzed using large panel sequencing approaches at various time points to reconstruct the clonal evolutionary history of the tumor.Results: Our complementary analysis of tumor tissue and circulating tumor DNA samples allowed us to better characterize the histological and molecular alterations associated with resistance to osimertinib. SCLC transformation was linked to the presence of several concomitant gene alterations, including EGFR, TP53 and RB1, but also to specific signal bypass, such as EGFR and MET amplifications and activation of the PI3K/AKT/mTOR pathway.Conclusion: Our report emphasizes the mutational landscape of SCLC histological transformation and highlights the importance of combining tissue and liquid biopsy profiling before and during osimertinib treatment to predict such histological transformation

Differential Sensitivity of Germline and Somatic <i>BRCA</i> Variants to PARP Inhibitor in High-Grade Serous Ovarian Cancer

Purpose: The introduction of PARP inhibitors (PARPis) as a treatment option for patients with high-grade serous ovarian cancer (HGSOC) modified the approach of BRCA testing worldwide. In this study, we aim to evaluate the impact of BRCA1 and BRCA2 variants on treatment response and survival outcomes in patients diagnosed in our institution. Methods: A total of 805 HGSOC samples underwent BRCA1 and BRCA2 variant detection by using next-generation sequencing (NGS). Among them, a pathogenic alteration was detected in 104 specimens. Clinicopathological features and germline status were recovered, and alteration types were further characterized. The clinical significance of variant type in terms of response to chemotherapy and to PARPis as well as overall survival were evaluated using univariate analysis. Results: In our cohort, 13.2% of the HGSOC samples harbored a pathogenic BRCA1 or BRCA2 variant, among which 58.7% were inherited. No difference was observed between germline and somatic variants in terms of the gene altered. Interestingly, patients with somatic variants only (no germline) demonstrated better outcomes under PARPi treatment compared to those with germline ones. Conclusion: The determination of the inheritance or acquisition of BRCA1 and BRCA2 alterations could provide valuable information for improving management strategies and predicting the outcome of patients with HGSOC

High-throughput detection of clinically targetable alterations using next-generation sequencing

International audienceNext-generation sequencing (NGS) has revolutionized the therapeutic care of patients by allowing high-throughput and parallel sequencing of large numbers of genes in a single run. However, most of available commercialized cancer panels target a large number of mutations that do not have direct therapeutic implications and that are not fully adapted to low quality formalin-fixed, paraffin-embedded (FFPE) samples. Here, we designed an amplicon-based NGS panel assay of 16 currently actionable genes according to the most recent recommendations of the French National Cancer Institute (NCI). We developed a panel of short amplicons (<150 bp) using dual-strand library preparation. The clinical validation of this panel was performed on well-characterized controls and 140 routine diagnostic samples, including highly degraded and cross-linked genomic DNA extracted from FFPE tumor samples. All mutations were detected with elevated inter-laboratory and inter-run reproducibility. Importantly, we could detect clinically actionable alterations in FFPE samples with variant allele frequencies as low as 1%. In addition, the overall molecular diagnosis rate was increased from 40.7% with conventional techniques to 59.2% with our NGS panel, including 41 novel actionable alterations normally not explored by conventional techniques. Taken together, we believe that this new actionable target panel represents a relevant, highly scalable and robust tool that is easy to implement and is fully adapted to daily clinical practice in hospital and academic laboratories