ABSTRACT
As one of the main pathmechanisms of Alzheimer's disease (AD), amyloid-ß (Aß) is widely considered to be the prime target for the development of AD therapy. Recently, imidazolylacetophenone oxime ethers or esters (IOEs) have shown neuroprotective effects against neuronal cells damage, suggesting their potential use in the prevention and treatment of AD. Thirty IOEs compounds from our lab in-house library were constructed and screened for the inhibitory effects on Aß42-induced cytotoxicity. Among them, TJ1, as a new IOEs hit, preliminarily showed the effect on inhibiting Aß42-induced cytotoxicity. Furthermore, the inhibitory effects of TJ1 on Aß42 aggregation were tested by ThT assays and TEM. The neuroprotective effects of TJ1 were evaluated in Aß42-stimulated SH-SY5Y cells, LPS-stimulated BV-2 cells, and H2O2- and RSL3-stimulated PC12 cells. The cognitive improvement of TJ1 was assessed in 5xFAD (C57BL/6J) transgenic mouse. These results showed that TJ1 had strong neuroprotective effects and high blood-brain barrier (BBB) permeability without obvious cytotoxicity. TJ1 impeded the self-accumulation process of Aß42 by acting on Aß oligomerization and fibrilization. Besides, TJ1 reversed Aß-, H2O2- and RSL3-induced neuronal cell damage and decreased neuroinflammation. In 5xFAD mice, TJ1 improved cognitive impairment, increased GSH level, reduced the level of Aß42 and Aß plaques, and attenuated the glia reactivation and inflammatory response in the brain,. Taken together, our results demonstrate that TJ1 improves cognitive impairments as a new neuroprotective candidate via targeting amyloidogenesis, which suggests the potential of TJ1 as a treatment for AD.
Subject(s)
Alzheimer Disease , Amyloid beta-Peptides , Blood-Brain Barrier , Disease Models, Animal , Mice, Inbred C57BL , Mice, Transgenic , Neuroprotective Agents , Animals , Alzheimer Disease/drug therapy , Alzheimer Disease/metabolism , Amyloid beta-Peptides/metabolism , Neuroprotective Agents/pharmacology , Neuroprotective Agents/therapeutic use , Humans , Mice , Rats , Blood-Brain Barrier/drug effects , Blood-Brain Barrier/metabolism , Peptide Fragments/metabolism , PC12 Cells , Neurons/drug effects , Neurons/metabolism , Neurons/pathology , Oximes/pharmacology , Oximes/therapeutic use , Cell Line, Tumor , MaleABSTRACT
BACKGROUND: Indoleamine 2,3-dioxygenase 1 (IDO1) levels correlate with poor outcomes in urothelial carcinoma (UC). IDO1 and programmed death-ligand 1 (PD-L1) are often co-expressed. Epacadostat is a potent and highly selective inhibitor of IDO1. In a subgroup analysis of patients with advanced UC participating in a phase I/II study, epacadostat-pembrolizumab treatment produced an objective response rate (ORR) of 35%. METHODS: ECHO-303/KEYNOTE-698 was a double-blinded, randomized phase III study of adults with metastatic or unresectable locally advanced UC with recurrence or progression following first-line platinum-based chemotherapy. Participants were randomized to epacadostat 100 mg twice daily (BID) plus pembrolizumab or placebo plus pembrolizumab until completion of 35 pembrolizumab infusions, disease progression, or unacceptable toxicity. The primary endpoint was investigator-assessed ORR per Response Evaluation Criteria in Solid Tumors version 1.1. RESULTS: Target enrollment was 648 patients; enrollment was halted early based on efficacy results from the phase III ECHO-301/KEYNOTE-252 study in metastatic melanoma. Forty-two patients were randomized to each treatment arm. Median duration of follow-up was 62 days in each arm. The investigator-assessed ORR (unconfirmed) was 26.2% (95% CI 16.35-48.11) for epacadostat plus pembrolizumab and 11.9% (95% CI 4.67-29.50) for placebo plus pembrolizumab. Two complete responses were reported, both in the placebo-plus-pembrolizumab arm. Circulating kynurenine levels increased from C1D1 to C2D1 in the placebo-plus-pembrolizumab arm and numerically decreased in the epacadostat-plus-pembrolizumab arm. The safety profile of epacadostat plus pembrolizumab was similar to that of pembrolizumab monotherapy, although a numerically greater proportion of patients in the combination vs. control arm experienced treatment-related grade ≥ 3 adverse events (16.7% vs. 7.3%). One patient in each arm died due to cardiovascular events, which were not deemed drug-related. No new safety concerns were identified for either agent. CONCLUSIONS: Epacadostat plus pembrolizumab demonstrated anti-tumor activity and was generally tolerable as second-line treatment of patients with unresectable locally advanced or recurrent/progressive metastatic UC. Epacadostat 100 mg BID, when administered with pembrolizumab, did not normalize circulating kynurenine in most patients. Further study of combined IDO1/PD-L1 inhibition in this patient population, particularly with epacadostat doses that result in durable normalization of circulating kynurenine, may be warranted. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03374488. Registered 12/15/2017.
Subject(s)
Antibodies, Monoclonal, Humanized , Antineoplastic Combined Chemotherapy Protocols , Sulfonamides , Humans , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/therapeutic use , Male , Female , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Aged , Middle Aged , Double-Blind Method , Sulfonamides/administration & dosage , Sulfonamides/therapeutic use , Oximes/administration & dosage , Oximes/therapeutic use , Carcinoma, Transitional Cell/drug therapy , Carcinoma, Transitional Cell/pathology , Aged, 80 and over , Adult , Indoleamine-Pyrrole 2,3,-Dioxygenase/antagonists & inhibitors , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism , Urologic Neoplasms/drug therapy , Urologic Neoplasms/pathology , Urinary Bladder Neoplasms/drug therapy , Urinary Bladder Neoplasms/pathologyABSTRACT
BACKGROUND: Pembrolizumab is a first-line therapy for certain patients with advanced/metastatic non-small cell lung cancer (NSCLC). Combining pembrolizumab with other immunotherapies may enhance tumor cell killing and clinical outcomes. Epacadostat is a selective inhibitor of indoleamine 2,3-dioxygenase 1, an immuno-regulatory enzyme involved in tryptophan to kynurenine metabolism that inhibits T cell-mediated immune responses. METHODS: In this randomized phase II study, patients with metastatic NSCLC expressing high (≥ 50%) programmed death-ligand 1 (PD-L1) levels received pembrolizumab 200 mg every 21 days plus oral epacadostat 100 mg twice daily (combination) or matching placebo (control). The primary objective was objective response rate (ORR); secondary objectives were progression-free survival (PFS), overall survival (OS), duration of response (DOR) and safety/tolerability. RESULTS: 154 patients were randomized (77 per group). Median (range) follow-up was 6.8 months (0.1-11.4) and 7.0 months (0.2-11.9) in the combination and control groups, respectively Confirmed ORR was similar between groups (combination: 32.5%, 95% CI 22.2-44.1; control: 39.0%, 95% CI 28.0-50.8; difference: - 6.5, 95% CI - 21.5 to 8.7; 1-sided P = 0.8000). Median (range) DOR was 6.2 months (1.9 + to 6.5 +) and not reached (1.9 + to 8.6 +) in the combination and control groups, respectively. Although not formally tested, median PFS was 6.7 and 6.2 months for the combination and control groups, respectively, and median OS was not reached in either group. Circulating kynurenine levels increased from C1D1 to C2D1 (P < 0.01) in the control group and decreased from C1D1 to C2D1 (P < 0.01) in the combination group but were not normalized in most patients. The most frequent serious adverse events (AEs) (≥ 2%) were pneumonia (4.0%), anemia (2.7%), atelectasis (2.7%) and pneumonitis (2.7%) in the combination group and pneumonia (3.9%), pneumonitis (2.6%) and hypotension (2.6%) in the control group. Two deaths due to drug-related AEs were reported, both in the control group. CONCLUSIONS: Addition of epacadostat to pembrolizumab therapy for PD-L1-high metastatic NSCLC was generally well tolerated but did not demonstrate an improved therapeutic effect. Evaluating higher doses of epacadostat that normalize kynurenine levels when given in combination with checkpoint inhibitors may be warranted. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03322540. Registered 10/26/2017.
Subject(s)
Antibodies, Monoclonal, Humanized , Antineoplastic Combined Chemotherapy Protocols , B7-H1 Antigen , Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Sulfonamides , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Non-Small-Cell Lung/mortality , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Monoclonal, Humanized/adverse effects , Male , Female , Middle Aged , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Lung Neoplasms/mortality , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Double-Blind Method , B7-H1 Antigen/antagonists & inhibitors , Sulfonamides/administration & dosage , Sulfonamides/therapeutic use , Sulfonamides/adverse effects , Adult , Oximes/administration & dosage , Oximes/therapeutic use , Oximes/adverse effects , Aged, 80 and over , Progression-Free SurvivalABSTRACT
A 76-year-old female patient presented with an iodine-refractory papillary thyroid carcinoma (PTC), diagnosed eight years earlier, with several lymph node recurrences requiring successive surgeries. Fluorodeoxyglucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT) imaging revealed a new unresectable loco-regional recurrence. The patient was diagnosed with a somatic BRAF V600E mutation. Therefore, dabrafenib and trametinib combination therapy was introduced and closely monitored by a dedicated multidisciplinary team, involving pharmaceutical consultations. As early as six weeks after treatment initiation, the patient reported multiple adverse events (AEs) to the clinical pharmacy team, who provided advice on resolving AEs or improving tolerance. Close interprofessional collaboration among healthcare workers involved in the care pathway allowed for the identification of the most opportune times for temporary suspension of treatment (four suspensions over seven months) or dose reduction (two reductions over 3.5 months). This resulted in a total treatment duration (one year) longer than the average times reported in the literature. The patient showed a rapid and excellent response to treatment immediately after initiation, culminating in a complete metabolic response assessed by [18F]FDG PET/CT imaging at nine months. Twenty-five months after treatment discontinuation, the disease remained controlled. Overall, dabrafenib and trametinib combination could offer excellent outcomes in selected patients with refractory BRAF-mutated PTC, with additional clinical pharmacy initiatives allowing for the optimized management of AEs and prolonged treatment periods.
Subject(s)
Imidazoles , Oximes , Pyridones , Pyrimidinones , Thyroid Neoplasms , Humans , Female , Oximes/therapeutic use , Oximes/administration & dosage , Imidazoles/therapeutic use , Imidazoles/administration & dosage , Pyridones/therapeutic use , Pyridones/administration & dosage , Aged , Pyrimidinones/therapeutic use , Pyrimidinones/administration & dosage , Thyroid Neoplasms/drug therapy , Positron Emission Tomography Computed Tomography/methods , Iodine Radioisotopes/therapeutic use , Iodine Radioisotopes/administration & dosage , Thyroid Cancer, Papillary/drug therapy , Treatment Outcome , Proto-Oncogene Proteins B-raf/geneticsABSTRACT
BACKGROUND: Sarcopenia, characterized by progressive muscle dysfunction, is a common complication of chronic obstructive pulmonary disease (COPD). Our previous study revealed serum Lipoprotein-associated phospholipaseA2 (Lp-PLA2) level significantly increased in COPD and associated with exercise tolerance. This study further investigated the functions and target potential of Lp-PLA2 for sarcopenia in COPD. METHODS: The circulating Lp-PLA2 level/enzyme activity in COPD patients and age-matched healthy volunteers were measured. Clinical parameters on skeletal muscle were measured and their correlations with Lp-PLA2 were analyzed. We explored the involvement of Lp-PLA2 in vivo and treatment effectiveness of darapladib (a specific Lp-PLA2 inhibitor) in CS-induced muscle dysfunction models. RESULTS: Circulating Lp-PLA2 level/enzyme activity was elevated in COPD patients compared with healthy controls, negatively associated with skeletal muscle mass and function. In CS-induced muscle dysfunction murine models, up-regulated serum Lp-PLA2 level/enzyme activity was verified again. In CS-exposed mouse models, darapladib treatment reversed muscle mass loss and muscle dysfunction, meanwhile rescued upregulation of MuRF1 and atrogin-1, and activation of inflammatory factors, oxidant enzymes and NF-κB signaling. CONCLUSIONS: Lp-PLA2 could be a potential indicator for sarcopenia in COPD. Darapladib, a Lp-PLA2 inhibitor, can alleviate CS-induced skeletal muscle dysfunction and represents a potential therapeutic for sarcopenia in COPD.
Subject(s)
1-Alkyl-2-acetylglycerophosphocholine Esterase , Pulmonary Disease, Chronic Obstructive , Sarcopenia , Pulmonary Disease, Chronic Obstructive/drug therapy , Pulmonary Disease, Chronic Obstructive/complications , Humans , Sarcopenia/drug therapy , Sarcopenia/etiology , 1-Alkyl-2-acetylglycerophosphocholine Esterase/metabolism , 1-Alkyl-2-acetylglycerophosphocholine Esterase/blood , Male , Animals , Mice , Female , Aged , Middle Aged , Muscle, Skeletal/metabolism , Muscle, Skeletal/drug effects , Benzaldehydes/pharmacology , Benzaldehydes/therapeutic use , Oximes/therapeutic use , Oximes/pharmacology , Biomarkers/blood , Disease Models, Animal , Biphenyl Compounds , Diethylamines , Pyrimidinones , SulfidesABSTRACT
The over-activation of tryptophan (Trp) metabolism to kynurenine (Kyn) catalyzed by Indoleamine 2,3-dioxygenase-1 (IDO1) enzyme, is one of the main metabolic pathways involved in tumor microenvironment (TME) immune escape and cancer treatment failure. The most efficient of IDO1 inhibitors is Epacadostat (EPA). Since monotherapy with single-agent IDO1 inhibitor regimen has led to an insufficient anti-tumor activity, we examined the efficacy of simultaneous treatment by Liposomal epacadostat (Lip-EPA) as a potent IDO inhibitor, in combination with docetaxel (DTX) as a complement immunogenic cell death (ICD) agent against B16F10 model. First, the in vitro combination index (CI) of epacadostat (EPA) and DTX was investigated by using the unified theory. Then, the in vivo efficacy of the combination therapy was assessed. Results indicated the synergestic cytotoxic effect of the combination on B16F10 compared to normal fibroblast cells (NIH). The immune profiling demonstrated a significant increase in the percentage of infiltrated T lymphocytes and IFN-γ release, a significant decrease in the percentage of regulatory T cells (Treg) population and the subsequent low levels of IL-10 generation in mice treated with Lip-EPA + DTX. Further, a significant tumor growth delay (TGD = 69.15 %) and an increased life span (ILS > 47.83 %) was observed with the combination strategy. Histopathology analysis revealed a remarkable increase in the Trp concentration following combination treatment, while Kyn levels significantly decreased. Results showed that the nano-liposomal form of IDO1 inhibitor in combination with chemotherapy could significantly improve the imunity response and dominate the tumor immuno-suppressive micro-environment, which merits further investigations.
Subject(s)
Docetaxel , Indoleamine-Pyrrole 2,3,-Dioxygenase , Liposomes , Melanoma, Experimental , Mice, Inbred C57BL , Sulfonamides , Tumor Microenvironment , Animals , Indoleamine-Pyrrole 2,3,-Dioxygenase/antagonists & inhibitors , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism , Docetaxel/pharmacology , Docetaxel/therapeutic use , Tumor Microenvironment/drug effects , Tumor Microenvironment/immunology , Melanoma, Experimental/drug therapy , Melanoma, Experimental/immunology , Sulfonamides/pharmacology , Sulfonamides/administration & dosage , Sulfonamides/therapeutic use , Mice , Cell Line, Tumor , Immunotherapy/methods , Oximes/pharmacology , Oximes/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Humans , Female , Nanoparticles , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic useABSTRACT
INTRODUCTION: Mitogen-activated extracellular signal-regulated kinase (MEK) inhibitors are in use for several indications for adults and children. Cutaneous toxicities are among the most common adverse effects. We aimed to describe the spectrum of cutaneous adverse events, its frequency, and severity in a cohort of pediatric patients. METHODS: We reviewed all records of patients in our tertiary treatment center treated with MEK inhibitors between January 2016 and January 2023 for all indications. RESULTS: Among 33 patients, 76% reported cutaneous adverse effects. The highest prevalence was in the group of patients treated with trametinib (90%), followed by the group treated with selumetinib (50%) and the group treated with a combination of trametinib and B-Raf proto-oncogene serine/threonine-protein kinase inhibitor (dabrafenib, 34%). Xerosis, dermatitis, paronychia, and hair heterochromia were most frequently reported. Severity was graded 1 or 2 for most adverse events, and 237 visits to the dermatology clinic related to these adverse events were recorded. CONCLUSIONS: Cutaneous adverse events are common in the pediatric population as in adults, but the clinical spectrum is different. Although considered mild, multiple dermatological consultations reflect the distress caused by these events. Dermatologists have a central role in the multidisciplinary care of pediatric patients receiving these agents.
Subject(s)
Drug Eruptions , Protein Kinase Inhibitors , Proto-Oncogene Mas , Humans , Retrospective Studies , Male , Female , Child , Adolescent , Child, Preschool , Drug Eruptions/etiology , Protein Kinase Inhibitors/adverse effects , Pyridones/adverse effects , Pyrimidinones/adverse effects , Infant , Severity of Illness Index , Imidazoles/adverse effects , Oximes/adverse effects , Oximes/therapeutic use , Benzimidazoles/adverse effects , Paronychia/chemically inducedABSTRACT
Although dabrafenib plus trametinib has been approved for BRAF V600E mutation positive advanced non-small cell lung cancer (NSCLC), data on its efficacy against uncommon BRAF mutations are still limited due to their rare frequency. We report a case of 70-year-old woman with BRAF V600_W604 deletion-insertion R-positive stage IVA lung adenocarcinoma, who was successfully treated with dabrafenib plus trametinib. Herein, we discuss the oncogenic role of uncommon BRAF mutations and highlight the importance of performing comprehensive genomic profiling on patients without any targetable gene alterations in companion diagnostics.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Carcinoma, Non-Small-Cell Lung , Imidazoles , Lung Neoplasms , Oximes , Proto-Oncogene Proteins B-raf , Pyridones , Pyrimidinones , Aged , Female , Humans , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Imidazoles/therapeutic use , Imidazoles/administration & dosage , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Mutation , Oximes/therapeutic use , Oximes/administration & dosage , Proto-Oncogene Proteins B-raf/genetics , Pyridones/therapeutic use , Pyridones/administration & dosage , Pyrimidinones/therapeutic use , Pyrimidinones/administration & dosageABSTRACT
The combination therapy of v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) and mitogen-activated protein kinase kinase (MEK) inhibitors is approved for treating patients with BRAF V600E-positive tumours, including melanoma and lung cancer. Several case reports indicated autoimmune side effects associated with the use of BRAF and MEK inhibitors. Still, the effects of these drugs on the immune system were not fully elucidated. Here, we report a patient with large-vessel vasculitis diagnosed after initiation of treatment with dabrafenib and trametinib for BRAF V600E-positive metastatic lung adenocarcinoma. She was a never-smoker woman in her early 70s who presented with a chronic cough and was diagnosed with BRAF V600E-positive metastatic lung adenocarcinoma by transbronchial lung biopsy. She was successfully treated with prednisolone and methotrexate while BRAF and MEK inhibitors were continued. We should be careful about autoimmune diseases using BRAF and MEK inhibitors.
Subject(s)
Adenocarcinoma of Lung , Imidazoles , Lung Neoplasms , Oximes , Protein Kinase Inhibitors , Proto-Oncogene Proteins B-raf , Pyridones , Pyrimidinones , Vasculitis , Humans , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Proto-Oncogene Proteins B-raf/genetics , Female , Pyridones/adverse effects , Pyridones/therapeutic use , Pyrimidinones/therapeutic use , Pyrimidinones/adverse effects , Lung Neoplasms/drug therapy , Aged , Adenocarcinoma of Lung/drug therapy , Imidazoles/adverse effects , Imidazoles/therapeutic use , Oximes/adverse effects , Oximes/therapeutic use , Vasculitis/chemically induced , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/therapeutic use , Prednisolone/therapeutic use , Methotrexate/therapeutic use , Methotrexate/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic useABSTRACT
This report highlights the first pediatric case of pilocytic astrocytoma with BRAF V599ins mutation, successfully treated with dabrafenib.
Subject(s)
Astrocytoma , Imidazoles , Oximes , Proto-Oncogene Proteins B-raf , Humans , Astrocytoma/drug therapy , Astrocytoma/genetics , Proto-Oncogene Proteins B-raf/genetics , Oximes/therapeutic use , Imidazoles/therapeutic use , Mutation , Brain Neoplasms/drug therapy , Brain Neoplasms/genetics , Male , Female , ChildABSTRACT
Lenvatinib is a multi-target inhibitor that exerts anti-tumor effects by inhibiting angiogenesis and is now commonly used as a first-line treatment for hepatocellular carcinoma. However, with the widespread use of lenvatinib, the problem of serious and fatal hepatotoxicity has become increasingly prominent. Currently, the mechanism behind this toxicity is not yet understood, and as a result, there is a lack of safe and effective intervention strategies with minimal side effects. Here, we established the model of lenvatinib-induced liver injury in vivo and in vitro and found that lenvatinib caused hepatotoxicity by inducing apoptosis. Further mechanistic studies in cellular models revealed that lenvatinib upregulated death receptor signaling pathway, which activated the downstream effector Caspase-8, and ultimately led to apoptosis. Meanwhile, lenvatinib-induced apoptosis was associated with ROS generation and DNA damage. In addition, after screening marketed drugs and natural products in combination with cellular modeling, we identified a potential co-administered drug, dabrafenib, which could alleviate lenvatinib-induced hepatotoxicity. Further mechanistic studies revealed that dabrafenib attenuated lenvatinib-induced hepatotoxicity by inhibiting the activation of the death receptor signaling pathway. Subsequently, cancer cell proliferation assays confirmed that dabrafenib did not antagonize the antitumor effects of lenvatinib. In conclusion, our results validate that apoptosis caused by the death receptor signaling pathway is the key cause of lenvatinib-induced hepatotoxicity, and dabrafenib alleviates lenvatinib-induced hepatotoxicity by inhibiting this pathway.
Subject(s)
Apoptosis , Chemical and Drug Induced Liver Injury , Imidazoles , Oximes , Phenylurea Compounds , Quinolines , Signal Transduction , Quinolines/pharmacology , Animals , Chemical and Drug Induced Liver Injury/prevention & control , Chemical and Drug Induced Liver Injury/etiology , Chemical and Drug Induced Liver Injury/metabolism , Oximes/pharmacology , Oximes/therapeutic use , Signal Transduction/drug effects , Phenylurea Compounds/pharmacology , Humans , Apoptosis/drug effects , Imidazoles/pharmacology , Mice , Male , Receptors, Death Domain/metabolism , Antineoplastic Agents/toxicity , Liver/drug effects , Liver/metabolism , Liver/pathology , Hep G2 CellsABSTRACT
Background: Metastatic neuroendocrine carcinoma (NEC) is associated with short survival. Other than platinum-based chemotherapy, there is no clear standard regimen. Current guidelines suggest that combination treatment with BRAF-inhibitors should be considered for patients with BRAF V600E-mutated NEC. However, since only eight such patients have been reported in the literature, our object was to confirm the validity of this recommendation. Methods: This was a single-center retrospective cohort study conducted at Uppsala University Hospital. The included patients 1) had a histopathologically confirmed diagnosis of NEC, 2) were diagnosed between January 1st, 2018 and December 31st, 2023, 3) had tumor tissue genetically screened by a broad next-generation sequencing (NGS) panel, and 4) showed a tumor mutation for which there is a currently available targeted therapy. Results: We screened 48 patients diagnosed with NEC between January 1st, 2018 and December 31st, 2023. Twelve had been analyzed with a broad NGS-panel, and two had a targetable mutation. Both these patients harbored a BRAF V600E-mutated colon-NEC and were treated with BRAF- and MEK-inhibitors dabrafenib and trametinib in second-line. At first radiological evaluation (RECIST 1.1), both patients had a reduction of tumor size, which decreased by 31 and 40%. Both had short response periods, and their overall survival was 12 and 9 months. Conclusions: BRAF-mutated NEC is sensitive to treatment with BRAF- and MEK-inhibitor combination. These results further support that DNA sequencing should be considered as standard of care in NECs to screen for potential treatment targets.
Subject(s)
Carcinoma, Neuroendocrine , Oximes , Protein Kinase Inhibitors , Proto-Oncogene Proteins B-raf , Pyridones , Pyrimidinones , Adult , Aged , Female , Humans , Male , Middle Aged , Carcinoma, Neuroendocrine/genetics , Carcinoma, Neuroendocrine/drug therapy , High-Throughput Nucleotide Sequencing , Imidazoles/therapeutic use , Imidazoles/administration & dosage , Mutation , Oximes/therapeutic use , Oximes/administration & dosage , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins B-raf/genetics , Pyridones/therapeutic use , Pyridones/administration & dosage , Pyrimidinones/therapeutic use , Retrospective Studies , Treatment OutcomeSubject(s)
Guillain-Barre Syndrome , Imidazoles , Oximes , Pyridones , Pyrimidinones , Humans , Pyridones/adverse effects , Pyridones/therapeutic use , Pyrimidinones/adverse effects , Pyrimidinones/therapeutic use , Oximes/adverse effects , Oximes/therapeutic use , Imidazoles/adverse effects , Imidazoles/therapeutic use , Guillain-Barre Syndrome/drug therapy , Melanoma/drug therapy , Female , Male , Middle Aged , Antineoplastic Agents/adverse effects , Antineoplastic Agents/therapeutic useABSTRACT
Multiple sclerosis is an autoimmune disease that causes inflammatory damage to the central nervous system. At present, the pathogenesis of the disease is unknown. There is a lack of few effective therapy medications available. Therefore, it is necessary to further explore the pathogenesis of this illness and develop potential therapeutic drugs. Dabrafenib is potential therapeutic medicine for nervous system disease. In this study, we preliminarily studied the possible mechanism of dabrafenib in the treatment of multiple sclerosis from the perspective of ferroptosis. First, we observed that dabrafenib significantly improved symptoms of gait abnormalities, limb weakness or paralysis, and down-regulated levels of spinal cord inflammation in an experimental autoimmune encephalitis (EAE) model. Meanwhile, we also observed that dabrafenib could inhibit the proteins of ferroptosis in spinal cord tissue of EAE mice by Western blot. The results of immunohistochemical analysis showed that the effect of dabrafenib on ferroptosis mainly occurred in microglia. Second, dabrafenib was demonstrated to be able to inhibit the S phase of the cell cycle, reduce ROS levels, and reinstate mitochondrial activity in the LPS-induced BV2 inflammatory cell model. Futhermore, we found that dabrafenib inhibits P-JAK2 and P-STAT3 activation by acting Axl receptor, which in turn prevents neurogenic inflammation in microglia. The co-stimulated BV2 cell model with LPS and Erastin also verified these findings. Ultimately, the Axl knockout mice used to construct the EAE model allowed for the confirmation that dabrafenib prevented ferroptosis in microglia by up-regulating Axl receptor, which reduced the inflammatory demyelination associated with EAE. In summary, our research demonstrates the advantages of dabrafenib in multiple sclerosis treatment, which can prevent ferroptosis in microglia in multiple sclerosis through up-regulating Axl receptor, thus halting the progression of multiple sclerosis.
Subject(s)
Axl Receptor Tyrosine Kinase , Encephalomyelitis, Autoimmune, Experimental , Ferroptosis , Imidazoles , Oximes , Proto-Oncogene Proteins , Receptor Protein-Tyrosine Kinases , Up-Regulation , Animals , Imidazoles/pharmacology , Imidazoles/therapeutic use , Encephalomyelitis, Autoimmune, Experimental/drug therapy , Encephalomyelitis, Autoimmune, Experimental/pathology , Encephalomyelitis, Autoimmune, Experimental/metabolism , Ferroptosis/drug effects , Proto-Oncogene Proteins/metabolism , Mice , Oximes/pharmacology , Oximes/therapeutic use , Receptor Protein-Tyrosine Kinases/metabolism , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Up-Regulation/drug effects , Mice, Inbred C57BL , Female , Microglia/drug effects , Microglia/metabolism , Microglia/pathology , STAT3 Transcription Factor/metabolism , Cell Line , Spinal Cord/drug effects , Spinal Cord/pathology , Spinal Cord/metabolism , Neuroinflammatory Diseases/drug therapy , Neuroinflammatory Diseases/pathology , Neuroinflammatory Diseases/metabolism , Signal Transduction/drug effectsABSTRACT
The first organophosphorus nerve agent was discovered accidently during the development of pesticides, shortly after the first use of chemical weapons (chlorine, phosgene) on the battlefield during World War I. Despite the Chemical Weapons Convention banning these substances, they have still been employed in wars, terrorist attacks or political assassinations. Characterised by their high lethality, they target the nervous system by inhibiting the acetylcholinesterase (AChE) enzyme, preventing neurotransmission, which, if not treated rapidly, inevitably leads to serious injury or the death of the person intoxicated. The limited efficacy of current antidotes, known as AChE reactivators, pushes research towards new treatments. Numerous paths have been explored, from modifying the original pyridinium oximes to developing hybrid reactivators seeking a better affinity for the inhibited AChE. Another crucial approach resides in molecules more prone to cross the blood-brain barrier: uncharged compounds, bio-conjugated reactivators or innovative formulations. Our aim is to raise awareness on the threat and toxicity of organophosphorus nerve agents and to present the main synthetic efforts deployed since the first AChE reactivator, to tackle the task of efficiently treating victims of these chemical warfare agents.
Subject(s)
Nerve Agents , Organophosphorus Compounds , Humans , Nerve Agents/toxicity , Organophosphorus Compounds/toxicity , Animals , Cholinesterase Reactivators/pharmacology , Cholinesterase Reactivators/therapeutic use , Cholinesterase Reactivators/chemistry , Medical Countermeasures , Acetylcholinesterase/metabolism , Cholinesterase Inhibitors/toxicity , Chemical Warfare Agents/toxicity , Antidotes/pharmacology , Antidotes/therapeutic use , Oximes/pharmacology , Oximes/therapeutic use , Oximes/chemistryABSTRACT
Although generally well tolerated compared with chemotherapy, molecular targeted therapy used in metastatic melanoma may be associated with life-threatening toxicity. We report the case of a patient with metastatic melanoma treated by dabrafenib plus trametinib who developed intracranial hemorrhage. Physicians should be aware of this rare but life-threatening adverse event of B-rapidly accelerated fibrosarcoma (BRAF) and mitogen-activated protein kinase kinase (MEK) inhibitors. However, they should be also careful about the bleeding origin, which can prove to be a new onset of melanoma metastasis or anticoagulation overdose, or even an uncontrolled arterial hypertension.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Intracranial Hemorrhages , Melanoma , Humans , Male , Middle Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Imidazoles/therapeutic use , Intracranial Hemorrhages/chemically induced , Melanoma/drug therapy , Melanoma/complications , Oximes/therapeutic use , Pyridones/therapeutic use , Pyrimidinones/therapeutic use , Skin Neoplasms/drug therapy , Skin Neoplasms/pathologyABSTRACT
PURPOSE: Understanding the function of BRAF mutants is crucial for determining the best treatment strategy. This study aimed to characterize a rare BRAF variant, BRAFThr599dup, which was identified in a patient with lung adenocarcinoma (LUAD) by comprehensive genomic profiling. MATERIALS AND METHODS: We report a case of LUAD with BRAFThr599dup treated with dabrafenib and trametinib. We conditionally expressed wild-type BRAF, BRAFV600E, or BRAFThr599dup in Ba/F3 cells and BEAS-2B cells. Ba/F3 cells carrying double-mutant BRAF (BRAFThr599dup/R509H, BRAFV600E/R509H, or BRAFK601E/R509H) that lacked the dimerizing ability were also established. Knockout of endogenous BRAF or CRAF in Ba/F3-BRAFThr599dup cells and Ba/F3-BRAFV600E cells was performed using the CRISPR/Cas9 system. Cell viability, mitogen-activated protein kinase (MAPK) signaling activity, and sensitivity to dabrafenib and trametinib were evaluated. RESULTS: The patient was revealed to have BRAFThr599dup-positive tumor cells as a predominant clone, and dabrafenib and trametinib treatment showed modest efficacy. In Ba/F3 cells, both BRAFThr599dup and BRAFV600E similarly caused interleukin-3-independent proliferation and activated the MAPK pathway. Moreover, BRAFThr599dup and BRAFV600E similarly caused a significant increase in the anchorage-independent growth ability of BEAS-2B cells. Along with Ba/F3-BRAFV600E cells, Ba/F3-BRAFThr599dup cells were highly sensitive to a monomer-specific BRAF inhibitor, dabrafenib, with a half-maximal inhibitory concentration value of 29.7 nM. In the absence of wild-type BRAF, wild-type CRAF, or an intact dimer interface, the ability to induce oncogenic addiction and MAPK pathway activation in Ba/F3-BRAFThr599dup cells was not affected, which was in contrast to the findings in the BRAFK601E/R509H double-mutant model. CONCLUSION: BRAFThr599dup is a potent driver oncogene that activates the MAPK pathway without the requirement for dimerization in vitro. Because BRAFThr599dup has been recurrently reported across various cancer types, our findings should be further investigated both mechanistically and clinically.
Subject(s)
Adenocarcinoma of Lung , Lung Neoplasms , Mutation , Proto-Oncogene Proteins B-raf , Humans , Proto-Oncogene Proteins B-raf/genetics , Adenocarcinoma of Lung/genetics , Adenocarcinoma of Lung/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/drug therapy , Pyrimidinones/therapeutic use , Imidazoles/therapeutic use , Pyridones/therapeutic use , Oximes/therapeutic use , Female , MaleABSTRACT
Oral and maxillofacial tumors pose a significant clinical challenge due to their tendency to recur, despite advancements in surgical removal techniques. The jaw's intricate structure further complicates treatments and affects patient quality of life. Consequently, emphasis has shifted towards pharmacological interventions, to potentially reduce invasive surgical procedures. One promising approach targets BRAF mutations, specifically the common V600E mutation. BRAF, a critical protein kinase, regulates cell growth and differentiation via the RAS-RAF-MEK-ERK-MAP kinase pathway. A specific nucleotide change at position 1799, swapping Thymine (T) for Adenine (A), results in the V600E mutation, causing unchecked cell growth. This mutation is common in certain oral and maxillofacial tumors like ameloblastoma. A recent neoadjuvant therapy targeting BRAF, involving the use of dabrafenib and trametinib, has showcased a promising, safe, and effective strategy for organ preservation in the treatment of mandibular ameloblastoma. This convergence of molecular insights and targeted therapies holds the key to managing BRAF-mutated oral and maxillofacial tumors effectively, promising improved patient outcomes.
Subject(s)
Ameloblastoma , Mutation , Proto-Oncogene Proteins B-raf , Humans , Proto-Oncogene Proteins B-raf/genetics , Ameloblastoma/genetics , Ameloblastoma/therapy , Ameloblastoma/diagnosis , Imidazoles/therapeutic use , Oximes/therapeutic use , Pyridones/therapeutic use , Pyridones/administration & dosage , Pyrimidinones/therapeutic use , Antineoplastic Agents/therapeutic use , Mouth Neoplasms/therapy , Mouth Neoplasms/genetics , Mouth Neoplasms/pathology , Neoadjuvant Therapy/methods , Molecular Targeted TherapyABSTRACT
BACKGROUND: Pembrolizumab plus epacadostat (indoleamine 2,3-dioxygenase-1 inhibitor) was well tolerated in Japanese patients with advanced solid tumors in part A of the nonrandomized, open-label, phase 1 KEYNOTE-434 study (NCT02862457). We report results from part B, which evaluated epacadostat plus pembrolizumab and chemotherapy in Japanese patients with advanced non-small-cell lung cancer (NSCLC). METHODS: Eligible patients aged ≥ 20 years had histologically or cytologically confirmed stage IIIB or IV NSCLC with no prior systemic therapy, and ECOG performance status of 0 or 1. Patients received epacadostat 100 mg orally twice-daily, pembrolizumab 200 mg intravenously every-3-weeks for ≤ 35 cycles, and 4 cycles of chemotherapy (cohort 1: cisplatin plus pemetrexed, non-squamous; cohort 2: carboplatin plus pemetrexed, non-squamous; cohort 3: carboplatin plus paclitaxel, squamous or non-squamous). Primary endpoint was incidence of dose-limiting toxicities (DLTs). Following unfavorable results from other studies, a protocol amendment removed epacadostat from the treatment combination. RESULTS: Of 19 patients, 7 were enrolled in cohort 1, and 6 each in cohorts 2 and 3. Median follow-up was 13.7 (range, 4.2-27.8) months. Five of 17 (29%) DLT-evaluable patients experienced ≥ 1 DLT (cohort 1, n = 1; cohorts 2 and 3, n = 2 each); most commonly maculopapular rash (grade 3, n = 3) and increased alanine aminotransferase (grade 2, n = 1; grade 3, n = 2). All patients experienced treatment-related adverse events (AEs); 58% experienced grade 3 or 4 treatment-related AEs. Objective response rate was 47%. CONCLUSION: The combination of epacadostat plus pembrolizumab and chemotherapy was found to be tolerable in Japanese patients with advanced NSCLC. TRIAL REGISTRATION: ClinicalTrials.gov , NCT02862457.