RÉSUMÉ
BACKGROUND: Davoceticept (ALPN-202) is an Fc fusion of a CD80 variant immunoglobulin domain designed to mediate programmed death-ligand 1 (PD-L1)-dependent CD28 co-stimulation while inhibiting the PD-L1 and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) checkpoints. The safety and efficacy of davoceticept monotherapy and davoceticept and pembrolizumab combination therapy in adult patients with advanced solid tumors were explored in NEON-1 and NEON-2, respectively. METHODS: In NEON-1 (n=58), davoceticept 0.001-10 mg/kg was administered intravenous either once weekly (Q1W) or once every 3 weeks (Q3W). In NEON-2 (n=29), davoceticept was administered intravenously at 2 dose levels (0.1 or 0.3 mg/kg) Q1W or Q3W with pembrolizumab (400 mg once every 6 weeks). In both studies, primary endpoints included incidence of dose-limiting toxicities (DLT); type, incidence, and severity of adverse events (AEs) and laboratory abnormalities; and seriousness of AEs. Secondary endpoints included antitumor efficacy assessed using RECIST v1.1, pharmacokinetics, anti-drug antibodies, and pharmacodynamic biomarkers. RESULTS: The incidence of treatment-related AEs (TRAEs) and immune-related adverse events (irAEs) was 67% (39/58) and 36% (21/58) with davoceticept monotherapy, and 62% (18/29) and 31% (9/29) with davoceticept and pembrolizumab combination, respectively. The incidence of ≥grade (Gr)3 TRAEs and ≥Gr3 irAEs was 12% (7/58) and 5% (3/58) with davoceticept monotherapy, and 24% (7/29) and 10% (3/29) with davoceticept and pembrolizumab combination, respectively. One DLT of Gr3 immune-related gastritis occurred during davoceticept monotherapy 3 mg/kg Q3W. During davoceticept combination with pembrolizumab, two Gr5 cardiac DLTs occurred; one instance each of cardiogenic shock (0.3 mg/kg Q3W, choroidal melanoma metastatic to the liver) and immune-mediated myocarditis (0.1 mg/kg Q3W, microsatellite stable metastatic colorectal adenocarcinoma), prompting early termination of both studies. Across both studies, five patients with renal cell carcinoma (RCC) exhibited evidence of clinical benefit (two partial response, three stable disease). CONCLUSIONS: Davoceticept was generally well tolerated as monotherapy at intravenous doses up to 10 mg/kg. Evidence of clinical activity was observed with davoceticept monotherapy and davoceticept in combination with pembrolizumab, notably in RCC. However, two fatal cardiac events occurred with the combination of low-dose davoceticept and pembrolizumab. Future clinical investigation with davoceticept should not consider combination with programmed death-1-inhibitor anticancer mechanisms, until its safety profile is more fully elucidated. TRIAL REGISTRATION NUMBER: NEON-1 (NCT04186637) and NEON-2 (NCT04920383).
Sujet(s)
Anticorps monoclonaux humanisés , Antigène CTLA-4 , Tumeurs , Humains , Anticorps monoclonaux humanisés/usage thérapeutique , Anticorps monoclonaux humanisés/pharmacologie , Mâle , Femelle , Tumeurs/traitement médicamenteux , Adulte d'âge moyen , Sujet âgé , Adulte , Antigène CTLA-4/antagonistes et inhibiteurs , Inhibiteurs de points de contrôle immunitaires/usage thérapeutique , Inhibiteurs de points de contrôle immunitaires/pharmacologie , Inhibiteurs de points de contrôle immunitaires/effets indésirables , Inhibiteurs de points de contrôle immunitaires/administration et posologie , Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Protocoles de polychimiothérapie antinéoplasique/pharmacologie , Antigène CD274/antagonistes et inhibiteurs , Antigène CD274/métabolisme , Sujet âgé de 80 ans ou plus , Antigène CD28RÉSUMÉ
dMMR tumors, which have high tumor mutational and neoantigen burdens, are highly responsive to immune checkpoint blockade. Wu et al.1 showed that combining COX inhibitors with PD-1 blockade could be a safe and effective treatment option for dMMR metastatic colorectal cancer. The study highlights the potential of this combination therapy in achieving deep and long-lasting responses in dMMR colorectal cancers.
Sujet(s)
Tumeurs colorectales , Inhibiteurs de points de contrôle immunitaires , Humains , Tumeurs colorectales/traitement médicamenteux , Tumeurs colorectales/génétique , Tumeurs colorectales/immunologie , Tumeurs colorectales/anatomopathologie , Inhibiteurs de points de contrôle immunitaires/usage thérapeutique , Inhibiteurs de points de contrôle immunitaires/pharmacologie , Inhibiteurs des cyclooxygénases/usage thérapeutique , Inhibiteurs des cyclooxygénases/pharmacologie , Récepteur-1 de mort cellulaire programmée/antagonistes et inhibiteurs , Présentation d'antigène/effets des médicaments et des substances chimiques , Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Protocoles de polychimiothérapie antinéoplasique/pharmacologieRÉSUMÉ
BACKGROUND: Cervical cancer has the second-highest mortality rate among malignant tumors of the female reproductive system. Immune checkpoint inhibitors such as programmed cell death protein 1 (PD-1) blockade are promising therapeutic agents, but their efficacy when combined with neoadjuvant chemotherapy (NACT) has not been fully tested, and how they alter the tumor microenvironment has not been comprehensively elucidated. METHODS: In this study, we conducted single-cell RNA sequencing using 46,950 cells from nine human cervical cancer tissues representing sequential different stages of NACT and PD-1 blockade combination therapy. We delineated the trajectory of cervical epithelial cells and identified the crucial factors involved in combination therapy. Cell-cell communication analysis was performed between tumor and immune cells. In addition, THP-1-derived and primary monocyte-derived macrophages were cocultured with cervical cancer cells and phagocytosis was detected by flow cytometry. The antitumor activity of blocking CD74 was validated in vivo using a CD74 humanized subcutaneous tumor model. RESULTS: Pathway enrichment analysis indicated that NACT activated cytokine and complement-related immune responses. Cell-cell communication analysis revealed that after NACT therapy, interaction strength between T cells and cancer cells decreased, but intensified between macrophages and cancer cells. We verified that macrophages were necessary for the PD-1 blockade to exert antitumor effects in vitro. Additionally, CD74-positive macrophages frequently interacted with the most immunoreactive epithelial subgroup 3 (Epi3) cancer subgroup during combination NACT. We found that CD74 upregulation limited phagocytosis and stimulated M2 polarization, whereas CD74 blockade enhanced macrophage phagocytosis, decreasing cervical cancer cell viability in vitro and in vivo. CONCLUSIONS: Our study reveals the dynamic cell-cell interaction network in the cervical cancer microenvironment influenced by combining NACT and PD-1 blockade. Furthermore, blocking tumor-associated macrophage-derived CD74 could augment neoadjuvant therapeutic efficacy.
Sujet(s)
Inhibiteurs de points de contrôle immunitaires , Traitement néoadjuvant , Macrophages associés aux tumeurs , Tumeurs du col de l'utérus , Tumeurs du col de l'utérus/traitement médicamenteux , Tumeurs du col de l'utérus/immunologie , Tumeurs du col de l'utérus/anatomopathologie , Humains , Femelle , Traitement néoadjuvant/méthodes , Macrophages associés aux tumeurs/métabolisme , Macrophages associés aux tumeurs/immunologie , Macrophages associés aux tumeurs/effets des médicaments et des substances chimiques , Souris , Animaux , Inhibiteurs de points de contrôle immunitaires/pharmacologie , Inhibiteurs de points de contrôle immunitaires/usage thérapeutique , Récepteur-1 de mort cellulaire programmée/antagonistes et inhibiteurs , Récepteur-1 de mort cellulaire programmée/métabolisme , Microenvironnement tumoral , Antigènes de différenciation des lymphocytes B/métabolisme , Protocoles de polychimiothérapie antinéoplasique/pharmacologie , Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Antigènes d'histocompatibilité de classe IIRÉSUMÉ
The combination of cisplatin and pemetrexed remains the gold standard chemotherapy for malignant pleural mesothelioma (MPM), although resistance and poor response pose a significant challenge. Cytidine deaminase (CDA) is a key enzyme in the nucleotide salvage pathway and is involved in the adaptive stress response to chemotherapy. The cytidine analog capecitabine and its metabolite 5'-deoxy-5-fluorocytidine (5'-DFCR) are converted via CDA to 5-fluorouracil, which affects DNA and RNA metabolism. This study investigated a schedule-dependent treatment strategy, proposing that initial chemotherapy induces CDA expression, sensitizing cells to subsequent capecitabine treatment. Basal CDA protein expression was low in different mesothelioma cell lines but increased in the corresponding xenografts. Standard chemotherapy increased CDA protein levels in MPM cells in vitro and in vivo in a schedule-dependent manner. This was associated with epithelial-to-mesenchymal transition and with HIF-1alpha expression at the transcriptional level. In addition, pretreatment with cisplatin and pemetrexed in combination sensitized MPM xenografts to capecitabine. Analysis of a tissue microarray (TMA) consisting of samples from 98 human MPM patients revealed that most human MPM samples had negative CDA expression. While survival curves based on CDA expression in matched samples clearly separated, significance was not reached due to the limited sample size. In non-matched samples, CDA expression before but not after neoadjuvant therapy was significantly associated with worse overall survival. In conclusion, chemotherapy increases CDA expression in xenografts, which is consistent with our in vitro results in MPM and lung cancer. A subset of matched patient samples showed increased CDA expression after therapy, suggesting that a schedule-dependent treatment strategy based on chemotherapy and capecitabine may benefit a selected MPM patient population.
Sujet(s)
Capécitabine , Cytidine deaminase , Mésothéliome malin , Pémétrexed , Tumeurs de la plèvre , Tests d'activité antitumorale sur modèle de xénogreffe , Humains , Capécitabine/pharmacologie , Animaux , Lignée cellulaire tumorale , Mésothéliome malin/traitement médicamenteux , Mésothéliome malin/métabolisme , Mésothéliome malin/anatomopathologie , Cytidine deaminase/métabolisme , Cytidine deaminase/génétique , Souris , Pémétrexed/pharmacologie , Tumeurs de la plèvre/traitement médicamenteux , Tumeurs de la plèvre/métabolisme , Tumeurs de la plèvre/anatomopathologie , Cisplatine/pharmacologie , Cisplatine/usage thérapeutique , Tumeurs du poumon/traitement médicamenteux , Tumeurs du poumon/métabolisme , Tumeurs du poumon/anatomopathologie , Transition épithélio-mésenchymateuse/effets des médicaments et des substances chimiques , Mésothéliome/traitement médicamenteux , Mésothéliome/métabolisme , Mésothéliome/anatomopathologie , Femelle , Protocoles de polychimiothérapie antinéoplasique/pharmacologie , Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Régulation de l'expression des gènes tumoraux/effets des médicaments et des substances chimiquesRÉSUMÉ
Rhabdomyosarcoma (RMS) is the most common childhood soft tissue sarcoma. For the alveolar subtype (ARMS), the presence of the PAX3::FOXO1 fusion gene and/or metastases are strong predictors of poor outcome. Metastatic PAX3::FOXO1+ ARMS often responds to chemotherapies initially, only to subsequently relapse and become resistant with most patients failing to survive beyond 8 years post-diagnosis. No curative intent phase II or phase III clinical trial has been available for patients in the past 10 years (ARST0921). Thus, metastatic ARMS represents a significantly unmet clinical need. Chemotherapy resistance in ARMS has previously been attributed to PAX3::FOXO1-mediated cell cycle checkpoint adaptation, which is mediated by an HDAC3-SMARCA4-miR-27a-PAX3::FOXO1 circuit that can be disrupted by HDAC3 inhibition. In this study, we investigated the therapeutic efficacy of combining the epigenetic regulator entinostat, a Class I Histone Deacetylase (HDAC1-3) inhibitor, with RMS-specific chemotherapies in patient derived xenograft (PDX) models of RMS. We identified single agent, additive or synergistic relationships between relapse-specific chemotherapies and clinically relevant drug exposures of entinostat in three PAX3::FOXO1+ ARMS mouse models. This preclinical data provides further rationale for clinical investigation of entinostat, already known to be well tolerated in a pediatric phase I clinical trial (ADVL1513).
Sujet(s)
Benzamides , Pyridines , Rhabdomyosarcome , Tests d'activité antitumorale sur modèle de xénogreffe , Humains , Pyridines/pharmacologie , Pyridines/usage thérapeutique , Animaux , Benzamides/usage thérapeutique , Benzamides/pharmacologie , Souris , Rhabdomyosarcome/traitement médicamenteux , Rhabdomyosarcome/génétique , Rhabdomyosarcome/anatomopathologie , Rhabdomyosarcome/métabolisme , Lignée cellulaire tumorale , Inhibiteurs de désacétylase d'histone/pharmacologie , Inhibiteurs de désacétylase d'histone/usage thérapeutique , Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Protocoles de polychimiothérapie antinéoplasique/pharmacologieRÉSUMÉ
INTRODUCTION: Soft tissue sarcomas (STS) represent a heterogenous group of rare tumors, primarily treated with surgery. Preoperative radiotherapy is often recommended for extremity high-risk STS. Neoadjuvant chemotherapy, typically based on doxorubicin with ifosfamide, has shown efficacy in limbs and trunk wall STS. Second-line chemotherapy, commonly utilized in the metastatic setting, is mostly histology-driven. Molecular targeted agents are used across various histologies, and although the use of immunotherapy in STS is still in its early stages, there is increasing interest in exploring its potential. AREAS COVERED: This article involved an extensive recent search on PubMed. It explored the current treatment landscape for localized and metastatic STS, focusing on the combined use of radiotherapy and chemotherapy for both extremity and retroperitoneal tumors, and with a particular emphasis on the most innovative histopathology driven therapeutic approaches. Additionally, ongoing clinical trials identified via clinicaltrials.gov are included. EXPERT OPINION: Recently there have been advancements in the treatment of STS, largely driven by the outcomes of clinical trials. However further research is imperative to comprehend the effect of chemotherapy, targeted therapy and immunotherapy in various STS, as well as to identify biomarkers able to predict which patients are most likely to benefit from these treatments.
Sujet(s)
Immunothérapie , Thérapie moléculaire ciblée , Traitement néoadjuvant , Sarcomes , Humains , Sarcomes/anatomopathologie , Sarcomes/thérapie , Sarcomes/traitement médicamenteux , Immunothérapie/méthodes , Traitement néoadjuvant/méthodes , Protocoles de polychimiothérapie antinéoplasique/administration et posologie , Protocoles de polychimiothérapie antinéoplasique/pharmacologie , Association thérapeutique , Tumeurs des tissus mous/anatomopathologie , Tumeurs des tissus mous/thérapie , Tumeurs des tissus mous/traitement médicamenteux , Marqueurs biologiques tumoraux/métabolismeRÉSUMÉ
BACKGROUND: Cancer remains a formidable global health challenge, currently affecting nearly 20 million individuals worldwide. Due to the absence of universally effective treatments, ongoing research explores diverse strategies to combat this disease. Recent efforts have concentrated on developing combined drug regimens and targeted therapeutic approaches. OBJECTIVE: This study aimed to investigate the anticancer efficacy of a conjugated drug system, consisting of doxorubicin and cisplatin (Dox-Cis), encapsulated within niosomes and modified with MUC-1 aptamers to enhance biocompatibility and target specific cancer cells. METHODS: The chemical structure of the Dox-Cis conjugate was characterized using Fourier Transform Infrared Spectroscopy (FTIR) and Liquid Chromatography Quadrupole Time-of-Flight Mass Spectrometry (LC-Q-TOF/MS). The zeta potential and morphological parameters of the niosomal vesicles were determined through Dynamic Light Scattering (DLS) and Transmission Electron Microscopy (TEM). In vitro assessments of cell viability and apoptosis were conducted on MUC-1 positive HeLa cells and MUC-1 negative U87 cells. RESULTS: The findings confirmed the successful conjugation of Dox and Cis within the niosomes. The Nio/Dox-Cis/MUC-1 formulation demonstrated enhanced efficacy compared to the individual drugs and their unencapsulated combination in both cell lines. Notably, the Nio/Dox-Cis/MUC-1 formulation exhibited greater effectiveness on HeLa cells (38.503 ± 1.407) than on U87 cells (46.653 ± 1.297). CONCLUSION: The study underscores the potential of the Dox-Cis conjugate as a promising strategy for cancer treatment, particularly through platforms that facilitate targeted drug delivery to cancer cells. This targeted approach could lead to more effective and personalized cancer therapies.
Sujet(s)
Aptamères nucléotidiques , Survie cellulaire , Cisplatine , Doxorubicine , Liposomes , Mucine-1 , Humains , Doxorubicine/pharmacologie , Doxorubicine/composition chimique , Mucine-1/métabolisme , Mucine-1/composition chimique , Liposomes/composition chimique , Cisplatine/pharmacologie , Cisplatine/composition chimique , Aptamères nucléotidiques/composition chimique , Aptamères nucléotidiques/pharmacologie , Survie cellulaire/effets des médicaments et des substances chimiques , Apoptose/effets des médicaments et des substances chimiques , Lignée cellulaire tumorale , Cellules HeLa , Protocoles de polychimiothérapie antinéoplasique/pharmacologie , Antinéoplasiques/pharmacologie , Antinéoplasiques/composition chimique , Préparation de médicament/méthodesRÉSUMÉ
Background: BMS-1166, a PD-1/PD-L1 inhibitor, inhibits the binding of PD-L1 to PD-1, restores T cell function, and enhances tumor immune response. However, mutations in the tumor suppressor or impaired cellular signaling pathways may also lead to cellular transformation. In this study, the SW480 and SW480R cell lines were used as the model to elucidate the treatment with BMS-1166, BEZ235, and their combination. Methods: MTT and colony-formation assays were used to evaluate cell proliferation. Wound-healing assay was used to assess cell migration. Cell cycle and apoptosis were analyzed by flow cytometry. The phosphorylation level of the key kinases in the PI3K/Akt/mTOR and MAPK pathways, PD-L1, and the protein levels related to the proliferation, migration, and apoptosis were assessed using western blotting. Results: BEZ235 enhanced BMS-1166-mediated cell proliferation and migration inhibition in SW480 and SW480R cells and promoted apoptosis. Interestingly, the downregulation of the negative regulator PTEN raised the PD-L1 level, which was abolished by the inhibition of Akt. BMS-1166 promoted PI3K, Akt, mTOR, and Erk phosphorylation. However, the combination of BEZ235 with BMS-1166 suppressed the expression of PI3K, p-Akt, p-mTOR, and p-Erk in SW480 and SW480R cells compared to BMS-1166 or BEZ235 single treatment by inhibiting the binding of PD1 to PD-L1. Conclusions: PD-1 binds to PD-L1 and activates the PI3K/mTOR and MAPK pathways, which might be the molecular mechanism of acquired resistance of CRC to BMS-1166. The combination of the two drugs inhibited the phosphorylation of PI3K, Akt, and Erk in the PI3K/mTOR and MAPK pathway, i.e., BEZ235 enhanced the BMS-1166 treatment effect by blocking the PI3K/mTOR pathway and interfering with the crosstalk of the MAPK pathway. Therefore, these findings provide a theoretical basis for BMS-1166 combined with BEZ235 in the trial treatment of colorectal cancer.
Sujet(s)
Apoptose , Mouvement cellulaire , Prolifération cellulaire , Tumeurs colorectales , Imidazoles , Inhibiteurs des phosphoinositide-3 kinases , Quinoléines , Sérine-thréonine kinases TOR , Humains , Protocoles de polychimiothérapie antinéoplasique/pharmacologie , Apoptose/effets des médicaments et des substances chimiques , Antigène CD274/métabolisme , Antigène CD274/antagonistes et inhibiteurs , Lignée cellulaire tumorale , Mouvement cellulaire/effets des médicaments et des substances chimiques , Prolifération cellulaire/effets des médicaments et des substances chimiques , Tumeurs colorectales/traitement médicamenteux , Tumeurs colorectales/anatomopathologie , Tumeurs colorectales/métabolisme , Synergie des médicaments , Imidazoles/pharmacologie , Inhibiteurs de mTOR/pharmacologie , Phosphatidylinositol 3-kinases/métabolisme , Inhibiteurs des phosphoinositide-3 kinases/pharmacologie , Quinoléines/pharmacologie , Transduction du signal/effets des médicaments et des substances chimiques , Sérine-thréonine kinases TOR/métabolisme , Sérine-thréonine kinases TOR/antagonistes et inhibiteursRÉSUMÉ
BACKGROUND: GP-2250, a novel analog of taurultam (TRLT), has emerged as a potent anti-neoplastic drug; however, the mechanisms underlying its effects are not well understood. Here, we investigated the mechanism of action and the biological effects of GP-2250 using in vitro and in vivo models. METHODS: We carried out a series of in vitro (MTT assay, Annexin V/PI assay, colony formation assay, reverse-phase protein array [RPPA], and HRLC/IC analysis) to determine the biological activity of GP-2250 and investigate the mechanism of action. In vivo experiments were carried out to determine the therapeutic efficacy of GP-2250 alone and in combination with standard-of-care drugs (e.g., paclitaxel, cisplatin, topotecan, and poly ADP-ribose polymerase [PARP] inhibitors). RESULTS: We investigated the cytotoxic effect of GP-2250 in 10 ovarian cancer cell lines and found GP-2250 combined with a PARP inhibitor had the greatest synergy. RPPA revealed that GP-2250 inhibited hypoxia-inducible factor-1α, AKT, and mammalian target of rapamycin (mTOR) activation and expression. High-resolution mass spectrometry revealed that hexokinase2 activity and protein expression were significantly reduced by GP-2250 exposure. Furthermore, GP-2250 reduced glycolysis and ATP synthesis in cancer cells. An in vivo pharmacodynamic experiment using the OVCAR8 mouse model demonstrated that 500 mg/kg GP-2250 was effective in downregulating AKT and mTOR activation and expression. In the in vivo therapy experiment using an orthotopic mouse model, a combination of GP-2250 with either PARP inhibitors or bevacizumab showed a significant reduction of tumor weights and nodules compared to those treated with a vehicle, control IgG groups, or monotherapy groups. CONCLUSIONS: Taken together, our data indicate that GP-2250 exerts profound effects on tumor metabolism and, in combination with PARP inhibitors or bevacizumab, showed promising anti-tumor efficacy. These findings could have implications for the clinical development of GP-2250.
Sujet(s)
Tumeurs de l'ovaire , Tests d'activité antitumorale sur modèle de xénogreffe , Animaux , Femelle , Tumeurs de l'ovaire/traitement médicamenteux , Tumeurs de l'ovaire/anatomopathologie , Tumeurs de l'ovaire/métabolisme , Humains , Souris , Lignée cellulaire tumorale , Protocoles de polychimiothérapie antinéoplasique/pharmacologie , Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Synergie des médicaments , Apoptose/effets des médicaments et des substances chimiques , Prolifération cellulaire/effets des médicaments et des substances chimiques , Antinéoplasiques/pharmacologie , Modèles animaux de maladie humaine , Sous-unité alpha du facteur-1 induit par l'hypoxie/métabolisme , Sérine-thréonine kinases TOR/métabolisme , Inhibiteurs de poly(ADP-ribose) polymérases/pharmacologie , Inhibiteurs de poly(ADP-ribose) polymérases/usage thérapeutiqueRÉSUMÉ
The efficiency of combinations of cytostatics cisplatin and adriamycin with antioxidant sodium 3-(3'-tert-butyl-4-hydroxyphenyl)propyl thiosulfate (TS-13), and nitric oxide (NO) donor NaNO2 was evaluated on two drug-resistant strains of leukemia P388 with changed redox-status of cells. Simultaneous use of both NO donor and TS-13 in combinations with the cytostatics did not increase the efficiency of therapy. In addition, antioxidant activity of TS-13, NaNO2, and their combinations was studied by the method of luminol-dependent chemiluminescence on the model systems with the use of the homogenized cells of sensitive strain and two drug-resistant strains of leukemia P388. It was shown that TS-13 and NO donor produced opposite effects: TS-13 decreased, while NO donor increased the content of free radicals in the model system. Combinations of antioxidant TS-13 and NO donor should be used with consideration for the redox-status of tumor treated.
Sujet(s)
Antioxydants , Cisplatine , Doxorubicine , Résistance aux médicaments antinéoplasiques , Leucémie P388 , Donneur d'oxyde nitrique , Oxydoréduction , Animaux , Souris , Oxydoréduction/effets des médicaments et des substances chimiques , Résistance aux médicaments antinéoplasiques/effets des médicaments et des substances chimiques , Antioxydants/pharmacologie , Doxorubicine/pharmacologie , Leucémie P388/traitement médicamenteux , Leucémie P388/anatomopathologie , Cisplatine/pharmacologie , Cisplatine/usage thérapeutique , Donneur d'oxyde nitrique/pharmacologie , Thiosulfates/pharmacologie , Nitrite de sodium/pharmacologie , Lignée cellulaire tumorale , Antinéoplasiques/pharmacologie , Protocoles de polychimiothérapie antinéoplasique/pharmacologieRÉSUMÉ
BACKGROUND: Lung cancer, especially non-small cell lung cancer (NSCLC), poses a significant health challenge globally due to its high mortality. Afatinib, a second-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), has shown superior efficacy over traditional chemotherapy in NSCLC treatment. However, issues like secondary resistance and adverse effects call for alternative therapies. HAD-B1, comprising 4 herbal medicines, has shown promise in lung cancer treatment in both preclinical and clinical settings. This study assesses the combination of HAD-B1 and Afatinib in advanced NSCLC patients to potentially improve outcomes by addressing the limitations of current EGFR-TKI therapies. METHOD: A randomized, open-label trial evaluated the efficacy and safety of HAD-B1 with Afatinib in 90 EGFR-mutation-positive NSCLC patients. Participants were divided into treatment and control groups, receiving Afatinib with or without HAD-B1. The study focused on the initial dose maintenance rate and disease control rate (DCR) of Afatinib, alongside secondary outcomes like survival rates and quality of life, under continuous safety monitoring. RESULTS: Among the 90 participants, no significant difference was found in initial dose maintenance (60.98% in the treatment group vs 52.50% in the control, P = .4414) or DCR (80.49% vs 90.00%, P = .2283). Secondary outcomes like PFS, TTP, and OS showed no notable differences. However, physical functioning significantly improved in the treatment group (P = .0475, PPS group). The control group experienced higher rates of adverse events of special interest and adverse drug reactions (P = .01), suggesting HAD-B1 with Afatinib might enhance physical function without increasing adverse effects. CONCLUSION: Combining HAD-B1 with Afatinib potentially improves quality of life and reduces adverse events in advanced NSCLC patients. Further research is necessary to confirm the long-term benefits of this combination therapy, aiming to advance NSCLC treatment outcomes. TRIAL REGISTRATION: Clinical Research Information Service (CRIS) of the Republic of Korea, https://cris.nih.go.kr/ (ID: KCT0005414).
Sujet(s)
Afatinib , Carcinome pulmonaire non à petites cellules , Récepteurs ErbB , Tumeurs du poumon , Mutation , Qualité de vie , Humains , Afatinib/usage thérapeutique , Afatinib/effets indésirables , Afatinib/pharmacologie , Carcinome pulmonaire non à petites cellules/traitement médicamenteux , Carcinome pulmonaire non à petites cellules/génétique , Carcinome pulmonaire non à petites cellules/anatomopathologie , Mâle , Tumeurs du poumon/traitement médicamenteux , Tumeurs du poumon/génétique , Tumeurs du poumon/anatomopathologie , Femelle , Adulte d'âge moyen , Récepteurs ErbB/génétique , Sujet âgé , Adulte , Inhibiteurs de protéines kinases/usage thérapeutique , Inhibiteurs de protéines kinases/effets indésirables , Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Protocoles de polychimiothérapie antinéoplasique/effets indésirables , Protocoles de polychimiothérapie antinéoplasique/pharmacologieRÉSUMÉ
BACKGROUND: Lenvatinib plus PD-1 inhibitors and interventional (LPI) therapy have demonstrated promising treatment effects in unresectable hepatocellular carcinoma (HCC). However, biomarkers for predicting the response to LPI therapy remain to be further explored. We aimed to develop a radiomics model to noninvasively predict the efficacy of LPI therapy. METHODS: Clinical data of patients with HCC receiving LPI therapy were collected in our institution. The clinical model was built with clinical information. Nine machine learning classifiers were tested and the multilayer perceptron classifier with optimal performance was used as the radiomics model. The clinical-radiomics model was constructed by integrating clinical and radiomics scores through logistic regression analysis. RESULTS: 151 patients were enrolled in this study (2:1 randomization, 101 and 50 in the training and validation cohorts), of which three achieved complete response, 69 showed partial response, 46 showed stable disease, and 33 showed progressive disease. The objective response rate, disease control rate, and conversion resection rates were 47.7, 78.1 and 23.2%. 14 features were selected from the initially extracted 1223 for radiomics model construction. The area under the curves of the radiomics model (0.900 for training and 0.893 for validation) were comparable to that of the clinical-radiomics model (0.912 for training and 0.892 for validation), and both were superior to the clinical model (0.669 for training and 0.585 for validation). Meanwhile, the radiomics model can categorize participants into high-risk and low-risk groups for progression-free survival (PFS) and overall survival (OS) in the training (HR 1.913, 95% CI 1.121 to 3.265, p=0.016 for PFS; HR 4.252, 95% CI 2.051 to 8.816, p=0.001 for OS) and validation sets (HR 2.347, 95% CI 1.095 to 5.031, p=0.012 for PFS; HR 2.592, 95% CI 1.050 to 6.394, p=0.019 for OS). CONCLUSION: The promising machine learning radiomics model was developed and validated to predict the efficacy of LPI therapy for patients with HCC and perform risk stratification, with comparable performance to clinical-radiomics model.
Sujet(s)
Carcinome hépatocellulaire , Tumeurs du foie , Apprentissage machine , Phénylurées , Quinoléines , Humains , Carcinome hépatocellulaire/traitement médicamenteux , Carcinome hépatocellulaire/imagerie diagnostique , Carcinome hépatocellulaire/anatomopathologie , Tumeurs du foie/traitement médicamenteux , Tumeurs du foie/imagerie diagnostique , Tumeurs du foie/anatomopathologie , Quinoléines/usage thérapeutique , Phénylurées/usage thérapeutique , Mâle , Femelle , Adulte d'âge moyen , Sujet âgé , Tomodensitométrie/méthodes , Inhibiteurs de points de contrôle immunitaires/usage thérapeutique , Inhibiteurs de points de contrôle immunitaires/pharmacologie , Adulte , Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Protocoles de polychimiothérapie antinéoplasique/pharmacologie ,RÉSUMÉ
PURPOSE: Small-cell lung cancer (SCLC) is an aggressive disease with a dismal prognosis. The addition of immune checkpoints inhibitors to standard platinum-based chemotherapy in first-line setting achieves a durable benefit only in a patient subgroup. Thus, the identification of predictive biomarkers is an urgent unmet medical need. EXPERIMENTAL DESIGN: Tumor samples from naive extensive-stage (ES) SCLC patients receiving atezolizumab plus carboplatin-etoposide were analyzed by gene expression profiling and two 9-color multiplex immunofluorescence panels, to characterize the immune infiltrate and SCLC subtypes. Associations of tissue biomarkers with time-to-treatment failure (TTF), progression-free survival (PFS) and overall survival (OS), were assessed. RESULTS: 42 patients were included. Higher expression of exhausted CD8-related genes was independently associated with a longer TTF and PFS while increased density of B lymphocytes correlated with longer TTF and OS. Higher percentage of M2-like macrophages close to tumor cells and of CD8+T cells close to CD4+T lymphocytes correlated with increased risk of TF and longer survival, respectively. A lower risk of TF, disease progression and death was associated with a higher density of ASCL1+tumor cells while the expression of POU2F3 correlated with a shorter survival. A composite score combining the expression of exhausted CD8-related genes, B lymphocyte density, ASCL1 tumor expression and quantification of CD163+macrophages close to tumor cells, was able to stratify patients into high-risk and low-risk groups. CONCLUSIONS: In conclusion, we identified tissue biomarkers and a combined score that can predict a higher benefit from chemoimmunotherapy in ES-SCLC patients.
Sujet(s)
Anticorps monoclonaux humanisés , Protocoles de polychimiothérapie antinéoplasique , Carboplatine , Étoposide , Tumeurs du poumon , Carcinome pulmonaire à petites cellules , Microenvironnement tumoral , Humains , Carboplatine/usage thérapeutique , Carboplatine/administration et posologie , Carboplatine/pharmacologie , Tumeurs du poumon/traitement médicamenteux , Tumeurs du poumon/génétique , Mâle , Anticorps monoclonaux humanisés/usage thérapeutique , Anticorps monoclonaux humanisés/pharmacologie , Femelle , Carcinome pulmonaire à petites cellules/traitement médicamenteux , Carcinome pulmonaire à petites cellules/génétique , Carcinome pulmonaire à petites cellules/immunologie , Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Protocoles de polychimiothérapie antinéoplasique/pharmacologie , Étoposide/usage thérapeutique , Étoposide/pharmacologie , Étoposide/administration et posologie , Sujet âgé , Adulte d'âge moyen , Analyse de profil d'expression de gènes/méthodes , Adulte , Stadification tumoraleRÉSUMÉ
Single-agent TAS102 (trifluridine/tipiracil) and regorafenib are FDA-approved treatments for metastatic colorectal cancer (mCRC). We previously reported that regorafenib combined with a fluoropyrimidine can delay disease progression in clinical case reports of multidrug-resistant mCRC patients. We hypothesized that the combination of TAS102 and regorafenib may be active in CRC and other gastrointestinal (GI) cancers and may in the future provide a treatment option for patients with advanced GI cancer. We investigated the therapeutic effect of TAS102 in combination with regorafenib in preclinical studies employing cell culture, colonosphere assays that enrich for cancer stem cells, and in vivo. TAS102 in combination with regorafenib has synergistic activity against multiple GI cancers in vitro including colorectal and gastric cancer, but not liver cancer cells. TAS102 inhibits colonosphere formation and this effect is potentiated by regorafenib. In vivo anti-tumor effects of TAS102 plus regorafenib appear to be due to anti-proliferative effects, necrosis and angiogenesis inhibition. Growth inhibition by TAS102 plus regorafenib occurs in xenografted tumors regardless of p53, KRAS or BRAF mutations, although more potent tumor suppression was observed with wild-type p53. Regorafenib significantly inhibits TAS102-induced angiogenesis and microvessel density in xenografted tumors, as well inhibits TAS102-induced ERK1/2 activation regardless of RAS or BRAF status in vivo. TAS102 plus regorafenib is a synergistic drug combination in preclinical models of GI cancer, with regorafenib suppressing TAS102-induced increase in microvessel density and p-ERK as contributing mechanisms. The TAS102 plus regorafenib drug combination may be further tested in gastric and other GI cancers.
Sujet(s)
Association médicamenteuse , Synergie des médicaments , Tumeurs gastro-intestinales , Mutation , Cellules souches tumorales , Néovascularisation pathologique , Phénylurées , Protéines proto-oncogènes B-raf , Protéines proto-oncogènes p21(ras) , Pyridines , Pyrrolidines , Facteur de transcription STAT-3 , Thymine , Trifluorothymidine , Uracile , Tests d'activité antitumorale sur modèle de xénogreffe , Humains , Trifluorothymidine/pharmacologie , Phénylurées/pharmacologie , Animaux , Pyridines/pharmacologie , Protéines proto-oncogènes B-raf/génétique , Protéines proto-oncogènes B-raf/métabolisme , Protéines proto-oncogènes p21(ras)/génétique , Protéines proto-oncogènes p21(ras)/métabolisme , Néovascularisation pathologique/traitement médicamenteux , Néovascularisation pathologique/génétique , Néovascularisation pathologique/métabolisme , Cellules souches tumorales/effets des médicaments et des substances chimiques , Cellules souches tumorales/métabolisme , Cellules souches tumorales/anatomopathologie , Tumeurs gastro-intestinales/traitement médicamenteux , Tumeurs gastro-intestinales/génétique , Tumeurs gastro-intestinales/anatomopathologie , Tumeurs gastro-intestinales/métabolisme , Uracile/pharmacologie , Uracile/analogues et dérivés , Souris , Facteur de transcription STAT-3/métabolisme , Facteur de transcription STAT-3/génétique , Thymine/pharmacologie , Lignée cellulaire tumorale , Pyrrolidines/pharmacologie , Pyrrolidines/usage thérapeutique , Protocoles de polychimiothérapie antinéoplasique/pharmacologie , Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Système de signalisation des MAP kinases/effets des médicaments et des substances chimiques , Transduction du signal/effets des médicaments et des substances chimiques , Prolifération cellulaire/effets des médicaments et des substances chimiques ,RÉSUMÉ
Breast cancer, a predominant global health issue, requires ongoing exploration of new therapeutic strategies. Palbociclib (PAL), a well-known cyclin-dependent kinase (CDK) inhibitor, plays a critical role in breast cancer treatment. While its efficacy is recognized, the interplay between PAL and cellular autophagy, particularly in the context of the RAF/MEK/ERK signaling pathway, remains insufficiently explored. This study investigates PAL's inhibitory effects on breast cancer using both in vitro (MCF7 and MDA-MB-468 cells) and in vivo (tumor-bearing nude mice) models. Aimed at elucidating the impact of PAL on autophagic processes and exploring the potential of combining it with trametinib (TRA), an MEK inhibitor, our research seeks to address the challenge of PAL-induced drug resistance. Our findings reveal that PAL significantly decreases the viability of MCF7 and MDA-MB-468 cells and reduces tumor size in mice while showing minimal cytotoxicity in MCF10A cells. However, PAL also induces protective autophagy, potentially leading to drug resistance via the RAF/MEK/ERK pathway activation. Introducing TRA effectively neutralized this autophagy, enhancing PAL's anti-tumor efficacy. A combination of PAL and TRA synergistically reduced cell viability and proliferation, and in vivo studies showed notable tumor size reduction. In conclusion, the PAL and TRA combination emerges as a promising strategy for overcoming PAL-induced resistance, offering a new horizon in breast cancer treatment.
Sujet(s)
Autophagie , Tumeurs du sein , Pipérazines , Pyridines , Pyridones , Pyrimidinones , Tests d'activité antitumorale sur modèle de xénogreffe , Humains , Animaux , Autophagie/effets des médicaments et des substances chimiques , Tumeurs du sein/traitement médicamenteux , Tumeurs du sein/anatomopathologie , Tumeurs du sein/métabolisme , Pyridines/pharmacologie , Pyridines/usage thérapeutique , Pyridones/pharmacologie , Pyridones/usage thérapeutique , Femelle , Pyrimidinones/pharmacologie , Pyrimidinones/usage thérapeutique , Souris , Pipérazines/pharmacologie , Pipérazines/usage thérapeutique , Lignée cellulaire tumorale , Résistance aux médicaments antinéoplasiques/effets des médicaments et des substances chimiques , Prolifération cellulaire/effets des médicaments et des substances chimiques , Synergie des médicaments , Protocoles de polychimiothérapie antinéoplasique/pharmacologie , Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Souris nude , Système de signalisation des MAP kinases/effets des médicaments et des substances chimiques , Inhibiteurs de protéines kinases/pharmacologie , Inhibiteurs de protéines kinases/usage thérapeutique , Survie cellulaire/effets des médicaments et des substances chimiques , Cellules MCF-7RÉSUMÉ
Background: Despite the availability of chemotherapy drugs such as 5-fluorouracil (5-FU), the treatment of some cancers such as gastric cancer remains challenging due to drug resistance and side effects. This study aimed to investigate the effect of celastrol in combination with the chemotherapy drug 5-FU on proliferation and induction of apoptosis in human gastric cancer cell lines (AGS and EPG85-257). Materials and Methods: In this in vitro study, AGS and EPG85-257 cells were treated with different concentrations of celastrol, 5-FU, and their combination. Cell proliferation was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. The synergistic effect of 5-FU and celastrol was studied using Compusyn software. The DNA content at different phases of the cell cycle and apoptosis rate was measured using flow cytometry. Results: Co-treatment with low concentrations (10% inhibitory concentration (IC10)) of celastrol and 5-FU significantly reduced IC50 (p < 0.05) so that 48 h after treatment, IC50 was calculated at 3.77 and 6.9 µM for celastrol, 20.7 and 11.6 µM for 5-FU, and 5.03 and 4.57 µM for their combination for AGS and EPG85-257 cells, respectively. The mean percentage of apoptosis for AGS cells treated with celastrol, 5-FU, and their combination was obtained 23.9, 41.2, and 61.9, and for EPG85-257 cells 5.65, 46.9, and 55.7, respectively. In addition, the 5-FU and celastrol-5-FU combination induced cell cycle arrest in the synthesis phase. Conclusions: Although celastrol could decrease the concentration of 5-fluorouracil that sufficed to suppress gastric cancer cells, additional studies are required to arrive at conclusive evidence on the anticancer effects of celastrol.
Sujet(s)
Apoptose , Prolifération cellulaire , Synergie des médicaments , Fluorouracil , Triterpènes pentacycliques , Tumeurs de l'estomac , Triterpènes , Humains , Triterpènes pentacycliques/pharmacologie , Fluorouracil/pharmacologie , Tumeurs de l'estomac/traitement médicamenteux , Tumeurs de l'estomac/anatomopathologie , Tumeurs de l'estomac/métabolisme , Apoptose/effets des médicaments et des substances chimiques , Prolifération cellulaire/effets des médicaments et des substances chimiques , Lignée cellulaire tumorale , Triterpènes/pharmacologie , Protocoles de polychimiothérapie antinéoplasique/pharmacologie , Cycle cellulaire/effets des médicaments et des substances chimiquesRÉSUMÉ
BACKGROUND: Treatment with regorafenib, a multiple-kinase inhibitor, to manage metastatic colorectal cancers (mCRCs) shows a modest improvement in overall survival but is associated with severe toxicities. Thus, to reduce regorafenib-induced toxicity, we used regorafenib at low concentration along with a dual JAK/HDAC small-molecule inhibitor (JAK/HDACi) to leverage the advantages of both JAK and HDAC inhibition to enhance antitumor activity. The therapeutic efficacy and safety of the combination treatment was evaluated with CRC models. METHODS: The cytotoxicity of JAK/HDACi, regorafenib, and their combination were tested with normal colonic and CRC cells exhibiting various genetic backgrounds. Kinomic, ATAC-seq, RNA-seq, cell cycle, and apoptosis analyses were performed to evaluate the cellular functions/molecular alterations affected by the combination. Efficacy of the combination was assessed using patient-derived xenograft (PDX) and experimental metastasis models of CRC. To evaluate the interplay between tumor, its microenvironment, and modulation of immune response, MC38 syngeneic mice were utilized. RESULTS: The combination therapy decreased cell viability; phosphorylation of JAKs, STAT3, EGFR, and other key kinases; and inhibited deacetylation of histone H3K9, H4K8, and alpha tubulin proteins. It induced cell cycle arrest at G0-G1 phase and apoptosis of CRC cells. Whole transcriptomic analysis showed that combination treatment modulated molecules involved in apoptosis, extracellular matrix-receptor interaction, and focal adhesion pathways. It synergistically reduces PDX tumor growth and experimental metastasis, and, in a syngeneic mouse model, the treatment enhances the antitumor immune response as evidenced by higher infiltration of CD45 and cytotoxic cells. Pharmacokinetic studies showed that combination increased the bioavailability of regorafenib. CONCLUSIONS: The combination treatment was more effective than with regorafenib or JAK/HDACi alone, and had minimal toxicity. A clinical trial to evaluate this combination for treatment of mCRCs is warranted.
Sujet(s)
Tumeurs colorectales , Inhibiteurs de désacétylase d'histone , Phénylurées , Pyridines , Tumeurs colorectales/traitement médicamenteux , Tumeurs colorectales/anatomopathologie , Tumeurs colorectales/métabolisme , Humains , Phénylurées/pharmacologie , Phénylurées/administration et posologie , Animaux , Souris , Pyridines/pharmacologie , Pyridines/administration et posologie , Inhibiteurs de désacétylase d'histone/pharmacologie , Inhibiteurs de désacétylase d'histone/usage thérapeutique , Inhibiteurs de désacétylase d'histone/administration et posologie , Métastase tumorale , Prolifération cellulaire/effets des médicaments et des substances chimiques , Tests d'activité antitumorale sur modèle de xénogreffe , Synergie des médicaments , Lignée cellulaire tumorale , Femelle , Apoptose/effets des médicaments et des substances chimiques , Inhibiteurs des Janus kinases/pharmacologie , Inhibiteurs des Janus kinases/administration et posologie , Inhibiteurs des Janus kinases/usage thérapeutique , Protocoles de polychimiothérapie antinéoplasique/pharmacologie , Protocoles de polychimiothérapie antinéoplasique/usage thérapeutiqueRÉSUMÉ
Triple-negative breast cancer (TNBC) is a subtype of breast cancer with high mortality and poor prognosis. Meanwhile, doxorubicin, a chemotherapeutic agent for triple-negative breast cancer, has poor sensitivity. The objective of this study was to examine the effect of cordycepin on doxorubicin sensitivity and efficacy in the TNBC xenograft model and explore the relevant molecular pathways. The combination of the drugs in nude mice carrying MDA-MB-231 xenografts significantly reduced the volume, size, and weight of xenografts and improved the tumor inhibition rate. The drug combination was significantly more effective than cordycepin or doxorubicin alone, reflecting the fact that cordycepin enhanced the anti-tumor effects of doxorubicin in MDA-MB-231 xenografts. At the same time, the monitoring of several biological parameters failed to detect any obvious side effects associated with this treatment. After predicting the importance of the TNF pathway in inhibiting tumor growth using network pharmacology methods, we verified the expression of TNF pathway targets via immunohistochemistry and quantitative PCR. Furthermore, a TNF-α inhibitor was able to abrogate the beneficial effects of cordycepin and doxorubicin treatment in MDA-MB-231 cells. This clearly indicates the role of TNF-α, or related molecules, in mediating the therapeutic benefits of the combined treatment in animals carrying TNBC xenografts. The observations reported here may present a new direction for the clinical treatment of TNBC.
Sujet(s)
Désoxyadénosine , Doxorubicine , Souris nude , Tumeurs du sein triple-négatives , Tests d'activité antitumorale sur modèle de xénogreffe , Doxorubicine/pharmacologie , Doxorubicine/usage thérapeutique , Tumeurs du sein triple-négatives/traitement médicamenteux , Tumeurs du sein triple-négatives/métabolisme , Tumeurs du sein triple-négatives/anatomopathologie , Désoxyadénosine/pharmacologie , Désoxyadénosine/usage thérapeutique , Animaux , Humains , Femelle , Souris , Lignée cellulaire tumorale , Synergie des médicaments , Facteur de nécrose tumorale alpha/métabolisme , Facteur de nécrose tumorale alpha/génétique , Protocoles de polychimiothérapie antinéoplasique/pharmacologie , Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Prolifération cellulaire/effets des médicaments et des substances chimiques , Souris de lignée BALB CRÉSUMÉ
Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, including abemaciclib, have been approved for the treatment of hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced, and metastatic breast cancer. Despite the high therapeutic efficacy of CDK4/6 inhibitors, they are associated with various adverse effects, including potentially fatal interstitial lung disease. Therefore, a combination of CDK4/6 inhibitors with letrozole or fulvestrant has been attempted but has demonstrated limitations in reducing adverse effects, highlighting the need to develop new combination therapies. This study proposes a combination strategy using CDK4/6 inhibitors and tricyclic antidepressants to enhance the therapeutic outcomes of these inhibitors while reducing their side effects. The therapeutic efficacies of abemaciclib and desipramine were tested in different cancer cell lines (H460, MCF7, and HCT-116). The antitumor effects of the combined abemaciclib and desipramine treatment were evaluated in a xenograft colon tumor model. In vitro cell studies have shown the synergistic anticancer effects of combination therapy in the HCT-116 cell line. The combination treatment significantly reduced tumor size compared with control or single treatment without causing apparent toxicity to normal tissues. Although additional in vivo studies are necessary, this study suggests that the combination therapy of abemaciclib and desipramine may represent a novel therapeutic approach for treating solid tumors.
Sujet(s)
Aminopyridines , Benzimidazoles , Désipramine , Synergie des médicaments , Tests d'activité antitumorale sur modèle de xénogreffe , Humains , Benzimidazoles/pharmacologie , Benzimidazoles/administration et posologie , Aminopyridines/pharmacologie , Aminopyridines/administration et posologie , Animaux , Souris , Désipramine/pharmacologie , Lignée cellulaire tumorale , Protocoles de polychimiothérapie antinéoplasique/pharmacologie , Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Femelle , Kinase-4 cycline-dépendante/antagonistes et inhibiteurs , Kinase-4 cycline-dépendante/métabolisme , Prolifération cellulaire/effets des médicaments et des substances chimiques , Souris nude , Kinase-6 cycline-dépendante/antagonistes et inhibiteurs , Kinase-6 cycline-dépendante/métabolisme , Cellules MCF-7 , Cellules HCT116 , Antinéoplasiques/pharmacologie , Antinéoplasiques/usage thérapeutique , Antinéoplasiques/administration et posologie , Souris de lignée BALB CRÉSUMÉ
Promising outcomes have been reported in elder patients with acute myeloid leukemia (AML) using combined therapy of venetoclax (VEN) and azacytidine (AZA) in recent years. However, approximately one-third of patients appear to be refractory to this therapy. Vitamin K2 (VK2) shows apoptosis-inducing activity in AML cells, and daily oral VK2 (menaquinone-4, GlakayR) has been approved for patients with osteoporosis in Japan. We observed a high response rate to AZA plus VEN therapy, with no 8-week mortality in the newly diagnosed AML patients consuming daily VK2 in our hospital. The median age of the patients was 75.9 years (range 66-84) with high-risk features. Patients received AZA 75 mg/m2 on D1-7, VEN 400 mg on D1-28, and daily VK2 45 mg. The CR/CRi ratio was 94.7% (18/19), with a CR rate of 79%. Complete cytogenetic CR was achieved in 15 of 19 (79%) patients, and MRD negativity in 2 of 15 (13%) evaluable CR patients. Owing to the extremely high response rate in clinical settings, we further attempted to investigate the underlying mechanisms. The combination of VK2 and VEN synergistically induced apoptosis in all five AML cell lines tested. VK2, but not VEN, induced mitochondrial reactive oxygen species (ROS), leading to the transcriptional upregulation of NOXA, followed by MCL-1 repression. ROS scavengers repressed VK2 induced-NOXA expression and led to the cancellation of pronounced apoptosis and the downregulation of MCL-1 by VK2 plus VEN. Additionally, knockdown and knockout of NOXA resulted in abrogation of the MCL-1 repression as well as enhanced cytotoxicity by the two-drug combination, indicating that VK2 suppresses MCL-1 via ROS-mediated NOXA induction. These data suggest that the dual inhibition of BCL-2 by VEN and MCL-1 by VK2 is responsible for the remarkable clinical outcomes in our patients. Therefore, large-scale clinical trials are required.