E7386 enhances lenvatinib’s antitumor activity in preclinical models and human hepatocellular carcinoma.
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ABSTRACT:
PROVIDER: PRJNA1273097 | ENA |
REPOSITORIES: ENA
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Project description:To study the antitumor and antiangiogenic activity of combining E7386 (an oral protein-protein interaction inhibitor targeting CREB-binding protein (CBP)/β-catenin) with lenvatinib and explore a novel mechanism of action of E7386 that boosts antitumor response.
2025-08-21 | GSE299215 | GEO
Project description:Introduction: The flavonoid myricetin has been shown to induce cell cycle arrest and mitochondrial-dependent apoptosis in preclinical cancer models. We hypothesised that myricetin-derived flavonoids with redox properties and improved physicochemical attributes that enhance cell uptake and mitochondrial targeting might have increased potential as antitumour agents, since mitochondria are the main site of production of reactive oxygen species (ROS) and redox status is known to regulate the development and advancement of certain cancers. In this study we assessed a small library of novel flavonoids, then focussed on the lead compound, second-generation analogue OncamexTM, its mechanism of action and structure-activity relationships as an anti-proliferative agent. Methods: With this aim, we studied the effect of OncamexTM in a panel of 7 breast cancer cell lines using proliferation, cytotoxicity and apoptosis assays. The redox properties and mitochondrial delivery of the drug were studied using cyclic voltammetry and fluorescence microscopy, respectively. The mechanism of action was further studied using western blotting, gene expression analysis and immunohistochemistry (IHC) of treated xenograft tissue from in vivo mice models. Results: Sulforhodamine B (SRB) proliferation assays demonstrated strong, anti-proliferative properties of OncamexTM, with IC50 values in the low micromolar range. Treatment for 8 h exerted concentration-dependent reduction in cell viability and induction of cytotoxicity and apoptosis, with increased caspase activation. Microarray analysis suggested that OncamexTM regulates changes in cell cycle and apoptosis at gene expression level. Fluorescence microscopy was used to investigate mitochondrial targeting and ROS regulation in treated cells. OncamexTM was found to induce production of superoxide at concentrations which exerted anti-proliferative effects. Initial in vivo studies in mice implanted with a MDA-MB-231 breast cancer xenograft showed that OncamexTM inhibited tumour growth, reducing tissue viability and Ki-67 proliferation, with no overall systemic toxicity. Conclusions: OncamexTM is a novel flavonoid capable of specific delivery to the mitochondria and induction of ROS production. We have shown its antitumor activity in preclinical models of breast cancer, both in vitro and in initial in vivo models, where tumour growth was arrested without inducing toxicity, support the potential of this novel drug for its continued development as an anticancer agent. Total RNA was obtained from 5 breast cancer cell lines subjected to 6 hours of 10µM OncamexTM and matched untreated controls (1% DMSO)
2015-09-01 | E-GEOD-70949 | biostudies-arrayexpress
Project description:Melanoma is one of the tumor types with the highest risk of brain metastasis. However, the biology of melanoma brain metastasis and the contribution of the brain immune microenvironment to the responses to therapies remain insufficiently characterized. By using preclinical models and single-cell transcriptomics, we identify a mechanism to promote antitumor immunity in melanoma brain metastasis. We show that activation of the Rela/NF-kB pathway in microglia promotes melanoma brain metastasis and that targeting this pathway elicits microglia reprogramming towards a proinflammatory phenotype that enhances antitumor immunity and reduces brain metastatic burden. Additionally, proinflammatory microglial markers in melanoma brain metastasis correlate with better responses to immune checkpoint inhibitors in patients and we show that Rela/NF-kB targeting improves responses to these therapies in the brain. Thus, we propose targeting Rela/NF-kB in activated microglia as a strategy to promote antitumor immunity and responses to immune checkpoint inhibitors in melanoma brain metastasis.
2025-02-07 | GSE285670 | GEO
Project description:Exercise improves immune checkpoint inhibitor (ICI) efficacy in cancers like melanoma, however, the mechanisms through which exercise mediates this antitumor effect remain obscure. Here we identify the gut microbiota as playing a previously unrecognized, critical role in how exercise improves ICI efficacy in preclinical melanoma. Our study demonstrates that exercise stimulates microbial one-carbon metabolism, increasing levels of the metabolite formate, which subsequently enhances Tc1-mediated ICI efficacy. We further establish that microbiota-derived formate is both sufficient and required to enhance Tc1 cell fate in vitro and promote tumor antigen-specific Tc1 immunity in vivo. Mechanistically, we identified the transcription factor nuclear factor erythroid 2-related factor-2 (Nrf2) as a crucial mediator of formate-driven Tc1 function enhancement in vitro and a key player in the exercise-mediated antitumor effect in vivo. Finally, we identify human microbiota-derived formate as a potential biomarker of enhanced Tc1-mediated antitumor immunity and support its functional role in driving melanoma suppression.
2025-07-23 | GSE294230 | GEO
Project description:Dnase1l3 enhances antitumor immunity and suppresses tumor progression
| PRJNA803220 | ENA
Project description:Hepatocellular carcinoma (HCC) is a major cause of cancer-related mortality worldwide, largely due to its complex and immunosuppressive tumor immune microenvironment (TIME), which significantly impairs the efficacy of conventional therapies and immune checkpoint blockade (ICB). This study investigates the role of C-C motif chemokine ligand 3 (CCL3) in modulating the HCC TIME, focusing on its impact on immune cell recruitment, macrophage-mediated antigen presentation, and the overall antitumor immune response. We analyzed CCL3 expression in human HCC samples and examined its correlation with inflammatory gene signatures and immune cell infiltration. Using high-dimensional single-cell RNA sequencing (scRNA-seq), multiparameter flow cytometry, and multiplex immunofluorescence, we elucidated how CCL3 influences macrophage functionality and T cell activation. In preclinical HCC models and ex vivo tumor fragment assays, we explored the mechanisms by which CCL3 affects macrophage function and its broader implications for antitumor immunity. Our findings reveal that CCL3 effectively recruits immune cells to the HCC TIME, promotes the formation of tertiary lymphoid structures, and enhances macrophage-mediated antigen phagocytosis and presentation, leading to improved T cell effector functions and cytotoxic activity. This research underscores the critical role of CCL3 in reshaping the HCC TIME to enhance antitumor immunity and suggests that targeting CCL3 could be a promising strategy to improve the efficacy of immunotherapy in liver cancer.
2025-03-03 | GSE277065 | GEO
Project description:Hepatocellular carcinoma (HCC) is a major cause of cancer-related mortality worldwide, largely due to its complex and immunosuppressive tumor immune microenvironment (TIME), which significantly impairs the efficacy of conventional therapies and immune checkpoint blockade (ICB). This study investigates the role of C-C motif chemokine ligand 3 (CCL3) in modulating the HCC TIME, focusing on its impact on immune cell recruitment, macrophage-mediated antigen presentation, and the overall antitumor immune response. We analyzed CCL3 expression in human HCC samples and examined its correlation with inflammatory gene signatures and immune cell infiltration. Using high-dimensional single-cell RNA sequencing (scRNA-seq), multiparameter flow cytometry, and multiplex immunofluorescence, we elucidated how CCL3 influences macrophage functionality and T cell activation. In preclinical HCC models and ex vivo tumor fragment assays, we explored the mechanisms by which CCL3 affects macrophage function and its broader implications for antitumor immunity. Our findings reveal that CCL3 effectively recruits immune cells to the HCC TIME, promotes the formation of tertiary lymphoid structures, and enhances macrophage-mediated antigen phagocytosis and presentation, leading to improved T cell effector functions and cytotoxic activity. This research underscores the critical role of CCL3 in reshaping the HCC TIME to enhance antitumor immunity and suggests that targeting CCL3 could be a promising strategy to improve the efficacy of immunotherapy in liver cancer.
2025-03-05 | GSE277066 | GEO
Project description:Introduction: The flavonoid myricetin has been shown to induce cell cycle arrest and mitochondrial-dependent apoptosis in preclinical cancer models. We hypothesised that myricetin-derived flavonoids with redox properties and improved physicochemical attributes that enhance cell uptake and mitochondrial targeting might have increased potential as antitumour agents, since mitochondria are the main site of production of reactive oxygen species (ROS) and redox status is known to regulate the development and advancement of certain cancers. In this study we assessed a small library of novel flavonoids, then focussed on the lead compound, second-generation analogue OncamexTM, its mechanism of action and structure-activity relationships as an anti-proliferative agent. Methods: With this aim, we studied the effect of OncamexTM in a panel of 7 breast cancer cell lines using proliferation, cytotoxicity and apoptosis assays. The redox properties and mitochondrial delivery of the drug were studied using cyclic voltammetry and fluorescence microscopy, respectively. The mechanism of action was further studied using western blotting, gene expression analysis and immunohistochemistry (IHC) of treated xenograft tissue from in vivo mice models. Results: Sulforhodamine B (SRB) proliferation assays demonstrated strong, anti-proliferative properties of OncamexTM, with IC50 values in the low micromolar range. Treatment for 8 h exerted concentration-dependent reduction in cell viability and induction of cytotoxicity and apoptosis, with increased caspase activation. Microarray analysis suggested that OncamexTM regulates changes in cell cycle and apoptosis at gene expression level. Fluorescence microscopy was used to investigate mitochondrial targeting and ROS regulation in treated cells. OncamexTM was found to induce production of superoxide at concentrations which exerted anti-proliferative effects. Initial in vivo studies in mice implanted with a MDA-MB-231 breast cancer xenograft showed that OncamexTM inhibited tumour growth, reducing tissue viability and Ki-67 proliferation, with no overall systemic toxicity. Conclusions: OncamexTM is a novel flavonoid capable of specific delivery to the mitochondria and induction of ROS production. We have shown its antitumor activity in preclinical models of breast cancer, both in vitro and in initial in vivo models, where tumour growth was arrested without inducing toxicity, support the potential of this novel drug for its continued development as an anticancer agent.
2015-09-01 | GSE70949 | GEO
Project description:Role of regorafenib in antitumor immunity in hepatocellular carcinoma
| PRJNA626615 | ENA
Project description:Dnase1l3 enhances antitumor immunity and suppresses tumor progression [scRNAseq]
| PRJNA803189 | ENA