RESUMEN
OBJECTIVE: To evaluate the safety and preliminary efficacy of YSCH-01 (Recombinant L-IFN adenovirus) in subjects with advanced solid tumors. METHODS: In this single-center, open-label, investigator-initiated trial of YSCH-01, 14 patients with advanced solid tumors were enrolled. The study consisted of two distinct phases: (1) the dose escalation phase and (2) the dose expansion phase; with three dose groups in the dose escalation phase based on dose levels (5.0×109 viral particles (VP)/subject, 5.0×1010 VP/subject, and 5.0×1011 VP/subject). Subjects were administered YSCH-01 injection via intratumoral injections. The safety was assessed using National Cancer Institute Common Terminology Criteria for Adverse Events V.5.0, and the efficacy evaluation was performed using Response Evaluation Criteria in Solid Tumor V.1.1. RESULTS: 14 subjects were enrolled in the study, including 9 subjects in the dose escalation phase and 5 subjects in the dose expansion phase. Of the 13 subjects included in the full analysis set, 4 (30.8%) were men and 9 (69.2%) were women. The most common tumor type was lung cancer (38.5%, 5 subjects), followed by breast cancer (23.1%, 3 subjects) and melanoma (23.1%, 3 subjects). During the dose escalation phase, no subject experienced dose-limiting toxicities. The content of recombinant L-IFN adenovirus genome and recombinant L-IFN protein in blood showed no trend of significant intergroup changes. No significant change was observed in interleukin-6 and interferon-gamma. For 11 subjects evaluated for efficacy, the overall response rate with its 95% CI was 27.3% (6.02% to 60.97%) and the disease control rate with its 95% CI was 81.8% (48.22% to 97.72%). The median progression-free survival was 4.97 months, and the median overall survival was 8.62 months. In addition, a tendency of decrease in the sum of the diameters of target lesions was observed. For 13 subjects evaluated for safety, the overall incidence of adverse events (AEs) was 92.3%, the overall incidence of adverse drug reactions (ADRs) was 84.6%, and the overall incidence of >Grade 3 AEs was 7.7%, while no AEs/ADRs leading to death occurred. The most common AEs were fever (69.2%), nausea (30.8%), vomiting (30.8%), and hypophagia (23.1%). CONCLUSIONS: The study shows that YSCH-01 injections were safe and well tolerated and exhibited preliminary efficacy in patients with advanced solid tumors, supporting further investigation to evaluate its efficacy and safety. TRIAL REGISTRATION NUMBER: NCT05180851.
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Neoplasias , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adenoviridae/genética , Neoplasias/tratamiento farmacológico , Viroterapia Oncolítica/métodos , Viroterapia Oncolítica/efectos adversos , Resultado del TratamientoRESUMEN
Survivin holds significant importance as a member of the inhibitor of apoptosis protein (IAP) family due to its predominant expression in tumours rather than normal terminally differentiated adult tissues. The high expression level of survivin in tumours is closely linked to chemotherapy resistance, heightened tumour recurrence, and increased tumour aggressiveness and serves as a negative prognostic factor for cancer patients. Consequently, survivin has emerged as a promising therapeutic target for cancer treatment. In this review, we delve into the various biological characteristics of survivin in cancers and its pivotal role in maintaining immune system homeostasis. Additionally, we explore different therapeutic strategies aimed at targeting survivin.
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Neoplasias , Adulto , Humanos , Survivin/uso terapéutico , Neoplasias/tratamiento farmacológico , Proteínas Inhibidoras de la Apoptosis/genética , Proteínas Inhibidoras de la Apoptosis/metabolismo , Proteínas Inhibidoras de la Apoptosis/uso terapéutico , Apoptosis , Proteínas Asociadas a Microtúbulos/fisiología , Proteínas Asociadas a Microtúbulos/uso terapéuticoRESUMEN
Background: The development of new therapies for malignant gliomas has been stagnant for decades. Through the promising outcomes in clinical trials of oncolytic virotherapy, there is now a glimmer of hope in addressing this situation. To further enhance the antitumor immune response of oncolytic viruses, we have equipped a modified oncolytic adenovirus (oAds) with a recombinant interferon-like gene (YSCH-01) and conducted a comprehensive evaluation of the safety and efficacy of this modification compared to existing treatments. Methods: To assess the safety of YSCH-01, we administered the oAds intracranially to Syrian hamsters, which are susceptible to adenovirus. The efficacy of YSCH-01 in targeting glioma was evaluated through in vitro and in vivo experiments utilizing various human glioma cell lines. Furthermore, we employed a patient-derived xenograft model of recurrent glioblastoma to test the effectiveness of YSCH-01 against temozolomide. Results: By modifying the E1A and adding survivin promoter, the oAds have demonstrated remarkable safety and an impressive ability to selectively target tumor cells. In animal models, YSCH-01 exhibited potent therapeutic efficacy, particularly in terms of its distant effects. Additionally, YSCH-01 remains effective in inhibiting the recurrent GBM patient-derived xenograft model. Conclusions: Our initial findings confirm that a double-modified oncolytic adenovirus armed with a recombinant interferon-like gene is both safe and effective in the treatment of malignant glioma. Furthermore, when utilized in combination with a targeted therapy gene strategy, these oAds exhibit a more profound effect in tumor therapy and an enhanced ability to inhibit tumor growth at remote sites.
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Liver cancer is the sixth most common malignancy and the fourth leading cause of cancer-related death worldwide. Hepatocellular carcinoma (HCC) is the primary type of liver cancer. Small nucleolar RNA (snoRNA) dysfunctions have been associated with cancer development. SnoRD126 is an orphan C/D box snoRNA. How snoRD126 activates the PI3K-AKT pathway, and which domain of snoRD126 exerts its oncogenic function was heretofore completely unknown. Here, we demonstrate that snoRD126 binds to hnRNPK protein to regulate FGFR2 expression and activate the PI3K-AKT pathway. Importantly, we identified the critical domain of snoRD126 responsible for its cancer-promoting functions. Our study further confirms the role of snoRD126 in the progression of HCC and suggests that knockdown snoRD126 may be of potential value as a novel therapeutic approach for the treatment of HCC.
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Carcinoma Hepatocelular/metabolismo , Regulación Neoplásica de la Expresión Génica/genética , Neoplasias Hepáticas/metabolismo , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/genética , Adulto , Anciano , Carcinoma Hepatocelular/genética , Línea Celular Tumoral , Proliferación Celular/genética , Femenino , Ribonucleoproteína Heterogénea-Nuclear Grupo K/genética , Ribonucleoproteína Heterogénea-Nuclear Grupo K/metabolismo , Humanos , Neoplasias Hepáticas/genética , Masculino , Persona de Mediana Edad , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Nucleolar Pequeño/genéticaRESUMEN
Metabolic enzymes and metabolites display non-metabolic functions in immune cell signalling that modulate immune attack ability. However, whether and how a tumour's metabolic remodelling contributes to its immune resistance remain to be clarified. Here we perform a functional screen of metabolic genes that rescue tumour cells from effector T cell cytotoxicity, and identify the embryo- and tumour-specific folate cycle enzyme methylenetetrahydrofolate dehydrogenase 2 (MTHFD2). Mechanistically, MTHFD2 promotes basal and IFN-γ-stimulated PD-L1 expression, which is necessary for tumourigenesis in vivo. Moreover, IFN-γ stimulates MTHFD2 through the AKT-mTORC1 pathway. Meanwhile, MTHFD2 drives the folate cycle to sustain sufficient uridine-related metabolites including UDP-GlcNAc, which promotes the global O-GlcNAcylation of proteins including cMYC, resulting in increased cMYC stability and PD-L1 transcription. Consistently, the O-GlcNAcylation level positively correlates with MTHFD2 and PD-L1 in pancreatic cancer patients. These findings uncover a non-metabolic role for MTHFD2 in cell signalling and cancer biology.
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Aminohidrolasas/genética , Antígeno B7-H1/genética , Carcinogénesis/genética , Regulación Neoplásica de la Expresión Génica , Metilenotetrahidrofolato Deshidrogenasa (NADP)/genética , Enzimas Multifuncionales/genética , Neoplasias Pancreáticas/genética , Procesamiento Proteico-Postraduccional , Linfocitos T Citotóxicos/inmunología , Aminohidrolasas/antagonistas & inhibidores , Aminohidrolasas/inmunología , Animales , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/inmunología , Carcinogénesis/inmunología , Carcinogénesis/patología , Línea Celular Tumoral , Embrión de Mamíferos , Fibroblastos/inmunología , Fibroblastos/patología , Ácido Fólico/inmunología , Ácido Fólico/metabolismo , Humanos , Masculino , Diana Mecanicista del Complejo 1 de la Rapamicina/genética , Diana Mecanicista del Complejo 1 de la Rapamicina/inmunología , Metilenotetrahidrofolato Deshidrogenasa (NADP)/antagonistas & inhibidores , Metilenotetrahidrofolato Deshidrogenasa (NADP)/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Desnudos , Enzimas Multifuncionales/antagonistas & inhibidores , Enzimas Multifuncionales/inmunología , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/patología , Cultivo Primario de Células , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/inmunología , Proteínas Proto-Oncogénicas c-myc/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/inmunología , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/inmunología , Transducción de Señal , Linfocitos T Citotóxicos/patología , Carga Tumoral , Escape del Tumor , Uridina Difosfato N-Acetilglucosamina/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Small nucleolar RNA (snoRNA) plays important role in various histogenesis. Whether snoRNA plays a role in adipogenesis is unknown. SNORD126 is a C/D box snoRNA. We previously demonstrated that SNORD126 promoted hepatocellular carcinoma cell growth by activating the phosphoinositide 3-kinase-protein kinase B (Akt) pathway through upregulating fibroblast growth factor receptor 2 expression. In the present study, we found that the expression of SNORD126 was downregulated in the obesity-related tissues in high-fat diet-fed rats. Overexpression of SNORD126 in 3T3-L1 cells promoted adipocytes differentiation. SNORD126 significantly increased the expression of CCAAT/enhancer-binding protein α, fatty acid-binding protein 4, peroxisome proliferative-activated receptor-γ, and the phosphorylation of Akt and p70S6K. Overexpression of SNORD126 in human adipose-derived stem cells stimulated adipogenesis and increased phosphorylation of Akt. Meanwhile, SNORD126 increased the messenger RNA and protein levels of cyclin D1 and cyclin-dependent kinase 2, which promoted mitotic clonal expansion progression during the early stage of 3T3-L1 cell differentiation. We further found that SNORD126 accelerated the growth of the groin fat pad and increased phosphorylation of Akt and p70S6K in rats. Overall, our results suggested that SNORD126 promoted adipocyte differentiation through increasing phosphorylation of Akt and p70S6K both in vitro and in vivo.
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Adipogénesis/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Nucleolar Pequeño/metabolismo , Transducción de Señal , Células 3T3-L1 , Adipocitos/citología , Adipocitos/metabolismo , Tejido Adiposo/citología , Tejido Adiposo/metabolismo , Animales , Diferenciación Celular/genética , Dieta Alta en Grasa , Fase G1 , Regulación de la Expresión Génica , Humanos , Masculino , Ratones , Obesidad/genética , Ratas Sprague-Dawley , Fase S , Células Madre/citología , Células Madre/metabolismoRESUMEN
The Vestigial-Like Family Member 4 (VGLL4) functions as a native inhibitor of cell proliferation and tumor growth through multiple signaling pathways. We first discovered that VGLL4 causes G2/M phase arrest in hepatocellular carcinoma (HCC) cells. Then, we designed a novel survivin-regulated oncolytic adenovirus Ad-sp-VGLL4 carrying the VGLL4 gene. Ad-sp-VGLL4 exerted high HCC-targeting-selectivity but is less harmful to normal cells. This adenovirus construction enhanced antitumor activity due to G2/M phase arrest and enhanced apoptosis. It's also indicated that Ad-sp-VGLL4 could suppress the growth of transplanted tumor of HCC in vivo experiment. Taken together, our results suggest that Ad-sp-VGLL4 possesses strong antitumor capacity and has great potential use for HCC therapy.
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Adenoviridae/genética , Carcinoma Hepatocelular/terapia , Regulación Neoplásica de la Expresión Génica , Neoplasias Hepáticas/terapia , Virus Oncolíticos/genética , Factores de Transcripción/genética , Adenoviridae/metabolismo , Animales , Apoptosis/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Proliferación Celular , Femenino , Puntos de Control de la Fase G2 del Ciclo Celular/genética , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Ratones , Ratones Desnudos , Viroterapia Oncolítica/métodos , Virus Oncolíticos/metabolismo , Transducción de Señal , Survivin/genética , Survivin/metabolismo , Factores de Transcripción/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Purpose: Antiproliferative, antiviral, and immunomodulatory activities of endogenous type I IFNs (IFN1) prompt the design of recombinant IFN1 for therapeutic purposes. However, most of the designed IFNs exhibited suboptimal therapeutic efficacies against solid tumors. Here, we report evaluation of the in vitro and in vivo antitumorigenic activities of a novel recombinant IFN termed sIFN-I.Experimental Design: We compared primary and tertiary structures of sIFN-I with its parental human IFNα-2b, as well as affinities of these ligands for IFN1 receptor chains and pharmacokinetics. These IFN1 species were also compared for their ability to induce JAK-STAT signaling and expression of the IFN1-stimulated genes and to elicit antitumorigenic effects. Effects of sIFN-I on tumor angiogenesis and immune infiltration were also tested in transplanted and genetically engineered immunocompetent mouse models.Results: sIFN-I displayed greater affinity for IFNAR1 (over IFNAR2) chain of the IFN1 receptor and elicited a greater extent of IFN1 signaling and expression of IFN-inducible genes in human cells. Unlike IFNα-2b, sIFN-I induced JAK-STAT signaling in mouse cells and exhibited an extended half-life in mice. Treatment with sIFN-I inhibited intratumoral angiogenesis, increased CD8+ T-cell infiltration, and robustly suppressed growth of transplantable and genetically engineered tumors in immunodeficient and immunocompetent mice.Conclusions: These findings define sIFN-I as a novel recombinant IFN1 with potent preclinical antitumorigenic effects against solid tumor, thereby prompting the assessment of sIFN-I clinical efficacy in humans. Clin Cancer Res; 23(8); 2038-49. ©2016 AACR.
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Antineoplásicos/química , Antineoplásicos/farmacología , Interferón-alfa/química , Interferón-alfa/farmacología , Animales , Femenino , Citometría de Flujo , Humanos , Immunoblotting , Interferón alfa-2 , Ratones , Ratones Endogámicos C57BL , Ratones Desnudos , Neoplasias Experimentales/tratamiento farmacológico , Proteínas Recombinantes/química , Proteínas Recombinantes/farmacología , Resonancia por Plasmón de Superficie , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Small nucleolar RNA (snoRNA) dysfunctions have been associated with cancer development. SNORD126 is an orphan C/D box snoRNA that is encoded within introns 5-6 of its host gene, cyclin B1-interacting protein 1 (CCNB1IP1). The cancer-associated molecular mechanisms triggered by SNORD126 are not fully understood. Here, we demonstrate that SNORD126 is highly expressed in hepatocellular carcinoma (HCC) and colorectal cancer (CRC) patient samples. SNORD126 increased Huh-7 and SW480 cell growth and tumorigenicity in nude mice. Knockdown of SNORD126 inhibited HepG2 and LS174T cell growth. We verified that SNORD126 was not processed into small RNAs with miRNA activity. Moreover, SNORD126 did not show a significant expression correlation with CCNB1IP1 in HCC samples or regulate CCNB1IP1 expression. Our gene expression profile analysis indicated that SNORD126-upregulated genes frequently mapped to the PI3K-AKT pathway. SNORD126 overexpression increased the levels of phosphorylated AKT, GSK-3ß, and p70S6K and elevated fibroblast growth factor receptor 2 (FGFR2) expression. siRNA-mediated knockdown or AZD4547-mediated inactivation of FGFR2 in SNORD126-overexpressing Huh-7 cells inhibited AKT phosphorylation and suppressed cell growth. These findings indicate an oncogenic role for SNORD126 in cancer and suggest its potential as a therapeutic target.
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Carcinoma Hepatocelular/patología , Neoplasias Colorrectales/patología , Neoplasias Hepáticas/patología , ARN Nucleolar Pequeño/metabolismo , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/metabolismo , Animales , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Proliferación Celular , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Resistencia a Antineoplásicos/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Masculino , Ratones Desnudos , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Nucleolar Pequeño/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
OBJECTIVE: To determine whether inhibiting cardiac carnitine palmitoyltransferase-1b (CPT-1b) improves obesity-related cardiomyopathy. METHODS: Four-week-old male C57BL/6J mice were fed with high-fat diet (HFD) for 12 weeks to induce obesity. At 6 weeks of age, mice were subjected to intramyocardial injection with lentivirus to down-regulate the expression of either cardiac CPT-1b or green fluorescent protein. Morphological, biochemical, functional, histological, and ultrastructural profiles were assessed at 16 weeks of age. RESULTS: HFD administration elicited obesity, cardiac hypertrophy, and systolic dysfunction accompanied with altered biochemical parameters. In addition, HFD consumption promoted lipid accumulation and reactive oxygen species generation in cardiomyocytes and damaged myocardial ultrastructure. Cardiac CPT-1b silencing protected against HFD-induced cardiac remodeling by decreasing heart weight/tibial length ratio and increasing left ventricular ejection fraction and fractional shortening, as well as normalizing left ventricular diameter. Meanwhile, CPT-1b inhibition mitigated the changes in biochemical parameters, aggravated myocardial lipid accumulation, reduced intramyocardial reactive oxygen species production, and partly amended myocardial ultrastructural alterations in obese mice. CONCLUSIONS: Cardiac CPT-1b suppression protects against the aggravation of cardiac morphology and function associated with HFD feeding. CPT-1b represents a potential therapeutic target for the treatment of cardiac dysfunction related to metabolic diseases such as obesity and diabetes.
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Cardiomegalia/genética , Cardiomiopatías/genética , Carnitina O-Palmitoiltransferasa/genética , Obesidad/genética , Animales , Cardiomegalia/metabolismo , Cardiomiopatías/metabolismo , Dieta Alta en Grasa , Regulación hacia Abajo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Miocardio/metabolismo , Miocitos Cardíacos/metabolismo , Obesidad/metabolismo , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Hepatocellular carcinoma (HCC) is characterized by alterations in multiple genes. High expression of CD147 on the surface of HCC cells promotes proliferation. The monoclonal antibody HAb18 recognizes CD147. We constructed an oncolytic adenoviral vector to express HAb18 (ZD55-HAb18) in HCC cells. Interleukin 24 (IL24) was co-expressed through the use of an F2A linker. ZD55-HAb18-IL24 decreased HCC cell viability to a greater degree than either ZD55-HAb18 or ZD55-IL24 alone. ZD55-HAb18-IL24 also induced apoptosis and autophagy in PLC/PRF/5 HCC cells. Intratumoral injection of ZD55-HAb18-IL24 repressed tumor growth in a PLC/PRF/5 xenograft model. Our results suggest that antibody-antitumor gene conjugation elicited a stronger antitumor effect than the antibody alone, and that this strategy could broaden the applications of antibody-based therapies in HCC.