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1.
Gene Ther ; 19(11): 1048-57, 2012 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-22113313

RESUMEN

The limitations of the current oncolytic adenoviruses for cancer therapy include insufficient potency and poor distribution of the virus throughout the tumor mass. To address these problems, we generated an oncolytic adenovirus expressing the hyperfusogenic form of the gibbon-ape leukemia virus (GALV) envelope glycoprotein under the control of the adenovirus major late promoter. The oncolytic properties of the new fusogenic adenovirus, ICOVIR16, were analyzed both in vitro and in vivo, and compared with that of its non-fusogenic counterpart, ICOVIR15. Our results indicate that GALV expression by ICOVIR16 induced extensive syncytia formation and enhanced tumor cell killing in a variety of tumor cell types. When injected intratumorally or intravenously into mice with large pre-established melanoma or pancreatic tumors, ICOVIR16 rapidly reduced tumor burden, and in some cases, resulted in complete eradication of the tumors. Importantly, GALV expression induced tumor cell fusion in vivo and enhanced the spreading of the virus throughout the tumor. Taken together, these results indicate that GALV expression can improve the antitumoral potency of an oncolytic adenovirus and suggest that ICOVIR16 is a promising candidate for clinical evaluation in patients with cancer.


Asunto(s)
Adenoviridae/genética , Vectores Genéticos , Células Gigantes , Virus de la Leucemia del Gibón/genética , Virus Oncolíticos , Adenoviridae/metabolismo , Animales , Línea Celular Tumoral , Cricetinae , Femenino , Regulación Viral de la Expresión Génica , Orden Génico , Terapia Genética , Vectores Genéticos/administración & dosificación , Vectores Genéticos/efectos adversos , Vectores Genéticos/metabolismo , Células Gigantes/virología , Humanos , Inyecciones , Masculino , Ratones , Neoplasias/genética , Neoplasias/patología , Neoplasias/terapia , Carga Tumoral , Ensayos Antitumor por Modelo de Xenoinjerto
2.
ESMO Open ; 6(3): 100102, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33838601

RESUMEN

BACKGROUND: Two promising therapeutic strategies in oncology are chimeric antigen receptor-T cell (CAR-T) therapies and antibody-drug conjugates (ADCs). To be effective and safe, these immunotherapies require surface antigens to be sufficiently expressed in tumors and less or not expressed in normal tissues. To identify new targets for ADCs and CAR-T specifically targeting breast cancer (BC) molecular and pathology-based subtypes, we propose a novel in silico strategy based on multiple publicly available datasets and provide a comprehensive explanation of the workflow for a further implementation. METHODS: We carried out differential gene expression analyses on The Cancer Genome Atlas BC RNA-sequencing data to identify BC subtype-specific upregulated genes. To fully explain the proposed target-discovering methodology, as proof of concept, we selected the 200 most upregulated genes for each subtype and undertook a comprehensive analysis of their protein expression in BC and normal tissues through several publicly available databases to identify the potentially safest and viable targets. RESULTS: We identified 36 potentially suitable and subtype-specific tumor surface antigens (TSAs), including fibroblast growth factor receptor-4 (FGFR4), carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6), GDNF family receptor alpha 1 (GFRA1), integrin beta-6 (ITGB6) and ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1). We also identified 63 potential TSA pairs that might be appropriate for co-targeting strategies. Finally, we validated subtype specificity in a cohort of our patients, multiple BC cell lines and the METABRIC database. CONCLUSIONS: Overall, our in silico analysis provides a framework to identify novel and specific TSAs for the development of new CAR-T and antibody-based therapies in BC.


Asunto(s)
Neoplasias de la Mama , Inmunoconjugados , Receptores Quiméricos de Antígenos , Antígenos CD , Neoplasias de la Mama/tratamiento farmacológico , Moléculas de Adhesión Celular , Femenino , Proteínas Ligadas a GPI , Humanos , Inmunoterapia Adoptiva , Linfocitos T
3.
Gene Ther ; 16(12): 1441-51, 2009 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-19710704

RESUMEN

The E2F-1 promoter has been used to confer tumor-selective E1A expression in oncolytic adenoviruses. Tumor specificity is mainly conferred by a unique structure of E2F-responsive sites organized in palindromes. Binding of the E2F-pRb complex to these palindromes results in repression of transcription in normal cells. Owing to deregulation of the Rb/p16 pathway in tumor cells, binding of free E2F activates transcription and initiates an autoactivation loop involving E1A and E4-6/7. ICOVIR-7 is a new oncolytic adenovirus designed to increase the E2F dependency of E1A gene expression. It incorporates additional palindromes of E2F-responsive sites in an insulated E2F-1 promoter controlling E1A-Delta24. The E2F palindromes inhibited replication in normal cells, resulting in a low systemic toxicity at high doses in immunocompetent mice. The Delta24 deletion avoids a loop of E2F-mediated self-activation in nontumor cells. Importantly, the additional E2F-binding hairpins boost the positive feedback loop on the basis of E1A-mediated transcriptional regulation of E4-6/7 turned on in cancer cells and increased antitumoral potency as shown in murine subcutaneous xenograft models treated by intravenous injection. These results suggest that the unique genetic combination featured in ICOVIR-7 may be promising for treating disseminated neoplasias.


Asunto(s)
Adenoviridae/genética , Proteínas E1A de Adenovirus/biosíntesis , Factor de Transcripción E2F1/genética , Virus Oncolíticos/genética , Regiones Promotoras Genéticas , Animales , Línea Celular , Línea Celular Tumoral , Regulación Viral de la Expresión Génica , Humanos , Masculino , Ratones , Ratones Desnudos , Viroterapia Oncolítica/métodos , Replicación Viral
4.
Gene Ther ; 15(17): 1240-5, 2008 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-18509378

RESUMEN

Fusogenic membrane glycoproteins (FMGs) may enhance the cytotoxicity of conditionally replicative adenoviruses. However, expression at early stages of infection impairs virus replication. We have inserted the hyperfusogenic form of the gibbon ape leukemia virus (GALV) envelope glycoprotein as a new splice unit of the major late promoter (MLP) to generate a replication-competent adenovirus expressing this protein. At high multiplicity of infection (MOI), this virus replicated efficiently forming clumps of fused cells and showing a faster release. In contrast, at low MOI, infected cells formed syncytia where only one nucleus contained virus DNA, decreasing total virus production but increasing cytotoxicity.


Asunto(s)
Terapia Genética/métodos , Vectores Genéticos/genética , Células Gigantes/fisiología , Virus de la Leucemia del Gibón/fisiología , Viroterapia Oncolítica/métodos , Proteínas Virales de Fusión/genética , Línea Celular Tumoral , Expresión Génica , Ingeniería Genética , Humanos , Virus de la Leucemia del Gibón/genética , Regiones Promotoras Genéticas , Transgenes , Replicación Viral
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