{"id":29734,"date":"2018-09-18T09:21:25","date_gmt":"2018-09-18T07:21:25","guid":{"rendered":"https:\/\/carpem.stage.spacerdesign.com\/a-new-gene-therapy-track-to-fight-cancer\/"},"modified":"2018-09-18T09:21:25","modified_gmt":"2018-09-18T07:21:25","slug":"a-new-gene-therapy-track-to-fight-cancer","status":"publish","type":"post","link":"https:\/\/carpem.stage.spacerdesign.com\/en\/a-new-gene-therapy-track-to-fight-cancer\/","title":{"rendered":"A new gene therapy track to fight cancer"},"content":{"rendered":"<p style=\"text-align: center;\"><span style=\"color: #ff8c00;\"><span style=\"font-size: 14px;\"><strong>A Suicide Gene Therapy Combining the Improvement of Cyclophosphamide Tumor Cytotoxicity and the Development of an Anti-Tumor Immune Response.<\/strong><\/span><\/span><\/p>\n<p>&nbsp;<\/p>\n<p style=\"text-align: justify;\">Touati W, Tran T, Seguin J, Diry M, Jean-Pierre F, Baillou C, Lescaille G, Andre F, Tartour E, Lemoine FM, Beaune P, de Waziers I. <strong>Curr Gene Ther<\/strong>. 2014 Apr<\/p>\n<p style=\"text-align: justify;\">Gene-directed enzyme prodrug therapy (GDEPT) consists in targeted delivery to tumor cells of a suicide gene responsible for in situ conversion of a prodrug into cytotoxic metabolites. One of the major limitations of this strategy in clinical application was the poor prodrug activation capacity of suicide gene. We built a highly efficient suicide gene capable of bioactivating the prodrug cyclophosphamide (CPA) by fusing a CYP2B6 triple mutant with NADPH cytochrome P450 reductase (CYP2B6TM-RED). Expression of this fusion gene via a recombinant lentivirus (LV) vector converted resistant human (A549) and murine (TC1) pulmonary cell lines into CPA-susceptible cell lines. We tested the efficiency of our GDEPT strategy in C57Bl\/6 immunocompetent mice, using TC1 cells expressing the HPV-16 E6\/E7 oncoproteins. In mice bearing tumors composed only of TC1-CYP2B6TM-RED cells, four CPA injections (140 mg\/Kg once a week) completely eradicated the tumors for more than two months. Tumors having only 25% of TC1-CYP2B6TM-RED cells were also completely eradicated by five CPA injections, demonstrating a major in vivo bystander effect. Moreover, surviving mice were rechallenged with parental TC1 cells. The tumors regressed spontaneously 7 days after cell inoculation or grew more slowly than in control naive mice due to a strong immune response mediated by anti-E7CD8+T cells. These data suggest that combining the CYPB6TM-RED gene with CPA may hold promise as a highly effective treatment for solid tumors in humans.<\/p>\n<p style=\"text-align: justify;\"><strong><a href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/?term=touati+w\" target=\"_blank\" rel=\"noopener\">Pubmed<\/a><\/strong><\/p>\n<p><!--:--><!--:fr--><\/p>\n<p style=\"text-align: center;\"><span style=\"color: #ff8c00;\"><span style=\"font-size: 14px;\"><strong>Une nouvelle piste de th\u00e9rapie g\u00e9nique pour lutter contre le cancer<\/strong><\/span><\/span><\/p>\n<p style=\"text-align: justify;\">Le groupe de recherche d&#8217;Isabelle de Waziers (Inserm 1147, \u00e9quipe 1 du CARPEM) vient de publier des travaux prometteurs dans Current Gene Therapy.<\/p>\n<div id=\"picture\" style=\"text-align: justify;\"><a href=\"https:\/\/carpem.stage.spacerdesign.com\/wp-content\/uploads\/2013\/08\/Isabelle-dW.jpg\"><img class=\"alignleft size-medium wp-image-2134\" src=\"https:\/\/carpem.stage.spacerdesign.com\/wp-content\/uploads\/2013\/08\/Isabelle-dW-300x134.jpg\" alt=\"Isabelle dW\" width=\"300\" height=\"134\" \/><\/a>L&#8217;\u00e9quipe du Dr de Waziers a mis \u00e0 profit son expertise dans le domaine du m\u00e9tabolisme des x\u00e9nobiotiques pour d\u00e9velopper une m\u00e9thode originale de th\u00e9rapie consistant \u00e0 sensibiliser les tumeurs \u00e0 un anticanc\u00e9reux par transfert d\u2019un<strong> <span style=\"color: #6b8e23;\">g\u00e8ne \u00ab\u00a0suicide\u00a0\u00bb<\/span><\/strong>. Cette approche vise \u00e0 introduire, dans les cellules tumorales, un g\u00e8ne dont le produit permet la transformation <em>in situ<\/em> d\u2019un m\u00e9dicament inactif (pro-drogue) en m\u00e9tabolites cytotoxiques (<span style=\"color: #6b8e23;\"><strong>Gene-Directed Enzyme Prodrug Therapy\u00a0: GDEPT<\/strong><\/span>). Ils ont produit un lentivirus recombinant exprimant un g\u00e8ne \u00ab\u00a0suicide\u00a0\u00bb (LV-2B6TM-RED) capable de m\u00e9taboliser tr\u00e8s efficacement un anticanc\u00e9reux, le <span style=\"color: #6b8e23;\"><strong>cyclophosphamide<\/strong><\/span> (CPA) en m\u00e9tabolites cytotoxiques. Ils ont montr\u00e9 <em>ex vivo<\/em> et <em>in vivo<\/em> que l\u2019expression de ce transg\u00e8ne dans les cellules tumorales (poumon, ORL) les sensibilisait au CPA entra\u00eenant une mort des cellules tumorales et une disparition des tumeurs. Enfin, il semble que l\u2019effet cytotoxique du CPA d\u00e9clenche une r\u00e9ponse immunitaire dirig\u00e9e contre les cellules tumorales optimisant ainsi la strat\u00e9gie.<\/div>\n<div style=\"text-align: justify;\"><\/div>\n<blockquote>\n<p style=\"text-align: justify;\"><span style=\"font-size: 12px;\">&#8220;<em>Gr\u00e2ce \u00e0 ce <\/em>g\u00e8ne suicide<em> optimis\u00e9, le cyclophosphamide est tr\u00e8s efficacement transform\u00e9 en compos\u00e9s toxiques, et ce dans la tumeur elle-m\u00eame. Les compos\u00e9s toxiques form\u00e9s peuvent en outre diffuser passivement \u00e0 travers les membranes des cellules malignes, de sorte qu\u2019un petit nombre de cellules tumorales contenant le transg\u00e8ne est suffisant pour \u00e9liminer la tumeur enti\u00e8re<\/em> &#8220;, explique le Dr Isabelle de Waziers<\/span><\/p>\n<\/blockquote>\n<p style=\"text-align: justify;\">Retrouver l&#8217;article de vulgarisation consacr\u00e9 \u00e0 ces travaux sur <a href=\"http:\/\/www.inserm.fr\/actualites\/rubriques\/actualites-recherche\/une-nouvelle-piste-de-therapie-genique-pour-lutter-contre-le-cancer\" target=\"_blank\" rel=\"noopener\">le site de l&#8217;Inserm<\/a><\/p>\n<p style=\"text-align: center;\"><span style=\"color: #ff8c00;\"><span style=\"font-size: 14px;\"><strong>A Suicide Gene Therapy Combining the Improvement of Cyclophosphamide Tumor Cytotoxicity and the Development of an Anti-Tumor Immune Response.<\/strong><\/span><\/span><\/p>\n<p>&nbsp;<\/p>\n<p style=\"text-align: justify;\">Touati W, Tran T, Seguin J, Diry M, Jean-Pierre F, Baillou C, Lescaille G, Andre F, Tartour E, Lemoine FM, Beaune P, de Waziers I. <strong>Curr Gene Ther<\/strong>. 2014 Apr<\/p>\n<p style=\"text-align: justify;\">Gene-directed enzyme prodrug therapy (GDEPT) consists in targeted delivery to tumor cells of a suicide gene responsible for in situ conversion of a prodrug into cytotoxic metabolites. One of the major limitations of this strategy in clinical application was the poor prodrug activation capacity of suicide gene. We built a highly efficient suicide gene capable of bioactivating the prodrug cyclophosphamide (CPA) by fusing a CYP2B6 triple mutant with NADPH cytochrome P450 reductase (CYP2B6TM-RED). Expression of this fusion gene via a recombinant lentivirus (LV) vector converted resistant human (A549) and murine (TC1) pulmonary cell lines into CPA-susceptible cell lines. We tested the efficiency of our GDEPT strategy in C57Bl\/6 immunocompetent mice, using TC1 cells expressing the HPV-16 E6\/E7 oncoproteins. In mice bearing tumors composed only of TC1-CYP2B6TM-RED cells, four CPA injections (140 mg\/Kg once a week) completely eradicated the tumors for more than two months. Tumors having only 25% of TC1-CYP2B6TM-RED cells were also completely eradicated by five CPA injections, demonstrating a major in vivo bystander effect. Moreover, surviving mice were rechallenged with parental TC1 cells. The tumors regressed spontaneously 7 days after cell inoculation or grew more slowly than in control naive mice due to a strong immune response mediated by anti-E7CD8+T cells. These data suggest that combining the CYPB6TM-RED gene with CPA may hold promise as a highly effective treatment for solid tumors in humans.<\/p>\n<p style=\"text-align: justify;\"><strong><a href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/?term=touati+w\" target=\"_blank\" rel=\"noopener\">Pubmed<\/a><\/strong><\/p>\n","protected":false},"excerpt":{"rendered":"<p>A Suicide Gene Therapy Combining the Improvement of Cyclophosphamide Tumor Cytotoxicity&#8230;<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[317],"tags":[271],"class_list":{"0":"post-29734","1":"post","2":"type-post","3":"status-publish","4":"format-standard","6":"category-publications-en","7":"tag-english"},"yoast_head":"<!-- This site is optimized with the Yoast SEO plugin v22.7 - https:\/\/yoast.com\/wordpress\/plugins\/seo\/ -->\n<title>A new gene therapy track to fight cancer - 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