Using lentiviral vectors for efficient pancreatic cancer gene therapy

Ravet, Emmanuel; Lulka, Hubert; Gross, Fabian; Casteilla, Louis; Buscail, Louis; Cordelier, Pierre

doi:10.1038/cgt.2009.79

Cited by 32 publications

(28 citation statements)

References 54 publications

(49 reference statements)

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“…Our group extensively demonstrated the efficacy of lentiviral-based vectors to transduce and kill PDAC cells both in vitro and in vivo. 10,12,13,33 However, despite recent advances in lentiviral-based ex vivo therapeutic gene delivery in patients suffering from monogenic diseases, [14][15][16][17][18] the use of HIV as the origin of a vector system for in situ and in vivo cancer gene therapy is still surprisingly controversial. This is probably because of the pathogenic nature of the wild-type virus itself, but also to the inherent property of LVs to affect the host genome.…”

Section: Discussionmentioning

confidence: 99%

“…The DNA vector TRIP-DU3-EF1a-EGFP, encoding for EGFP, has been described elsewhere. 10 CopGFP and deoxycytidine kinase (DCK) cDNA were PCR-amplified from pMIRZIP-has-miR-21 13 and normal pancreatic cells, respectively, and cloned into pPS-EF1-LCS-T2A (System Biosciences) following the manufacturer's recommendations. Successful cloning was verified by sequencing.…”

Section: Cellsmentioning

confidence: 99%

“…The viral titers were determined on HT1080 cells and expressed in transduction unit/ml (TU/ml) as described elsewhere. 10 Vector concentrations were quantified by p24 ELISA (Ingen). All batches were checked whether they were replicative virus-free after transduction of 293FT cells and analysis of cellular extracts and culture supernatant for p24 presence, up to 3 passages (10 days) in culture.…”

Section: Integrative-defective Vectors For Pancreatic Cancer Gene Tramentioning

confidence: 99%

“…[5][6][7] However, the low efficacy of gene transfer using PEI, 5,7 the inherent immunogenic-ity of adenovirus, 8 and the manufacturing hurdles of SV40 vectors 9 challenge the use of these delivery vehicles in clinical trials. On the other hand, we recently found that lentiviral vectors (LVs) demonstrated the highest efficacy and reliability to inhibit PDAC cell proliferation both in vitro and in vivo, [10][11][12][13] and elected LVs as promising gene delivery vectors for PDAC gene therapy. However, despite successful lentiviral-based gene therapy applications in patients after infusion of corrected cells, [14][15][16][17] and more recently, after direct intracranial gene transfer, 18 the risk of insertional mutagenesis and subsequent malignant transformation of transduced cells, 19 historically demonstrated in patients during the X-SCID trial using gamma-retroviral vectors, continue to hinder the development of other integrating vectors such as LVs for in situ and in vivo cancer gene therapy, including PDAC.…”

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Initial Characterization of Integrase-Defective Lentiviral Vectors for Pancreatic Cancer Gene Therapy

et al. 2016

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Section: Discussionmentioning

confidence: 99%

Section: Cellsmentioning

confidence: 99%

Section: Integrative-defective Vectors For Pancreatic Cancer Gene Tramentioning

confidence: 99%

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Initial Characterization of Integrase-Defective Lentiviral Vectors for Pancreatic Cancer Gene Therapy

et al. 2016

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“…The delivery of INFA in carcinoembryogenic antigen (CEA)-expressing pancreatic tumors cells resulted in major cytotoxicity through CD8 + and natural killer (NK) cells at the tumor site [55]. Moreover, transfer of INFB with a lentivirus in xenograft models resulted in tumor progression inhibition [56]. CEA transfer in T cells was tested in a preclinical model to target antitumor response [57].…”

Section: Increasing Immune System Responsementioning

confidence: 99%

Gene Therapy of Pancreatic Cancer

Dabernat¹,

Lafitte²,

Bedel³

et al. 2013

J Genet Syndr Gene Ther

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Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive tumors with a 5-year survival rate of less than 5%. The poor prognosis of the disease is associated with late diagnosis and a high degree of drug resistance has not been overcome during the past decades. Gemcitabine-based regimens are the first line therapy for advanced pancreatic cancer but are not curative. Recent new combination chemotherapies achieved significant benefits but toxicity makes their use controversial. Novel approaches are currently being developed; in particular cancer gene therapies are undergoing preclinical and clinical validation and are the topic of the present review. We will present different ways to design gene therapy against pancreatic cancers that have been validated in preclinical studies. We also reviewed the clinical trials already published or still ongoing.Citation: Dabernat S, Lafitte M, Bedel A, de Verneuil H, Moreau-Gaudry F (2013) Gene Therapy of Pancreatic Cancer. J Genet Syndr Gene Ther 4: 138. doi:10.4172/2157-7412.1000138 Page 2 of 6Volume 4 • Issue 4 • 1000138 Suicide Gene Therapy of Cancer J Genet Syndr Gene Ther ISSN: 2157-7412 JGSGT, an open access journal gene restoration efficiency [12]. Restoring a wild type SMAD4 did not always block tumor cells [13] rendering the use of this tumor suppressor controversial [14]. Many oncogenes can be deregulated and/or mutated in pancreatic cancers. Among them, mutations in the KRAS oncogene occur in almost all pancreatic adenorcinomas [9]. Thus, it is tempting to use direct anti-KRAS strategies to inhibit tumor growth (Figure 1b), since disappointing results have been obtained with inhibition of farnesyl transferases [1]. RNAi directed against mutated KRAS showed anti-tumor activity [15], limited the aggressive phenotype of the tumor cells [16] and potentiated gemcitabine antitumor activity [17]. Preclinical studies showed encouraging results with viral delivery systems such as oncolytic adenovirus [18]. However, this strategy has not been further tested in phase I clinical trials.In fact, pancreatic adenocarcinomas present very complex genetic alterations profiles. The Pancreatic Cancer Genome project has analyzed 23,219 transcripts and identified an average of 63 somatic mutations per PDAC affecting 12 core signaling pathways and the overexpression of 500 different genes in 24 tumors [19]. These highly versatile and unpredictable molecular patterns can explain the failure of single gene/pathway targeted adjuvant therapies. It is now critical to test therapies targeting several pathways or therapies that induce specific tumor cell death. Delivering a Suicide GeneWith the suicide gene approach, a gene that encodes a protein triggering tumor cell death is delivered to the tumor cells ( Figure 1c). The expression of the therapeutic gene can directly kill the cells (diphtheria toxin, [20]), or can render the cells sensitive to certain otherwise non toxic prodrugs (Gene Directed Enzyme Prodrug Therapy, GDEPT,[21]), or based on gemcitabine association ...

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