Unlike for other digestive cancer entities, chemotherapy, radiotherapy, and targeted therapies have, so far, largely failed to improve patient survival in pancreatic adenocarcinoma (PDAC), which remains the fourth leading cause of cancer-related death in Europe and the United States. In this context, gene therapy may offer a new avenue for patients with PDAC. In this review, we explore the research currently ongoing in French laboratories aimed at defeating PDAC using nonviral therapeutic gene delivery, targeted transgene expression, or oncolytic virotherapy that recently or will soon bridge the gap between experimental models of cancer and clinical trials. These studies are likely to change clinical practice or thinking about PDAC management, as they represent a major advance not only for PDAC but may also significantly influence the field of gene-based molecular treatment of cancer.
Get full access to this article
View all access options for this article.
References
1.
SiegelR, NaishadhamD, and JemalA. Cancer statistics, 2013. CA Cancer J Clin, 2013; 3:11–30.
2.
JonesS, ZhangXS, ParsonsDW, et al.Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science, 2008; 321:1801–1806.
3.
YachidaS, JonesS, BozicI, et al.Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature, 2010; 467:1114–1117.
4.
ConroyT, DesseigneF, YchouM, et al.FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med, 2011; 364:1817–1825.
5.
Gourgou-BourgadeS, Bascoul-MolleviC, DesseigneF, et al.Impact of FOLFIRINOX compared with gemcitabine on quality of life in patients with metastatic pancreatic cancer: results from the PRODIGE 4/ACCORD 11 randomized trial. J Clin Oncol, 2013; 31:23–29.
6.
Von HoffDD, RamanathanRK, BoradMJ, et al.Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial. J Clin Oncol, 2011; 29:4548–4554.
7.
Von HoffDD, ErvinT, ArenaFP, et al.Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med, 2013; 369:1691–1703.
8.
DrewY, MulliganEA, VongW-T, et al.Therapeutic potential of poly(ADP-ribose) polymerase inhibitor AG014699 in human cancers with mutated or methylated BRCA1 or BRCA2. J Natl Cancer Inst, 2011; 103:334–346.
9.
ProvenzanoPP, CuevasC, ChangAE, et al.Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell, 2012; 21:418–429.
10.
RhimAD, ObersteinPE, ThomasDH, et al.Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell, 2014; 25:735–747.
11.
HechtJR, FarrellJJ, SenzerN, et al.EUS or percutaneously guided intratumoral TNFerade biologic with 5-fluorouracil and radiotherapy for first-line treatment of locally advanced pancreatic cancer: a phase I/II study. Gastrointest Endosc, 2012; 75:332–338.
12.
HermanJM, WildAT, WangH, et al.Randomized phase III multi-institutional study of TNFerade biologic with fluorouracil and radiotherapy for locally advanced pancreatic cancer: final results. J Clin Oncol, 2013; 31:886–894.
13.
ChawlaSP, ChuaVS, FernandezL, et al.Advanced phase I/II studies of targeted gene delivery in vivo: intravenous Rexin-G for gemcitabine-resistant metastatic pancreatic cancer. Mol Ther, 2010; 18:435–441.
14.
BuscailL, BournetB, VernejoulF, et al.First-in-man phase I clinical trial of gene therapy for advanced pancreatic cancer: safety, biodistribution and preliminary clinical findings. Mol Ther, 2015; 23:779–789.
15.
CarrereN, VernejoulF, SouqueA, et al.Characterization of the bystander effect of somatostatin receptor sst2 after in vivo gene transfer into human pancreatic cancer cells. Hum Gene Ther, 2005; 16:1175–1193.
16.
VernejoulF, FaureP, BenaliN, et al.Antitumor effect of in vivo somatostatin receptor subtype 2 gene transfer in primary and metastatic pancreatic cancer models. Cancer Res, 2002; 62:6124–6131.
17.
Guillermet-GuibertJ, Saint-LaurentN, DavenneL, et al.Novel synergistic mechanism for sst2 somatostatin and TNFα receptors to induce apoptosis: crosstalk between NF-κB and JNK pathways. Cell Death Differ, 2007; 14:197–208.
18.
BuscailL, DelesqueN, EstèveJP, et al.Stimulation of tyrosine phosphatase and inhibition of cell proliferation by somatostatin analogues: mediation by human somatostatin receptor subtypes SSTR1 and SSTR2. Proc Natl Acad Sci U S A, 1994; 91:2315–2319.
19.
RochaixP, DelesqueN, EstèveJP, et al.Gene therapy for pancreatic carcinoma: local and distant antitumor effects after somatostatin receptor sst2 gene transfer. Hum Gene Ther, 1999; 10:995–1008.
20.
VernejoulF, GhénassiaL, SouqueA, et al.Gene therapy based on gemcitabine chemosensitization suppresses pancreatic tumor growth. Mol Ther, 2006; 14:758–767.
21.
DoodyAM, KorleyJN, DangKP, et al.Characterizing the structure/function parameter space of hydrocarbon-conjugated branched polyethylenimine for DNA delivery in vitro. J Control Release, 2006; 116:227–237.
22.
ForrestML, MeisterGE, KoerberJT, et al.Partial acetylation of polyethylenimine enhances in vitro gene delivery. Pharm Res, 2004; 21:365–371.
23.
OskueeRK, DehshahriA, ShierWT, et al.Alkylcarboxylate grafting to polyethylenimine: a simple approach to producing a DNA nanocarrier with low toxicity. J Gene Med, 2009; 11:921–932.
24.
ThomasM, and KlibanovAM. Enhancing polyethylenimine's delivery of plasmid DNA into mammalian cells. Proc Natl Acad Sci U S A, 2002; 99:14640–14645.
25.
MidouxP, PichonC, YaouancJ-J, et al.Chemical vectors for gene delivery: a current review on polymers, peptides and lipids containing histidine or imidazole as nucleic acids carriers. Br J Pharmacol, 2009; 157:166–178.
26.
BertrandE, GonçalvesC, BillietL, et al.Histidinylated linear PEI: a new efficient non-toxic polymer for gene transfer. Chem Commun (Camb), 2011; 47:12547–12549.
27.
BreuzardG, TertilM, GonçalvesC, et al.Nuclear delivery of NFκB-assisted DNA/polymer complexes: plasmid DNA quantitation by confocal laser scanning microscopy and evidence of nuclear polyplexes by FRET imaging. Nucleic Acids Res, 2008; 36:e71.
28.
GonçalvesC, ArdourelM-Y, DecovilleM, et al.An optimized extended DNA κB site that enhances plasmid DNA nuclear import and gene expression. J Gene Med, 2009; 11:401–411.
29.
PigeonL, GonçalvesC, GossetD, et al.An E3-14.7K peptide that promotes microtubules-mediated transport of plasmid DNA increases polyplexes transfection efficiency. Small, 2013; 9:3845–3851.
30.
KatzMHG, WangH, FlemingJB, et al.Long-term survival after multidisciplinary management of resected pancreatic adenocarcinoma. Ann Surg Oncol, 2009; 16:836–847.
31.
RiallTS, CameronJL, LillemoeKD, et al.Resected periampullary adenocarcinoma: 5-year survivors and their 6- to 10-year follow-up. Surgery, 2006; 140:764–772.
32.
PitardB, Bello-RoufaïM, LambertO, et al.Negatively charged self-assembling DNA/poloxamine nanospheres for in vivo gene transfer. Nucleic Acids Res, 2004; 32:e159.
33.
AltonEW, ArmstrongDK, AshbyD, et al.; UK Cystic Fibrosis Gene Therapy Consortium. Repeated nebulization of non-viral CFTR gene therapy in patients with cystic fibrosis: a randomized, double-blind, placebo-controlled, phase 2b trial. Lancet Respir Med, 2015; 3:684–691.
34.
Richard-FiardoP, HervouetC, MarsaultR, et al.Evaluation of tetrafunctional block copolymers as synthetic vectors for lung gene transfer. Biomaterials, 2015; 45:10–17.
35.
Richard-FiardoP, CambienB, PradelliE, et al.Effect of fractalkine–Fc delivery in experimental lung metastasis using DNA/704 nanospheres. Cancer Gene Ther, 2011; 18:761–772.
36.
BrownBD, VenneriMA, ZingaleA, et al.Endogenous microRNA regulation suppresses transgene expression in hematopoietic lineages and enables stable gene transfer. Nat Med, 2006; 12:585–591.
37.
EzzineS, VassauxG, PitardB, et al.RILES, a novel method for temporal analysis of the in vivo regulation of miRNA expression. Nucleic Acids Res, 2013; 41:e192–e192.
38.
PichardV, AubertD, BoniS, et al.Specific micro RNA-regulated TetR-KRAB transcriptional control of transgene expression in viral vector-transduced cells. PLoS One, 2012; 7:e51952.
39.
AmendolaM, GiustacchiniA, GentnerB, et al.A double-switch vector system positively regulates transgene expression by endogenous microRNA expression (miR-ON Vector). Mol Ther, 2013; 21:934–946.
40.
HumeauM, TorrisaniJ, and CordelierP. miRNA in clinical practice: pancreatic cancer. Clin Biochem, 2013; 46:933–936.
41.
KhanS, Ansarullah, KumarD, et al.Targeting microRNAs in pancreatic cancer: microplayers in the big game. Cancer Res, 2013; 73:6541–6547.
42.
GayralM, JoS, HanounN, et al.MicroRNAs as emerging biomarkers and therapeutic targets for pancreatic cancer. World J Gastroenterol, 2014; 20:11199–11209.
43.
Bofill-De RosX, GironellaM, and FillatC. miR-148a- and miR-216a-regulated oncolytic adenoviruses targeting pancreatic tumors attenuate tissue damage without perturbation of miRNA activity. Mol Ther, 2014; 22:1665–1677.
44.
Bofill-De RosX, VillanuevaE, and FillatC. Late-phase miRNA-controlled oncolytic adenovirus for selective killing of cancer cells. Oncotarget, 2015; 6:6179–6190.
45.
PolJ, BloyN, ObristF, et al.Trial Watch: oncolytic viruses for cancer therapy. Oncoimmunology, 2014; 3:e28694.
46.
TouchefeuY, HarringtonK, GalmicheJ, et al.Review article: gene therapy, recent developments and future prospects in gastrointestinal oncology. Aliment Pharmacol Ther, 2010; 32:953–968.
47.
WennierS, LiS, and McFaddenG. Oncolytic virotherapy for pancreatic cancer. Expert Rev Mol Med, 2011; 13:e18.
48.
XuC, LiH, SuC, et al.Viral therapy for pancreatic cancer: tackle the bad guys with poison. Cancer Lett, 2013; 333:1–8.
49.
BhattacharyyaM, FrancisJ, EddouadiA, et al.An oncolytic adenovirus defective in pRb-binding (dl922–947) can efficiently eliminate pancreatic cancer cells and tumors in vivo in combination with 5-FU or gemcitabine. Cancer Gene Ther, 2011; 18:734–743.
50.
HechtJR, BedfordR, AbbruzzeseJL, et al.A phase I/II trial of intratumoral endoscopic ultrasound injection of ONYX-015 with intravenous gemcitabine in unresectable pancreatic carcinoma. Clin Cancer Res, 2003; 9:555–561.
51.
LucasT, BenihoudK, VigantF, et al.Hexon modification to improve the activity of oncolytic adenovirus vectors against neoplastic and stromal cells in pancreatic cancer. PLoS One, 2015; 10:e0117254.
52.
GayralM, LulkaH, HanounN, et al.Targeted oncolytic herpes simplex virus type 1 eradicates experimental pancreatic tumors. Hum Gene Ther, 2015; 26:104–113.
53.
IlkowCS, SwiftSL, BellJC, et al.From scourge to cure: tumour-selective viral pathogenesis as a new strategy against cancer. PLoS Pathog, 2014; 10:e1003836.
54.
GammonDB, GowrishankarB, DuraffourS, et al.Vaccinia virus-encoded ribonucleotide reductase subunits are differentially required for replication and pathogenesis. PLoS Pathog, 2010; 6:e1000984.
55.
ElfordHL, FreeseM, PassamaniE, et al.Ribonucleotide reductase and cell proliferation. I. Variations of ribonucleotide reductase activity with tumor growth rate in a series of rat hepatomas. J Biol Chem, 1970; 245:5228–5233.
56.
MundschauLJ, and FallerDV. Endogenous inhibitors of the dsRNA-dependent eIF-2α protein kinase PKR in normal and ras-transformed cells. Biochimie, 1994; 76:792–800.
57.
AngelovaAL, GeletnekyK, NüeschJPF, et al.Tumor selectivity of oncolytic parvoviruses: from in vitro and animal models to cancer patients. Front Bioeng Biotechnol, 2015; 3:55.
58.
NüeschJPF, LacroixJ, MarchiniA, et al.Molecular pathways: rodent parvoviruses—mechanisms of oncolysis and prospects for clinical cancer treatment. Clin Cancer Res, 2012; 18:3516–3523.
59.
AngelovaAL, AprahamianM, GrekovaSP, et al.Improvement of gemcitabine-based therapy of pancreatic carcinoma by means of oncolytic parvovirus H-1PV. Clin Cancer Res, 2009; 15:511–519.
60.
RéjibaS, BigandC, ParmentierC, et al.Oncosuppressive suicide gene virotherapy “PVH1-yCD/5-FC” for pancreatic peritoneal carcinomatosis treatment: NFκB and Akt/PI3K involvement. PLoS One, 2013; 8:e70594.
61.
LiJ, BonifatiS, HristovG, et al.Synergistic combination of valproic acid and oncolytic parvovirus H-1PV as a potential therapy against cervical and pancreatic carcinomas. EMBO Mol Med, 2013; 5:1537–1555.
62.
MoehlerM, GoepfertK, HeinrichB, et al.Oncolytic virotherapy as emerging immunotherapeutic modality: potential of parvovirus H-1. Front Oncol, 2014; 4:92.
63.
GrekovaSP, AprahamianM, DaefflerL, et al.Interferon γ improves the vaccination potential of oncolytic parvovirus H-1PV for the treatment of peritoneal carcinomatosis in pancreatic cancer. Cancer Biol Ther, 2011; 12:888–895.
64.
GeletnekyK, HuesingJ, RommelaereJ, et al.Phase I/IIa study of intratumoral/intracerebral or intravenous/intracerebral administration of parvovirus H-1 (ParvOryx) in patients with progressive primary or recurrent glioblastoma multiforme: ParvOryx01 protocol. BMC Cancer, 2012; 12:99.
65.
GeletnekyK, LeoniA-L, Pohlmeyer-EschG, et al.Bioavailability, biodistribution, and CNS toxicity of clinical-grade parvovirus H1 after intravenous and intracerebral injection in rats. Comp Med, 2015; 65:36–45.Received for publication October 20, 2015; accepted after revision November 21, 2015.
