Special Issue "Cancers Gene Therapy"

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A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (31 October 2015)

Special Issue Editor

Guest Editor
Dr. Gabi Dachs

Research Associate Professor, Mackenzie Cancer Research Group, University of Otago, Christchurch, PO Box 4345, Christchurch 8140, New Zealand
Website | E-Mail
Interests: gene directed enzyme prodrug therapy (GDEPT); tumour hypoxia; nitroreductase; anti-vascular therapy; hypoxia-inducible factor 1 (HIF-1); ascorbate

Special Issue Information

Dear Colleagues,

Cancer gene therapy is designed to destroy tumours via the delivery of therapeutic genes to malignant cells. Why has the hype surrounding cancer gene therapy not (yet) resulted in an approved therapy? Adverse tumour characteristics, including inadequate blood supply and high interstitial fluid pressure, make cancer cells in solid tumours difficult to access. An innovative approach, covering all complicated aspects of this therapy, is required to revive the field. After all, it still has the potential to be the most selective of all cancer treatments, able to target even distant cancer deposits whilst sparing normal tissue.
This special issue aims to bring together both original studies and reviews covering novel aspects of gene therapy of cancer. We specifically like to invite articles covering the following areas:

•    Novel therapeutic genes or gene/prodrug combinations
•    Novel gene delivery methods, including reports on progress in systemic delivery
•    Novel vectors, encompassing viral, bacterial, cellular and synthetic vectors
•    Expression targeting via transcriptional regulation
•    Targeting of not only tumour cells, but also stromal cells, including blood vessels and inflammatory cells
•    Direct comparisons of gene therapy to current clinical therapies
•    New imaging methods to determine location and extend of gene spread
•    Sophisticated cell culture models able to mimic tumour conditions
•    Sophisticated, and potentially humanised, animal models
•    Clinical trial design
•    Safety considerations and mechanisms of side effects
•    Results from early clinical trials and proof of concept reports
•    Patient and public perceptions of gene therapy of cancer

Dr. Gabi Dachs
Guest Editor

Submission

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are refereed through a peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed Open Access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 800 CHF (Swiss Francs).

Keywords

therapeutic genes
vectors
expression targeting
stromal targeting
imaging
cell culture and animal models
clinical trials

Published Papers (7 papers)

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Research

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Open AccessFeature PaperArticle Electrotransfer of Plasmid DNA Encoding an Anti-Mouse Endoglin (CD105) shRNA to B16 Melanoma Tumors with Low and High Metastatic Potential Results in Pronounced Anti-Tumor Effects
Cancers 2016, 8(1), 3; doi:10.3390/cancers8010003
Received: 31 October 2015 / Revised: 17 December 2015 / Accepted: 17 December 2015 / Published: 24 December 2015
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Abstract
Endoglin overexpression is associated with highly proliferative tumor endothelium and also with some tumors, including melanoma. Its targeting has anti-tumor effectiveness, which can also be obtained by RNA interference. The aim of our study was to explore the anti-tumor effectiveness of endoglin silencing
[...] Read more.
Endoglin overexpression is associated with highly proliferative tumor endothelium and also with some tumors, including melanoma. Its targeting has anti-tumor effectiveness, which can also be obtained by RNA interference. The aim of our study was to explore the anti-tumor effectiveness of endoglin silencing by electrotransfer of plasmid DNA encoding short hairpin RNA against endoglin in two murine B16 melanoma variants with different metastatic potential on cells, spheroids and subcutaneous tumors in mice. The results demonstrate that endoglin silencing with gene electrotransfer reduces the proliferation, survival and migration of melanoma cells and also has anti-tumor effectiveness, as the therapy resulted in a high percentage of tumor cures (23% and 58% on B16F1 and B16F10 tumors, respectively). The effectiveness of the therapy correlated with endoglin expression in melanoma cells; in vitro the effects were more pronounced in B16F1 cells, which express more endoglin than B16F10. However, the opposite was observed in vivo in tumors, where there was a higher expression of endoglin and better anti-tumor effectiveness in the B16F10 tumor. In conclusion, targeting endoglin for the treatment of melanoma seems to be a concept worthy of further exploration due to the increased therapeutic effect of the therapy based on simultaneous vascular targeting and its direct effect on tumor cells. Full article
(This article belongs to the Special Issue Cancers Gene Therapy)
Open AccessArticle New Variants of Tomato Thymidine Kinase 1 Selected for Increased Sensitivity of E. coli KY895 towards Azidothymidine
Cancers 2015, 7(2), 966-980; doi:10.3390/cancers7020819
Received: 28 March 2015 / Revised: 19 May 2015 / Accepted: 27 May 2015 / Published: 8 June 2015
Cited by 2 | PDF Full-text (561 KB) | HTML Full-text | XML Full-text
Abstract
Nucleoside analogues (NA) are prodrugs that are phosphorylated by deoxyribonucleoside kinases (dNKs) as the first step towards a compound toxic to the cell. During the last 20 years, research around dNKs has gone into new organisms other than mammals and viruses. Newly discovered
[...] Read more.
Nucleoside analogues (NA) are prodrugs that are phosphorylated by deoxyribonucleoside kinases (dNKs) as the first step towards a compound toxic to the cell. During the last 20 years, research around dNKs has gone into new organisms other than mammals and viruses. Newly discovered dNKs have been tested as enzymes for suicide gene therapy. The tomato thymidine kinase 1 (ToTK1) is a dNK that has been selected for its in vitro kinetic properties and then successfully been tested in vivo for the treatment of malignant glioma. We present the selection of two improved variants of ToTK1 generated by random protein engineering for suicide gene therapy with the NA azidothymidine (AZT).We describe their selection, recombinant production and a subsequent kinetic and biochemical characterization. Their improved performance in killing of E. coli KY895 is accompanied by an increase in specificity for the NA AZT over the natural substrate thymidine as well as a decrease in inhibition by dTTP, the end product of the nucleoside salvage pathway for thymidine. The understanding of the enzymatic properties improving the variants efficacy is instrumental to further develop dNKs for use in suicide gene therapy. Full article
(This article belongs to the Special Issue Cancers Gene Therapy)
Figures

Open AccessArticle Investigation of siRNA Nanoparticle Formation Using Mono-Cationic Detergents and Its Use in Gene Silencing in Human HeLa Cells
Cancers 2013, 5(4), 1413-1425; doi:10.3390/cancers5041413
Received: 2 September 2013 / Revised: 25 October 2013 / Accepted: 28 October 2013 / Published: 1 November 2013
Cited by 2 | PDF Full-text (824 KB) | HTML Full-text | XML Full-text
Abstract
The focus of recent research has been on the development of siRNA vectors to achieve an innovative gene therapy. Most of the conventional vectors are siRNA nanoparticles complexed with cationic polymers and liposomes, making it difficult to release siRNA. In this study, we
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The focus of recent research has been on the development of siRNA vectors to achieve an innovative gene therapy. Most of the conventional vectors are siRNA nanoparticles complexed with cationic polymers and liposomes, making it difficult to release siRNA. In this study, we report on the use of MCD, a quaternary ammonium salt detergent containing a long aliphatic chain (L-chain) as an siRNA complexation agent using human HeLa cells (a model cancer cell). We prepared siRNA nanoparticles using various MCDs, and measured the diameters and zeta-potentials of the particles. The use of an MCD with a long L-chain resulted in the formation of a positively charged nanoparticle. In contrast, a negatively charged nanoparticle was formed when a MCD with a short L-chain was used. We next evaluated the gene silencing efficiency of the nanoparticles using HeLa cells expressing the luciferase protein. The results showed that the siRNA/MCD nanoparticles showed a higher gene silencing efficiency than Lipofectamine 2000. We also found that the efficiency of gene silencing is a function of the length of the alkyl chain in MCD and zeta-potential of the siRNA/MCD nanoparticles. Such information provides another viewpoint for designing siRNA vectors. Full article
(This article belongs to the Special Issue Cancers Gene Therapy)
Open AccessArticle The Flavin Reductase MsuE Is a Novel Nitroreductase that Can Efficiently Activate Two Promising Next-Generation Prodrugs for Gene-Directed Enzyme Prodrug Therapy
Cancers 2013, 5(3), 985-997; doi:10.3390/cancers5030985
Received: 31 May 2013 / Revised: 23 July 2013 / Accepted: 26 July 2013 / Published: 8 August 2013
Cited by 7 | PDF Full-text (742 KB) | HTML Full-text | XML Full-text
Abstract
Bacterial nitroreductase enzymes that can efficiently catalyse the oxygen-independent reduction of prodrugs originally developed to target tumour hypoxia offer great potential for expanding the therapeutic range of these molecules to aerobic tumour regions, via the emerging cancer strategy of gene-directed enzyme prodrug therapy
[...] Read more.
Bacterial nitroreductase enzymes that can efficiently catalyse the oxygen-independent reduction of prodrugs originally developed to target tumour hypoxia offer great potential for expanding the therapeutic range of these molecules to aerobic tumour regions, via the emerging cancer strategy of gene-directed enzyme prodrug therapy (GDEPT). Two promising hypoxia prodrugs for GDEPT are the dinitrobenzamide mustard PR-104A, and the nitrochloromethylbenzindoline prodrug nitro-CBI-DEI. We describe here use of a nitro-quenched fluorogenic probe to identify MsuE from Pseudomonas aeruginosa as a novel nitroreductase candidate for GDEPT. In SOS and bacteria-delivered enzyme prodrug cytotoxicity assays MsuE was less effective at activating CB1954 (a first-generation GDEPT prodrug) than the “gold standard” nitroreductases NfsA and NfsB from Escherichia coli. However, MsuE exhibited comparable levels of activity with PR-104A and nitro-CBI-DEI, and is the first nitroreductase outside of the NfsA and NfsB enzyme families to do so. These in vitro findings suggest that MsuE is worthy of further evaluation in in vivo models of GDEPT. Full article
(This article belongs to the Special Issue Cancers Gene Therapy)

Review

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Open AccessReview Advancing Clostridia to Clinical Trial: Past Lessons and Recent Progress
Cancers 2016, 8(7), 63; doi:10.3390/cancers8070063
Received: 16 May 2016 / Revised: 15 June 2016 / Accepted: 22 June 2016 / Published: 28 June 2016
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Abstract
Most solid cancers contain regions of necrotic tissue. The extent of necrosis is associated with poor survival, most likely because it reflects aggressive tumour outgrowth and inflammation. Intravenously injected spores of anaerobic bacteria from the genus Clostridium infiltrate and selectively germinate in these
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Most solid cancers contain regions of necrotic tissue. The extent of necrosis is associated with poor survival, most likely because it reflects aggressive tumour outgrowth and inflammation. Intravenously injected spores of anaerobic bacteria from the genus Clostridium infiltrate and selectively germinate in these necrotic regions, providing cancer-specific colonisation. The specificity of this system was first demonstrated over 60 years ago and evidence of colonisation has been confirmed in multiple tumour models. The use of “armed” clostridia, such as in Clostridium Directed Enzyme Prodrug Therapy (CDEPT), may help to overcome some of the described deficiencies of using wild-type clostridia for treatment of cancer, such as tumour regrowth from a well-vascularised outer rim of viable cells. Successful preclinical evaluation of a transferable gene that metabolises both clinical stage positron emission tomography (PET) imaging agents (for whole body vector visualisation) as well as chemotherapy prodrugs (for conditional enhancement of efficacy) would be a valuable early step towards the prospect of “armed” clostridia entering clinical evaluation. The ability to target the immunosuppressive hypoxic tumour microenvironment using CDEPT may offer potential for synergy with recently developed immunotherapy strategies. Ultimately, clostridia may be most efficacious when combined with conventional therapies, such as radiotherapy, that sterilise viable aerobic tumour cells. Full article
(This article belongs to the Special Issue Cancers Gene Therapy)
Open AccessReview Studies of Tumor Suppressor Genes via Chromosome Engineering
Cancers 2016, 8(1), 4; doi:10.3390/cancers8010004
Received: 10 November 2015 / Revised: 19 December 2015 / Accepted: 21 December 2015 / Published: 30 December 2015
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Abstract
The development and progression of malignant tumors likely result from consecutive accumulation of genetic alterations, including dysfunctional tumor suppressor genes. However, the signaling mechanisms that underlie the development of tumors have not yet been completely elucidated. Discovery of novel tumor-related genes plays a
[...] Read more.
The development and progression of malignant tumors likely result from consecutive accumulation of genetic alterations, including dysfunctional tumor suppressor genes. However, the signaling mechanisms that underlie the development of tumors have not yet been completely elucidated. Discovery of novel tumor-related genes plays a crucial role in our understanding of the development and progression of malignant tumors. Chromosome engineering technology based on microcell-mediated chromosome transfer (MMCT) is an effective approach for identification of tumor suppressor genes. The studies have revealed at least five tumor suppression effects. The discovery of novel tumor suppressor genes provide greater understanding of the complex signaling pathways that underlie the development and progression of malignant tumors. These advances are being exploited to develop targeted drugs and new biological therapies for cancer. Full article
(This article belongs to the Special Issue Cancers Gene Therapy)
Open AccessReview Lentiviral Vectors for Cancer Immunotherapy and Clinical Applications
Cancers 2013, 5(3), 815-837; doi:10.3390/cancers5030815
Received: 10 May 2013 / Revised: 7 June 2013 / Accepted: 21 June 2013 / Published: 2 July 2013
Cited by 11 | PDF Full-text (584 KB) | HTML Full-text | XML Full-text
Abstract
The success of immunotherapy against infectious diseases has shown us the powerful potential that such a treatment offers, and substantial work has been done to apply this strategy in the fight against cancer. Cancer is however a fiercer opponent than pathogen-caused diseases due
[...] Read more.
The success of immunotherapy against infectious diseases has shown us the powerful potential that such a treatment offers, and substantial work has been done to apply this strategy in the fight against cancer. Cancer is however a fiercer opponent than pathogen-caused diseases due to natural tolerance towards tumour associated antigens and tumour-induced immunosuppression. Recent gene therapy clinical trials with viral vectors have shown clinical efficacy in the correction of genetic diseases, HIV and cancer. The first successful gene therapy clinical trials were carried out with onco(g-)retroviral vectors but oncogenesis by insertional mutagenesis appeared as a serious complication. Lentiviral vectors have emerged as a potentially safer strategy, and recently the first clinical trial of patients with advanced leukemia using lentiviral vectors has proven successful. Additionally, therapeutic lentivectors have shown clinical efficacy for the treatment of HIV, X-linked adrenoleukodystrophy, and b-thalassaemia. This review aims at describing lentivectors and how they can be utilized to boost anti-tumour immune responses by manipulating the effector immune cells. Full article
(This article belongs to the Special Issue Cancers Gene Therapy)

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