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1.
Methods Mol Biol ; 2521: 1-21, 2022.
Article in English | MEDLINE | ID: mdl-35732990

ABSTRACT

Gene therapy has started in the late 1980s as novel, clinically applicable therapeutic option. It revolutionized the treatment of genetic diseases with the initial intent to repair or replace defective genes. Gene therapy has been adapted for treatment of malignant diseases to improve the outcome of cancer patients. In fact, cancer gene therapy has rapidly gained great interest and evolved into a research field with highest proportion of research activities in gene therapy. In this context, cancer gene therapy has long entered translation into clinical trials and therefore more than two-thirds of all gene therapy trials worldwide are aiming at the treatment of cancer disease using different therapeutic strategies. During the decades in cancer gene therapy, tremendous knowledge has accumulated. This led to significant improvements in vector design, transgene repertoire, more targeted interventions, use of novel gene therapeutic technologies such as CRISPR/Cas, sleeping beauty vectors, and development of effective cancer immunogene therapies. In this chapter, a brief overview of current key developments in cancer gene therapy is provided to gain insights into the recent directions in research as well as in clinical application of cancer gene therapy.


Subject(s)
Genetic Vectors , Neoplasms , Gene Transfer Techniques , Genes, Neoplasm , Genetic Therapy , Genetic Vectors/genetics , Humans , Neoplasms/genetics , Neoplasms/therapy , Transgenes
2.
Cancers (Basel) ; 13(17)2021 Aug 31.
Article in English | MEDLINE | ID: mdl-34503203

ABSTRACT

Pancreatic cancer (PC) is one of the most lethal cancers worldwide, associated with poor prognosis and restricted therapeutic options. Clostridium perfringens enterotoxin (CPE), is a pore-forming (oncoleaking) toxin, which binds to claudin-3 and -4 (Cldn3/4) causing selective cytotoxicity. Cldn3/4 are highly upregulated in PC and represent an effective target for oncoleaking therapy. We utilized a translation-optimized CPE vector (optCPE) for new suicide approach of PC in vitro and in cell lines (CDX) and patient-derived pancreatic cancer xenografts (PDX) in vivo. The study demonstrates selective toxicity in Cldn3/4 overexpressing PC cells by optCPE gene transfer, mediated by pore formation, activation of apoptotic/necrotic signaling in vitro, induction of necrosis and of bystander tumor cell killing in vivo. The optCPE non-viral intratumoral in vivo jet-injection gene therapy shows targeted antitumoral efficacy in different CDX and PDX PC models, leading to reduced tumor viability and induction of tumor necrosis, which is further enhanced if combined with chemotherapy. This selective oncoleaking suicide gene therapy improves therapeutic efficacy in pancreas carcinoma and will be of value for better local control, particularly of unresectable or therapy refractory PC.

3.
BMC Cancer ; 17(1): 129, 2017 02 13.
Article in English | MEDLINE | ID: mdl-28193196

ABSTRACT

BACKGROUND: Bacterial toxins have evolved to an effective therapeutic option for cancer therapy. The Clostridium perfringens enterotoxin (CPE) is a pore-forming toxin with selective cytotoxicity. The transmembrane tight junction proteins claudin-3 and -4 are known high affinity CPE receptors. Their expression is highly upregulated in human cancers, including breast, ovarian and colon carcinoma. CPE binding to claudins triggers membrane pore complex formation, which leads to rapid cell death. Previous studies demonstrated the anti-tumoral effect of treatment with recombinant CPE-protein. Our approach aimed at evaluation of a selective and targeted cancer gene therapy of claudin-3- and/or claudin-4- expressing colon carcinoma in vitro and in vivo by using translation optimized CPE expressing vector. METHODS: In this study the recombinant CPE and a translation optimized CPE expressing vector (optCPE) was used for targeted gene therapy of claudin-3 and/or -4 overexpressing colon cancer cell lines. All experiments were performed in the human SW480, SW620, HCT116, CaCo-2 and HT-29 colon cancer and the isogenic Sk-Mel5 and Sk-Mel5 Cldn-3-YFP melanoma cell lines. Claudin expression analysis was done at protein and mRNA level, which was confirmed by immunohistochemistry. The CPE induced cytotoxicity was analyzed by the MTT cytotoxicity assay. In addition patient derived colon carcinoma xenografts (PDX) were characterized and used for the intratumoral in vivo gene transfer of the optCPE expressing vector in PDX bearing nude mice. RESULTS: Claudin-3 and -4 overexpressing colon carcinoma lines showed high sensitivity towards both recCPE application and optCPE gene transfer. The positive correlation between CPE cytotoxicity and level of claudin expression was demonstrated. Transfection of optCPE led to targeted, rapid cytotoxic effects such as membrane disruption and necrosis in claudin overexpressing cells. The intratumoral optCPE in vivo gene transfer led to tumor growth inhibition in colon carcinoma PDX bearing mice in association with massive necrosis due to the intratumoral optCPE expression. CONCLUSIONS: This novel approach demonstrates that optCPE gene transfer represents a promising and efficient therapeutic option for a targeted suicide gene therapy of claudin-3 and/or claudin-4 overexpressing colon carcinomas, leading to rapid and effective tumor cell killing in vitro and in vivo.


Subject(s)
Claudin-3/genetics , Claudin-4/genetics , Colonic Neoplasms/therapy , Enterotoxins/therapeutic use , Genes, Transgenic, Suicide , Genetic Therapy , Animals , Bystander Effect , Clostridium perfringens , Colonic Neoplasms/genetics , Colonic Neoplasms/pathology , Female , Humans , Mice , Mice, Nude , Xenograft Model Antitumor Assays
4.
Expert Opin Biol Ther ; 16(4): 443-61, 2016.
Article in English | MEDLINE | ID: mdl-26761200

ABSTRACT

INTRODUCTION: This review presents recent developments in the use of nonviral vectors and transfer technologies in cancer gene therapy. Tremendous progress has been made in developing cancer gene therapy in ways that could be applicable to treatments. Numerous efforts are focused on methods of attacking known and novel targets more efficiently and specifically. In parallel to progress in nonviral vector design and delivery technologies, important achievements have been accomplished for suicide, gene replacement, gene suppression and immunostimulatory therapies. New nonviral cancer gene therapies have been developed based on emerging RNAi (si/shRNA-, miRNA) or ODN. AREAS COVERED: This review provides an overview of recent gene therapeutic strategies in which nonviral vectors have been used experimentally and in clinical trials. Furthermore, we present current developments in nonviral vector systems in association with important chemical and physical gene delivery technologies and their potential for the future. EXPERT OPINION: Nonviral gene therapy has maintained its position as an approach for treating cancer. This is reflected by the fact that more than 17% of all gene therapy trials employ nonviral approaches. Thus, nonviral vectors have emerged as a clinical alternative to viral vectors for the appropriate expression and delivery of therapeutic genes.


Subject(s)
Gene Transfer Techniques , Genetic Therapy/methods , Genetic Vectors , Neoplasms/therapy , Genes, Neoplasm/genetics , Genetic Therapy/trends , Humans , MicroRNAs/genetics
5.
Recent Results Cancer Res ; 209: 95-110, 2016.
Article in English | MEDLINE | ID: mdl-28101690

ABSTRACT

For suicide gene therapy, initially prodrug-converting enzymes (gene-directed enzyme-producing therapy, GDEPT) were employed to intracellularly metabolize non-toxic prodrugs into toxic compounds, leading to the effective suicidal killing of the transfected tumor cells. In this regard, the suicide gene therapy has demonstrated its potential for efficient tumor eradication. Numerous suicide genes of viral or bacterial origin were isolated, characterized, and extensively tested in vitro and in vivo, demonstrating their therapeutic potential even in clinical trials to treat cancers of different entities. Apart from this, growing efforts are made to generate more targeted and more effective suicide gene systems for cancer gene therapy. In this regard, bacterial toxins are an alternative to the classical GDEPT strategy, which add to the broad spectrum of different suicide approaches. In this context, lytic bacterial toxins, such as streptolysin O (SLO) or the claudin-targeted Clostridium perfringens enterotoxin (CPE) represent attractive new types of suicide oncoleaking genes. They permit as pore-forming proteins rapid and also selective toxicity toward a broad range of cancers. In this chapter, we describe the generation and use of SLO as well as of CPE-based gene therapies for the effective tumor cell eradication as promising, novel suicide gene approach particularly for treatment of therapy refractory tumors.


Subject(s)
Bacterial Toxins/genetics , Genes, Transgenic, Suicide , Genetic Therapy/methods , Neoplasms/therapy , Animals , Bacterial Proteins/biosynthesis , Bacterial Proteins/genetics , Bacterial Toxins/biosynthesis , Cell Death , Diphtheria Toxin/biosynthesis , Diphtheria Toxin/genetics , Enterotoxins/biosynthesis , Enterotoxins/genetics , Gene Expression Regulation , Humans , Neoplasms/genetics , Neoplasms/metabolism , Streptolysins/biosynthesis , Streptolysins/genetics
6.
Methods Mol Biol ; 1317: 69-85, 2015.
Article in English | MEDLINE | ID: mdl-26072402

ABSTRACT

Suicide gene therapy has been shown to be very efficient in tumor eradication. Numerous suicide genes were tested in vitro and in vivo demonstrating their therapeutic potential in clinical trials. Apart from this, still growing efforts are made to generate more targeted and more effective suicide gene systems for cancer gene therapy. In this regard bacterial toxins are an alternative, which add to the broad spectrum of different suicide strategies. In this context, the claudin-targeted bacterial Clostridium perfringens enterotoxin (CPE) is an attractive new type of suicide oncoleaking gene, which as pore-forming protein exerts specific and rapid toxicity towards claudin-3- and -4-overexpressing cancers. In this chapter we describe the generation and use of CPE-expressing vectors for the effective tumor cell killing as novel suicide gene approach particularly for treatment of therapy refractory tumors.


Subject(s)
Clostridium perfringens/metabolism , Enterotoxins/genetics , Enterotoxins/therapeutic use , Genes, Transgenic, Suicide , Genetic Therapy/methods , Blotting, Western , Bystander Effect , Cell Line, Tumor , Claudins/chemistry , Claudins/metabolism , Enzyme-Linked Immunosorbent Assay , Genetic Vectors/metabolism , Humans , Immunohistochemistry , L-Lactate Dehydrogenase/metabolism , Real-Time Polymerase Chain Reaction , Transfection
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