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ABSTRACT Gene therapy strategies in cancer have remained an active area of preclinical and clinical research. One of the current limitations to successful trials is the relative transduction efficiency to produce a therapeutic effect. While intratumoral injections are the mainstay of many treatment regimens to date, this approach is hindered by hydrostatic pressures within the tumor and is not always applicable to all tumor subtypes. Vascular-targeting strategies introduce an alternative method to deliver vectors with higher local concentrations and minimization Advances in Genetics, Vol. 67 Copyright 2009, Elsevier Inc. All rights reserved.
of systemic toxicity. Moreover, therapeutic targeting of angiogenic vasculature often leads to enhanced bystander effects, improving efficacy. While identification of functional and systemically accessible molecular targets is challenging, approaches, such as in vivo phage display and phage-based viral delivery vectors, provide a platform upon which vascular targeting of vectors may become a viable and translational approach. ß 2009, Elsevier Inc.
local injection and attempts to deliver these vectors systemically have met with poor results. One of the basic tenets of systemic targeting is that the first cellular layer a circulating agent would encounter is the endothelial lining of blood vessels. The introduction of vascular targeting to gene-delivery vehicles could permit higher local concentrations for transduction, increase exposure, and minimize systemic toxicity. This review focuses on therapeutic concepts for targeted cancer gene therapy, vectors suitable for site-directed delivery, and methods to identify suitable receptors for ligand-directed delivery.
II. THERAPEUTIC CONCEPTS IN CANCER GENE THERAPY The complexity of the tissue and tumor microenvironment permits a number of different targeting strategies toward different cell types relevant for therapy. The abundant genetic abnormalities in tumor cells present a clear target for genetic manipulation. In addition, introduction of genes into genetically stable cellular components in the tumor, such as the stroma and endothelial cells of blood vessels, provides an alternative strategy for delivery. Another approach involves stimulation of the immune system for tumor growth inhibition. The advantages and disadvantages of these methods along with current concepts for target genes are further explored in the following sections.
A. Immunomodulation Intense study in the area of immunology over the last decade has made cancer immunobiology one of the more promising and dominant approaches in cancer gene therapy (Blankenstein et al., 1996). The goal is to stimulate a host response against the tumor by enhancing or inducing the native immune system using direct vaccination and immunization of tumor antigens. To enhance the immunogenicity of tumors, transfection of an individual’s tumor cells and autologous vaccination have emerged as successful methods for gene delivery. The tumor cells transfected with a number of candidate genes for use in this type of treatment are genes expressing costimulators of T-cell activation (e.g., CD80, CD86, and CD40) (Vesosky and Hurwitz, 2003); cytokines (e.g., interleukin-2 (IL-2), IL-3, IL-4, IL-6, IL-7, IL-10, IL-12, granulocyte-macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor (TNF), and interferon- ) to facilitate differentiation and/or activation of effector cells (Qian et al., 2006); allogeneic MHC class I proteins (e.g., transfection of HLA-B7 into the tumors of HLA-B7-negative patients) (Nabel et al., 1993); or syngeneic MHC class II proteins whose expression enables the tumor cell to present antigens to T-lymphocytes and stimulates activation of T-helper cells (Hock et al., 1995).
elimination of residual tumor cells, but if the goal is to prevent metastases, further growth or recurrence, a long-term response needs to be induced.  Condition of patients’ immune response: All strategies described above rely on functions of the patients’ immune-system. If the patient is immune compromised because of his tumor or chemotherapy/radiation therapy, immunomodulation therapy may not be possible.  Tumor antigen: In order for the immunization protocols with tumor antigens to be successful, the immunizing agent needs to be validated and expression might have to be verified for each individual patient. These considerations, in addition to the type of cancer selected for treatment, are essential for the success of immunomodulating gene therapy for patients. With increases in understanding of the immune response, particularly in cancer patients, and the molecular mediators influencing activation or suppression, the future success of this gene therapy approach may improve.
B. Prodrug-converting enzymes The concept of suicide-genes as a treatment modality was introduced nearly 20 years ago and has emerged as standalone treatment modality; gene-directed enzyme prodrug therapy (GDEPT). The concept uses inactive prodrugs that can be converted into active, cytotoxic drugs by enzymatic reactions within cells.
This converting enzyme is the delivered agent to the tumor site and subsequently expressed by cellular machinery. Site-specific delivery of the drug-converting enzyme at the tumor site results in a high local accumulation of cytotoxic drugs, mediating tumor elimination, and little-to-no accumulation of drug elsewhere. Moreover, the localized conversion of cytotoxic drugs also leads to a very potent bystander effect. As such, complete tumor eradication can be achieved with as little as 10% transduction of the tumor mass (Aghi et al., 2000; Rooseboom et al., 2004). A widely used prototypical example is the herpes simplex virus thymidine kinase (HSV-TK) in combination with ganciclovir. Activation of HSV-TK phosphorylates ganciclovir to generate the toxic species (Eck et al., 1996; Moolten et al., 1990). This treatment strategy has been leveraged in numerous gene therapy trials including direct intratumoral injections in primary brain tumors and intraperitoneal injection for ovarian cancer patients. Another example is the expression of bacterial cytosine deaminase as the converting enzyme in combination with systemically delivered 5-fluorocytosine (5-FC). Transfected cells convert 5-FC to 5-fluorouracil (5-FU) leading to cytotoxic effects (Crystal et al., 1997; Ohwada et al., 1996). One overriding advantage of these two prototype systems is the use of clinically ready prodrugs to generate a therapeutic effect, thereby streamlining approval for regulatory agencies and avoiding further complications and delays for clinical translation.
extremely effective therapy (Levine, 1997). Indeed, an injectable recombinant human adenovirus expressing p53 (trademarked as GendicineTM) became the world’s first gene therapy product approved by a governmental agency (State Food and Drug Administration of China (SFDA)) for the treatment of cancer. This was a milestone in the field of gene therapy and paves the way for further translational efforts (Peng, 2005). Silencing activated oncogenes can be achieved using antisense-, ribozyme-, or RNAi-based therapies. Each of these silencing techniques relies on different mechanisms of action, but the net effect is blockage of mRNA translation into protein. In cancer biology, the following classes of genes have been targeted: (1) oncogenes; (2) cell-cycle regulatory genes; (3) drug-resistance genes; (4) angiogenic genes; (5) growth factor receptor genes; and (6) genes in cell signaling pathways (Lebedeva and Stein, 2001; McCaffrey et al., 2002; Scanlon, 2004; Scanlon et al., 1991; Singer et al., 2003; Stein, 2001). These techniques are in early preclinical phases, but have progressed with great enthusiasm.
tumor blood vessels are largely considered epigenetically stable. Therefore, selection of silencing or inhibitory products would affect normal cells throughout the body if transfected, raising the risk of unwanted side effects.
E. Combination therapies Therapeutic gene delivery in cancer can also result in enhancement of standard treatment/regimen efficacy. A majority of modern chemotherapies do not discriminate between normal and cancer cells. Cytotoxicity to proliferating normal cells, such as hematopoietic precursor cells, becomes dose-limiting in treatment with chemotherapeutics. Thus, methods to reduce toxicity to normal cells would be a major advance in treatment regimens. For example, bone marrow depletion remains a major side effect of chemotherapy. Transfection of bone marrow cells with multidrug-resistant 1 gene enhances cellular resistance to chemotherapy and allows patients to receive higher doses of conventional agents (Culver, 1996; Huber and Margrath, 1998; Lattime and Gerson, 2001; Mickisch et al., 1992; Templeton and Lasic, 2000). Another recently suggested approach for synergistic therapy is with the introduction of iodine transporters to the tumor cells by gene delivery. These transporters increase the uptake of radioactive iodine, and this approach demonstrated success in treatment of experimental thyroid tumors (Boelaert and Franklyn, 2003). Expansion to other tumor types has been used preclinically for therapy and imaging purposes.
F. Oncolytic viruses This strategy makes use of replicating recombinant viruses. The underlying concept is to administer the virus intratumorally after which viral replication will take place in the transduced cells. Infected cells will ultimately be disrupted and viral progeny is released, allowing the spread of infection. It is important to achieve cancer-specific replication to limit viral replication to the site of the tumor (Vecil and Lang, 2003). This can be accomplished by (1) selective cell entry, (2) selective transcription of genes necessary for replication (tumor tissuespecific promoter), or (3) deletion of genes necessary for replication in normal cells but not in tumor cells (e.g., deletion of E1B-gene in ONYX-015).
), have been explored in preclinical models of melanoma and, more recently, in spontaneous cancers in dogs through the Comparative Oncology Trials Consortium at the National Cancer Institute (Paoloni et al., 2009; Tandle et al., 2009). Finally, further study of the mechanism by which AAVP vectors targeted to the vasculature-mediated tumor therapy has implicated a heterotypic bystander killing effect. This endothelial cell–tumor cell interaction is largely mediated through intercellular gap junctions involving connexins 43 and 26 (Trepel et al., 2009). At present, much of the work involving targeted AAVP vectors has been in models of human disease. However, integration of clinically applicable PET imaging with 18FEAU and therapy with ganciclovir suggests that rapid translation to patient populations may be imminent. Furthermore, improvements in transgene regulation through developments in tissue-specific promoters may further enhance tissue specificity and improve the therapeutic index for this vector.
VEGF, vascular endothelial growth factor; bFGF, basic fibroblast growth factor; MCAM, melanoma a cell adhesion molecule; EC, endothelial cells; HMWMAA, high molecular weight melanoma-associated antigen; MMP, matrix metalloproteinase; CRKL, chicken tumor no. 10 regulator of kinase-like protein; HSP, heat shock protein; WAT, white adipose tissue; VCAM, vascular cell adhesion molecule.
which is a class of prokaryotic viruses, could use the same cellular receptors of eukaryotic viruses given a specific targeting peptide moiety. While the natural host of bacteriophage and eukaryotic virus is vastly different, the structure of the phage capsid protein provides good evidence that bacteriophage share ancestry with animal viruses. More than an evolutionary biology footnote, these findings do suggest that the receptors isolated by in vivo phage display will have cell internalization capability, a key feature if one wishes to utilize peptide motifs as gene therapy carriers targeted to specific cell subpopulations.
V. CONCLUSION One of the hallmark events in cancer progression is angiogenesis. In this chapter we have described how the unique characteristics of angiogenic tumor vasculature can be exploited to deliver genes specifically and efficiently. We explored various therapeutic gene therapy strategies and methods to uncover vascular ZIP-codes of proliferating endothelium have been described. The ligand–receptor pairs discovered by such technologies can be used to target gene-delivery vehicles. We have also highlighted a new hybrid gene-delivery vector (AAVP) which has shown antitumoral efficacy in multiple animal models and tumor subtypes. In conclusion, vascular-targeting strategies for cancer gene therapy may become a new treatment paradigm to improve and enhance current therapeutic protocols.
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