Designer nucleases to treat malignant cancers driven by viral oncogenes

AbstractViral oncogenic transformation of healthy cells into a malignant state is a well-established phenomenon but took decades from the discovery of tumor-associated viruses to their accepted and established roles in oncogenesis. Viruses cause ~ 15% of know cancers and represents a significant global health burden. Beyond simply causing cellular transformation into a malignant form, a number of these cancers are augmented by a subset of viral factors that significantly enhance the tumor phenotype and, in some cases, are locked in a state of oncogenic addiction, and substantial research has elucidated the mechanisms in these cancers providing a rationale for targeted inactivation of the viral components as a treatment strategy. In many of these virus-associated cancers, the prognosis remains extremely poor, and novel drug approaches are urgently needed. Unlike non-specific small-molecule drug screens or the broad-acting toxic effects of chemo- and radiation therapy, the age of designer nucleases permits a rational approach to inactivating disease-causing targets, allowing for permanent inactivation of viral elements to inhibit tumorigenesis with growing evidence to support their efficacy in this role. Although many challenges remain for the clinical application of designer nucleases towards viral oncogenes; the uniqueness and clear molecular mechanism of these targets, combined with the distinct advantages of specific and permanent inactivation by nucleases, argues for their development as next-generation treatments for this aggressive group of cancers.

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Protein phosphatases and DNA tumor viruses: transformation through the back door?

Cell Regulation ◽

10.1091/mbc.2.8.589 ◽

1991 ◽

Vol 2 (8) ◽

pp. 589-598 ◽

Cited By ~ 23

Author(s):

M C Mumby ◽

G Walter

Keyword(s):

Phosphatase Activity ◽

Protein Kinases ◽

Normal Growth ◽

Cellular Transformation ◽

Cellular Protein ◽

Oncogenic Viruses ◽

Biochemical Control ◽

Viral Oncogenes ◽

Tumor Viruses ◽

Back Door

Cellular transformation by many oncogenic viruses is mediated by alterations in signal transduction pathways that control normal growth and proliferation. Common targets for many transforming viruses are pathways regulated by protein phosphorylation. The biochemical control of proteins in these pathways is a dynamic process that is regulated by the relative activities of protein kinases and phosphatases. Although there are numerous examples of viral oncogenes that encode protein kinases (Hunter, 1991), until recently there has been no evidence linking altered phosphatase activity to transformation. In this review we describe a novel mechanism, utilized by small DNA tumor viruses, in which viral oncogenes bind to and regulate a cellular protein serine/threonine phosphatase. The currently available evidence indicates that alteration of phosphatase activity and subsequent changes in phosphorylation levels is an important step in transformation by these viruses.

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Biochemical composition and metabolic pathways of filarial worms Setaria cervi: search for new antifilarial agents

Journal of Helminthology ◽

10.1017/s0022149x07799133 ◽

2007 ◽

Vol 81 (3) ◽

pp. 261-280 ◽

Cited By ~ 12

Author(s):

Rumana Ahmad ◽

Arvind K. Srivastava

Keyword(s):

Metabolic Pathways ◽

Biochemical Composition ◽

Drug Targets ◽

Model Organism ◽

Wuchereria Bancrofti ◽

Rational Approach ◽

Causal Organism ◽

Setaria Cervi ◽

Chemotherapeutic Response ◽

Novel Drug

AbstractThe main problem regarding the chemotherapy of filariasis is that no safe and effective drug is available yet to combat the adult human filarial worms. Setaria cervi, the causal organism of setariasis and lumbar paralysis in cattle, is routinely employed as a model organism for conducting biochemical and enzymatic studies on filarial parasites. In view of the practical difficulties in procuring human strains of Wuchereria bancrofti and Brugia malayi for drug screening, the bovine filarial parasite S. cervi, resembling the human species in having microfilarial periodicity and chemotherapeutic response to known antifilarial agents, is widely used as a model in such studies. For a rational approach to antifilarial chemotherapy, knowledge of the biochemical composition and metabolic pathways of this helminth parasite may be of paramount importance, so that more potent antifilarial agents based on specific drug targets can be identified in drug discovery programmes. The present review provides an update on the biochemistry of the important metabolic pathways functioning within this potentially important bovine parasite, that have so far been studied, and on those that need to be investigated further so as to identify novel drug targets that can be exploited for designing new antifilarial drugs.

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“Hit-and-Run” Transformation by Adenovirus Oncogenes

Journal of Virology ◽

10.1128/jvi.75.7.3089-3094.2001 ◽

2001 ◽

Vol 75 (7) ◽

pp. 3089-3094 ◽

Cited By ~ 90

Author(s):

Michael Nevels ◽

Birgitt Täuber ◽

Thilo Spruss ◽

Hans Wolf ◽

Thomas Dobner

Keyword(s):

Dna Sequences ◽

Cellular Transformation ◽

Adenoviral Vectors ◽

Gene Products ◽

Mutagenic Potential ◽

Viral Origin ◽

Adenovirus E1a ◽

Viral Oncogenes ◽

E4 Region ◽

Hit And Run

ABSTRACT According to classical concepts of viral oncogenesis, the persistence of virus-specific oncogenes is required to maintain the transformed cellular phenotype. In contrast, the “hit-and-run” hypothesis claims that viruses can mediate cellular transformation through an initial “hit,” while maintenance of the transformed state is compatible with the loss (“run”) of viral molecules. It is well established that the adenovirus E1A and E1B gene products can cooperatively transform primary human and rodent cells to a tumorigenic phenotype and that these cells permanently express the viral oncogenes. Additionally, recent studies have shown that the adenovirus E4 region encodes two novel oncoproteins, the products of E4orf6 and E4orf3, which cooperate with the viral E1A proteins to transform primary rat cells in an E1B-like fashion. Unexpectedly, however, cells transformed by E1A and either E4orf6 or E4orf3 fail to express the viral E4 gene products, and only a subset contain E1A proteins. In fact, the majority of these cells lack E4- and E1A-specific DNA sequences, indicating that transformation occurred through a hit-and-run mechanism. We provide evidence that the unusual transforming activities of the adenoviral oncoproteins may be due to their mutagenic potential. Our results strongly support the possibility that even tumors that lack any detectable virus-specific molecules can be of viral origin, which could have a significant impact on the use of adenoviral vectors for gene therapy.

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The Role of VLBI in the Establishment of Coordinate Systems

International Astronomical Union Colloquium ◽

10.1017/s0252921100051083 ◽

1975 ◽

Vol 26 ◽

pp. 293-295 ◽

Cited By ~ 1

Author(s):

I. Zhongolovitch

Keyword(s):

General Solution ◽

Future Development ◽

Rational Approach ◽

Radio Telescopes ◽

Coordinate Systems ◽

Tectonic Plates ◽

Astronomical Observations ◽

Optical Instruments ◽

Fundamental Polyhedron

Considering the future development and general solution of the problem under consideration and also the high precision attainable by astronomical observations, the following procedure may be the most rational approach:1. On the main tectonic plates of the Earth’s crust, powerful movable radio telescopes should be mounted at the same points where standard optical instruments are installed. There should be two stations separated by a distance of about 6 to 8000 kilometers on each plate. Thus, we obtain a fundamental polyhedron embracing the whole Earth with about 10 to 12 apexes, and with its sides represented by VLBI.

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Electron microscopy of endocardial cell populations

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100083291 ◽

1978 ◽

Vol 36 (2) ◽

pp. 486-487

Author(s):

T. G. Sarphie ◽

C. R. Comer ◽

D. J. Allen

Keyword(s):

Electron Microscopy ◽

Plasma Membrane ◽

Cellular Transformation ◽

Cell Populations ◽

Cell Surfaces ◽

Kb Cells ◽

Dna Viruses ◽

Cell Cycles ◽

Ultrastructural Studies ◽

Endocardial Cell

Previous ultrastructural studies have characterized surface morphology during norma cell cycles in an attempt to associate specific changes with specific metabolic processes occurring within the cell. It is now known that during the synthetic ("S") stage of the cycle, when DNA and other nuclear components are synthesized, a cel undergoes a doubling in volume that is accompanied by an increase in surface area whereby its plasma membrane is elaborated into a variety of processes originally referred to as microvilli. In addition, changes in the normal distribution of glycoproteins and polysaccharides derived from cell surfaces have been reported as depreciating after cellular transformation by RNA or DNA viruses and have been associated with the state of growth, irregardless of the rate of proliferation. More specifically, examination of the surface carbohydrate content of synchronous KB cells were shown to be markedly reduced as the cell population approached division Comparison of hamster kidney fibroblasts inhibited by vinblastin sulfate while in metaphase with those not in metaphase demonstrated an appreciable decrease in surface carbohydrate in the former.

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Ultrastructural analysis of “Sensory” surface nerve endings and “putative” neurotransmitter sites in Schistosoma mansoni Miracidia

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100156791 ◽

1989 ◽

Vol 47 ◽

pp. 962-963

Author(s):

Betty Ruth Jones ◽

Steve Chi-Tang Pan

Keyword(s):

Nervous System ◽

Life Cycle ◽

Schistosoma Mansoni ◽

Snail Host ◽

Complex Life Cycle ◽

Rational Approach ◽

Effective Control ◽

The Social ◽

Social And Economic Development ◽

Basic Biology

INTRODUCTION: Schistosomiasis has been described as “one of the most devastating diseases of mankind, second only to malaria in its deleterious effects on the social and economic development of populations in many warm areas of the world.” The disease is worldwide and is probably spreading faster and becoming more intense than the overall research efforts designed to provide the basis for countering it. Moreover, there are indications that the development of water resources and the demands for increasing cultivation and food in developing countries may prevent adequate control of the disease and thus the number of infections are increasing.Our knowledge of the basic biology of the parasites causing the disease is far from adequate. Such knowledge is essential if we are to develop a rational approach to the effective control of human schistosomiasis. The miracidium is the first infective stage in the complex life cycle of schistosomes. The future of the entire life cycle depends on the capacity and ability of this organism to locate and enter a suitable snail host for further development, Little is known about the nervous system of the miracidium of Schistosoma mansoni and of other trematodes. Studies indicate that miracidia contain a well developed and complex nervous system that may aid the larvae in locating and entering a susceptible snail host (Wilson, 1970; Brooker, 1972; Chernin, 1974; Pan, 1980; Mehlhorn, 1988; and Jones, 1987-1988).

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