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Reoviruses and Cancer

Reoviruses and Cancer

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Published by kishonmano
Reoviruses and Cancer
Reoviruses and Cancer

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Categories:Types, Research, Science
Published by: kishonmano on Dec 06, 2012
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Reoviruses and Cancer
Alex Sharov
Humber College of Applied Arts and Technology, Regulatory Affairs Program
Kishon Manoharan
Humber College of Applied Arts and Technology, Regulatory Affairs Program
Background
Cancer is one of the most debilitating diseases in developed countries. NIH estimates that thecost to the American economy is 227 billion dollars a year (1). Moreover, an estimated 1500people die every day from various cancer types (1). Currently, there is a lack of effectivetreatments for late stage invasive tumors, with a high mortality rate and very aggressive therapies
that mostly do not improve patients’ conditions. Thus, novel therapies are needed to combat late
stage cancer types, and improve the lives of patients. One such therapy being developed is theuse of reoviruses, a naturally occurring double-stranded unenveloped RNA virus that isasymptomatic in humans but deadly to cancer cells (2).
Technical description
 Reoviruses exploits a property of the Ras pathway, a fundamental signaling pathway in cells thatmediates cytoskeletal integrity, proliferation, differentiation, cell adhesion, apoptosis and cellmigration (3). Mutations along this Ras pathway can lead to permanently active Ras proteins,which in turn can cause over-proliferation and loss of cell adhesion, key hallmarks of mostmetastatic cancer types. Ras mutations occur in approximately two-thirds of all tumors,especially in late stage invasive tumors such as: adenocarcinomas, thyroid tumors and Leukemia(1). Thus, reoviruses present a new opportunity to deal with aggressive tumors that have hadlimited success in the past. The lifecycle of a reovirus involves seven phases. The outer capsidcontains HA proteins that are involved in bringing reovirus particles into the host by endocytosis
 
(4). The next steps are: uncoating of the outer shell, transcription in the core complex (dsRNA tomRNA), protein synthesis, new core assembly, minus strand transcription, secondarytranscription followed by assembly and release (4). The release of the reovirus is through lysis,since the virus is unenveloped and cannot bud out of the membrane. Almost all adults have beenexposed to reoviruses at some point in their lives, but it is asymptomatic due to the host responsein cells (2). The dsRNA is a potent inducer of interferon, which in turn induces double-strandedRNA-dependent Protein Kinase R (PKR) (5). This PKR response blocks translation of reovirusesand prevents the replication and lysis of cells (2). Thus, the detection of reoviruses is onlythrough serological means normally (3). However, PKR regulation is affected in cancer cellswith mutated Ras pathways (2). Ras downregulates PKR function, in turn allowing reovirustranscription and protein synthesis to increase (2). This increase results in replication and celllysis of cancer cells with mutated Ras pathways (2).
Reolysin Case Study
The findings made by Thompson and Lee at the University of Calgary promoted the creation of Oncolytics Biotech, with their key biologic drug being Reolysin (6). Reolysin is a formulation of reovirus serotype 3, which is produced in HEK293 cells and grown in animal-free cell culturemedium in 20L stirred bioreactor tanks (7). This process is followed by a generation of a lysate,ultrafiltration, purification, polishing and sterile filtration (7). The creation of this formulation isallowing the expansion from small scale clinical trials, to larger phase 3 clinical trials, whichneed industrial scale processes (7). The route of administration of Reolysin is intravenously andwas applied to both pre-clinical animals (mainly mice) and humans in clinical trials.
 
Clinical Trials of Reolysin
The naturally occurring reovirus (Respiratory Enteric Orphan Virus) showed promising resultsfor it to be marketed during its pre-clinical stage. A study done by Dalhousie Universityexamined the reovirus in a study,
Oncolytic Reovirus Effectively Targets Breast Cancer StemCells,
where the results were published in 2009 in
The American Society of Gene Therapy
. Thestudy noted that the cancer stem cells (CSC) enhanced tumour-forming capabilities and werealso reluctant to anti-cancer therapies (8). To test the validity of the reovirus, tumours wereestablished in immunodeficient SCID non-obese diabetic mice (8). Eight mice were subdividedinto two groups where they were either treated with the reovirus or the mock treatment (8). Fromthe study, the results showed that the tumour regressed 15 days after the treatment commenced(8). Thus, this implemented that the reovirus was able to induced tumour regression and targetcancer stem cells, which was the takeout of the successful study.Reolysin, a biologic drug, developed by Oncolytics Biotech Inc is a variant of the reovirus that iscurrently undergoing clinical trials to test for the safety and efficacy of the drug (9). Oncolyticsstrongly endorses reolysin and the reovirus because of its ability to discriminate between cells.This is to say that the reovirus is able to infect and destroy cancer cells without destroyingnormal cells (9). This aspect of the reovirus is currently being evaluated in many ongoing clinicaltrials that use Reolysin in combination with radiation or chemotherapy. An ongoing study sinceOctober 2009, is observing Reolysin in combination with Paclitaxel and Carboplatin in patientswith squamous cell carcinoma of the lung (10). The purpose is to investigate if the intravenousadministration of Reolysin in combination with Paclitaxel and Carboplatin is safe and effectiveand safe in the treatment of squamous cell carcinoma of the lung (10). The study is set to becompleted by January 2013, however, laboratory studies with Reolysin and chemotherapy has

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