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Ferguson 2012

Created By: Kaylin Braden
http://www.hindawi.com/journals/av/2012/805629/

Abstract
Despite recent advances in both surgery and chemoradiotherapy, mortality rates for advanced cancer remain high. There is a pressing need for novel therapeutic strategies; one option is systemic oncolytic viral therapy. Intravenous administration affords the opportunity to treat both the primary tumour and any metastatic deposits simultaneously. Data from clinical trials have shown that oncolytic viruses can be systemically delivered safely with limited toxicity but the results are equivocal in terms of efficacy, particularly when delivered with adjuvant chemotherapy. A key reason for this is the rapid clearance of the viruses from the circulation before they reach their targets. This phenomenon is mainly mediated through neutralising antibodies, complement activation, antiviral cytokines, and tissue-resident macrophages, as well as nonspecific uptake by other tissues such as the lung, liver and spleen, and suboptimal viral escape from the vascular compartment. A range of methods have been reported in the literature, which are designed to overcome these hurdles in preclinical models. In this paper, the potential advantages of, and obstacles to, successful systemic delivery of oncolytic viruses are discussed. The next stage of development will be the commencement of clinical trials combining these novel approaches for overcoming the barriers with systemically delivered oncolytic viruses.

Introduction
Cancer remains a major health problem and is the 5th leading cause of death worldwide [1]. There have been many advances in the last few decades both in surgical care and chemoradiotherapy regimes. Certainly this has contributed to improved survival rates for commonly occurring cancers. However, relapse and disease progression are still all too common occurrences in modern medical practice. A variety of novel adjuvant therapies have been developed over the last decade, and oncolytic viruses have been particularly promising members of this cohort.Oncolytic viruses came to medical prominence in the 19th century when coincidental viral infections were observed to cause regression of some forms of haematological malignancies. Rabies inoculation was also demonstrated to regress a patient’s advanced cervical carcinoma [2]. A succession of studies in the 1950s and 60s were unable to establish oncolytic viral therapy as a viable anti-cancer modality. As a result, the field remained a medical curiosity until the advent of genetic engineering in the late 1980s. In the last decade, there have been rapid advancements in the oncolytic viral therapy field. Naturally occurring oncolytic viruses have been identified such as Vaccinia virus, Reovirus, and Newcastle disease virus. These viruses naturally preferentially infect tumour cells whilst sparing normal tissue. However, other viruses have been identified that once attenuated are also successful oncolytic agents such as herpes simplex virus type 1 and Adenovirus. These viruses have then been engineered to be more tumour specific and less pathogenic to normal tissues [2]. This has been achieved by a variety of modifications [3]. Herpes simplex virus has had two of its latency genes deleted (ICP0 & ICP4) and only has one copy of its virulence factor, γ134.5, remaining. As a further level of safety its thymidine kinase gene has been deleted. Deletion of the thymidine kinase gene means that viruses can only replicate efficiently in cells with upregulation of the EGFR/Ras signalling pathway, which is commonly the case in tumour cells [4, 5]. This approach has been widely employed successfully with Vaccinia virus developed for clinical trial use. Adenoviruses used in clinical trials have E1B 55 K gene deleted, which is involved in late viral RNA export and restricts E1B 55 K-deleted adenovirus replication in normal primary cells [6]. All of these modifications are designed to make the oncolytic viruses more tumour specific since these gene deletions do not hamper their ability to replicate in the dysregulated tumour environment; however, they prevent replication in adjacent or distant normal tissue.A yet more exciting development over the last decade has been the incorporation of transgenes into these viruses allowing expression of a variety of exogenous agents in the tumour microenvironment raising the very real prospect of truly immunomodulatory oncolytic viral therapy, and now the discussion has moved onto which transgenes might be the most effective. [1] A range of delivery methods have been employed for these novel agents, chief amongst them has been intratumoural delivery. A broad range of oncolytic viruses have been delivered via intratumoural injection with a measure of success in treating easily reachable solid tumours. However, death from cancer is often the result of inaccessible or metastatic disease. In this context, oncolytic viruses delivered intratumourally rely on viral replication at the tumour site and then systemic dissemination to the distant sites. However, this is transient and often ineffective due to the development of immune responses to the viral infection.Systemic delivery of oncolytic viruses (OVs) affords the opportunity to treat both the primary tumour and any overt or undiagnosed metastatic deposits simultaneously. As a result, this method of delivery is a very attractive option for the treatment of patients with advanced/metastatic disease or patients with inaccessible disease such as those with pancreatic cancer or brain cancer due to physiological barriers, such as blood-brain barrier.2.

Clinical Trials

There have been many clinical trials of a variety of OVs delivered systemically, as summarised in Table 1. Oncolytic adenovirus was one of the first oncolytic viruses to be developed and licensed for treatment of cancer [8, 24]. The first generation of oncolytic adenovirus, ONYX-015 (also known as dl1520, H101 in China), is a genetically modified adenovirus with deletion of the 55 kD gene in the E1B region. Nemunaitis et al. [10] in 2001 performed a dose escalation study using this agent in patients with advanced carcinoma with lung metastases. They demonstrated that ONYX-015 was safe to deliver systemically with no toxicity up to doses of particles, but the study was not designed for objective tumour responses. [2] Also commencing in 2001, a succession of studies delivered ONYX-015 via hepatic artery infusion for the treatment of metastatic colorectal carcinoma with liver deposits. In the first of these trials, a phase I dose escalation study, one patient (9%) responded after combination therapy with conventional chemotherapy and two patients (18%) had stable disease lasting several months. In a larger phase II follow-up trial, three patients (11%) had partial responses, nine (33%) had stable disease, and eleven (41%) patients had progressive disease. A final phase II trial by this group demonstrated similar results to the previous studies with overall median survival of 10.7 months with two patients (8%) having a partial response and a further eleven (46%) having stable disease [13]. Of those with stable disease the median survival was prolonged to nineteen months. In a different study, Small et al. [14] treated patients with hormone-refractory metastatic prostate cancer using a single intravenous infusion. Unlike ONYX-015, the adenovirus (CG7870) in this trial was modified so that E1A was under the control of the rat probasin promoter and E1B was under the control of the PSA promoter-enhancer, thus making it prostate specific. Results from this trial were disappointing with no complete nor partial responses, although five patients (22%) did have a 25% to 49% reduction in their serum PSA values.tab1Table 1: Completed clinical trials using systemically delivered oncolytic viruses for the treatment of solid tumours.PV701 is a naturally attenuated Newcastle disease virus, which has been used systemically in a number of clinical trials between 2002 and 2007 [15–18]. Three of these trials were phase I studies in patients with a variety of advanced/metastatic solid tumours [15, 16, 18]. In the Pecora et al. [15] study in 2002, 62 patients were assessed for a tumour response and two patients (3%) had a major response and 14 patients (23%) had stable disease for 4–30 months. Hotte et al. [18] performed a small phase I study and although not designed to assess efficacy, four major (22%) and two minor (11%) responses to the treatment were observed. A similarly sized trial by Laurie et al. [16] in 2006 reported stable disease in four patients (25%) for greater than six months. Freeman et al. [17] investigated the safety of using Newcastle disease virus in patients with recurrent glioblastoma multiforme and as with the other studies the treatment was well tolerated but the efficacy was again disappointing with only one patient (7%) having a complete response.NV1020 is a Herpes Simplex virus type 1 with deletions of the latency factors ICPO and ICP4, and only one copy of its virulence factor y134.5. Another element of safety is the insertion of the α4 promoter to control the HSV-1 TK gene expression, which sensitises the virus to antiviral drugs such as acyclovir. One phase I trial [19, 20] delivering NV1020 via hepatic artery infusion in patients with hepatic metastases from colorectal primaries refractory to first-line treatment reported seven patients (58%) with stable disease and two patients showing a partial response. Median survival in this group was 25 months. Another trial by Geevarghese et al. [21] in 2010 again delivered NV1020 by hepatic artery infusion in patients with advanced metastatic colorectal carcinoma but this time followed by conventional chemotherapy. After completion of the combined approach, there was a 68% response rate, with one patient with a partial response and fourteen patients with stable disease. Median survival in this study was 11.8 months.Interrogation of the various clinical trial registration sites (http://www.clinicaltrials.gov/, WHO trials register, https://www.clinicaltrialsregister.eu/, http://www.controlled-trials.com/) reveals that there are no ongoing nor pending trials systemically delivering Adenovirus, Newcastle disease virus, or Herpes Simplex virus type 1. Reolysin is a type 3 Dearing Reovirus in its wild-type form. Vidal et al. [23] completed the only trial using systemic delivery in 2008. They performed a phase I dose escalation study assessing the safety of a variety of doses. As such they observed no dose-limiting toxicity, and they further comment that antitumour activity was observed both radiologically and by tumour markers. However, no objective radiologic responses were observed in terms of Response Evaluation Criteria in Solid Tumours. Despite this they did report that eight patients showed disease stabilisation. There are also two phase II trials and one phase III trial that have been registered (NCT01166542, NCT01199263, NCT01280058). The phase III trial is in patients with metastatic or recurrent squamous cell carcinoma of the head and neck, whereas the two phase II trials are in recurrent ovarian/fallopian tube cancer and recurrent pancreatic cancer, respectively. All these trials are still recruiting (Table 2). [3] Ongoing or pending clinical trials using systemically delivered oncolytic viruses for the treatment of solid tumours.JX-594 is a Vaccinia virus based on the Wyeth strain with a thymidine kinase (TK) deletion and the insertion of human granulocyte macrophage colony stimulating factor (hGM-CSF) gene and Lac-Z into the TK-deleted region. These transgenes are under the control of pE/L and p7.5 promoters, respectively. Jennerex Biotherapeutics Inc. has reported the results of one trial using this agent systemically in patients with unresectable primary hepatocellular carcinoma. They performed a phase I safety study delivering JX-594 initially systemically then intratumourally with subsequent sorafenib treatment. Seven out of nine of their patients were suitable to be assessed: in six patients (67%), the tumours necrosed, and of these five patients (56%) had stable disease and one patient (11%) had a partial response. They have recently reported the results of another dose escalation study using JX-594 in patients with metastatic solid tumour disease, which was refractory to conventional therapy. The treatment was well tolerated and at higher doses of virus (to  PFU/kg), and they demonstrated that JX-594 can selectively infect, replicate, and express transgene products in target tumour tissue whilst sparing normal tissue. Although the study was not designed for efficacy, one patient had partial response [22]. Jennerex Biotherapeutics Inc. has two trials pending with respect to this agent, the details of which are illustrated in Table 2.In general these clinical trials have shown that oncolytic viruses can be delivered systemically with limited toxicity and latency. However, what they have not shown, and indeed were not powered to show, is that these agents are efficacious at treating either the primary tumour or metastatic disease. There is a complete lack of appropriately powered phase IIb or phase III trials using OVs delivered systemically, although there are a few pending for Reovirus. The data that are available demonstrate that systemically delivered oncolytic viruses offer only modest improvements, if at all, over and above conventional second-line therapy. Clearly if intravenously delivered OVs are to play a part in the future treatment of advanced cancer, there needs to be dramatic improvement.3.

Barriers to Systemic Delivery of Oncolytic Viruses
There are many obstacles to successful systemic delivery of viruses; host defences limit most oncolytic viruses’ ability to infect tumours after systemic administration. Blood cells, complement, antibodies, and antiviral cytokines [25], as well as nonspecific uptake by other tissues such as the lung, liver and spleen, tissue-resident macrophages, and additionally poor virus escape from the vascular compartment [3] are the main barriers to systemic delivery of oncolytic viruses (Figure 1). Clearly, in order for this method to be effective, the virus must persist in the circulation without depletion or degradation while selectively infecting tumour cells. [4] Hurdles of systemic delivery of oncolytic viruses to tumour cells. After intravenous injection, viruses are neutralised by pre-existing antibodies and complement activation. Oncolytic viruses also interact with blood cells. Sequestration into other organs and the reticuloendothelial system is a particular problem, often with resulting toxicities. Macrophages in the lung, liver (aka kupffer cells), and spleen are major players to clear oncolytic viruses after systemic delivery. From the blood stream, viruses have to pass through a mixture of extracellular matrix and cells (including normal and immune cells) before reaching the tumour. The connective tissue of the tumour matrix is important in the regulation and creation of the tumour vasculature; the tumour vasculature itself and interstitial pressures are also key factors involved in the ability of the virus to penetrate the tumour mass.

4. Neutralising Antibodies
Preexisting immunity is a major problem for systemically delivered viruses whether this has developed due to the ubiquitous nature of the virus, previous immunization, or prior oncolytic viral therapy. Vaccinia virus was used in the worldwide immunisation program for the eradication of smallpox and so many people who are now developing cancer have a preexisting immunity to this OV. Reovirus is universally present within the environment and as a result many people have immunity to it [26, 27]. Furthermore, White et al. [28] have demonstrated that the antibody titre to Reovirus increases dramatically after systemic delivery and others have shown that the presence of these antibodies significantly impairs effective intravenous administration [29, 30]. One simple strategy for overcoming this problem has been to sequentially deliver related viruses with different serotypes or chimeric viruses [31].Nature has already provided several solutions when considering the significant hurdles to effective systemic delivery with regards to Vaccinia virus, which can potentially be delivered systemically [32] since the Extracellular Enveloped Virus (EEV) form shrouds itself in a host cell-derived envelope and thus can evade both complement and neutralising antibodies [33–36]. Indeed, strains of Vaccinia virus can be engineered that produce more of this immune-evasive form [37]. However, in the clinical setting, it is the intracellular mature virion (IMV) form of the virus that will potentially be injected systemically, and it is this form that must successfully reach the target tissue before any EEV form can be produced. IMV—unlike EEV—is highly immunogenic and is rapidly cleared from the organism if intravenously delivered.Clearly methods need to be developed that can overcome this acquired immunity. One such strategy is the so-called “Trojan Horse” technique, where cells are taken from the model organism infected with the OV ex vivo and then reinfused. Yotnda et al. created transgenic cytotoxic T lymphocytes (CTL), which were transduced with the adenoviral E1 gene under the control of the cell activation-dependent CD40 ligand promoter. The CTLs were transduced ex vivo with a conditionally replicating chimera of Adenovirus 5 with the fiber protein of Ad35. This was added as the Ad35 fiber protein can infect cells through a coxsackie and adenovirus receptor-(CAR-) independent method this is required as there is low expression of CAR on CTLs. The transgenic CTL was specifically targeted, and upon binding and subsequent activation, Adenovirus was produced. This occurred since upon activation of the CTL by its specific antigen, the AKNA transcription factor is transiently expressed driving CD40 and E1A expression. Thus by this mechanism, Adenovirus production is tightly linked to CTL activation by its specific tumour-associated antigen resulting in a tumour-specific delivery of Adenovirus [38]. Work by Ilett et al. [39, 40] has shown that dendritic cells loaded in vitro with Reovirus will “deliver” the virus successfully to melanoma cells in the presence of neutralising serum. Furthermore, they have shown that Reoviruses loaded into mature dendritic cells are able to infect tumour sites effectively in vivo despite preexisting viral immunity. Other cells have been used as potential viral carriers in preclinical models such as cytokine-induced killer (CIK) cells [41], monocytes [42], endothelial cells [42], mesenchymal stem cells [43–45], T-cells [40, 46, 47], dendritic cells [40], and tumour cells [48–50]. Also, stimulated peripheral blood cells, infected with oncolytic Measles virus, have successfully infected Raji lymphomas or hepatocellular carcinoma in the presence of neutralizing antibodies [42]. However, the “Trojan Horse” strategy may not be effective for brain tumours, for which some carrier cells are not able to pass physiological barriers, such as the blood-brain.Another interesting approach has been developed by Yotnda et al. [51] in which they encapsulated a conditionally replicating competent plasmid based on ONYX-015 in a liposome. They showed that despite circulating Adenovirus antibodies, the liposome-coated viruses were able to infect subcutaneous tumours in mice.Fontanellas et al. [52] have attempted to overcome the host immunity which develops after repeated administration of Adenovirus by inhibition of T cells and depletion of B-cells with anti-CD20 antibody. Although this study was not targeted at cancer therapy, they demonstrated that this immunosuppressive regime was successful in facilitating gene transfer to hepatocytes despite preexisting Adenoviral immunity.Another immunosuppressive strategy is to use cyclophosphamide to modulate antiviral immunity in combination with intravenous Reovirus. This has been evaluated in a preclinical murine model by Qiao et al. [53], in which they reported delivery of  plaque-forming units per milligram of tumour with this regime with only mild toxicity to the mice, whereas without cyclophosphamide, effective seeding of the tumour was not achieved. For this particular regime, cyclophosphamide is often used at a lower dose and would not result in significant side effects while it is combined with oncolytic viruses.

11. Conclusions
To date, the systemic delivery of oncolytic viruses has been shown to be safe but not efficacious mainly due to immunological factors that facilitate rapid clearance of these agents. There is a range of novel methods that are being developed at a pre-clinical level to overcome these hurdles which have been reported to be successful in vivo mainly in murine models.However, we need to remember that mouse models are just that—they are models, which offer opportunities to investigate the effect of host factors on systemic delivery of oncolytic virus in vivo. The major problem is that the host immune responses to some oncolytic viruses in mice are completely different from those in humans reflecting their mutual genetic divergence 65 million years ago. Most importantly, for some oncolytic viruses such as oncolytic adenovirus, murine models of cancer are suboptimal as murine tissue and cells do not support adenovirus replication. Therefore, the information derived from these models about the host immune response to oncolytic adenovirus is certainly different and nonrepresentative of the situation in humans. Given these limitations, the next step will be the commencement of clinical trials combining these methods with systemically delivered oncolytic viruses, investigating whether these strategies work in humans. Several agents that can enhance the systemic delivery of oncolytic viruses have been separately used or tested in clinical trials. It is conceivable that a combination strategy to enhance the systemic delivery of oncolytic viruses should and will be employed in the near future. This strategy may provide an effective therapeutic approach for treatment of primary tumours, the metastatic deposits, and tumour entities, which are not easily accessible for conventional therapeutic agents because of physiological barriers. The blood-brain barrier is one such obstacle, which it has been demonstrated that several oncolytic viruses have been able to pass identifying them as potential candidates in the treatment of brain tumours.In conclusion, if an optimal approach to enhance the systemic delivery of oncolytic viruses can be achieved by rationally targeting different factors, the outcome for treatment of advanced cancers would be dramatically improved.
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Nettelback & Curiel 2008

Created By: Kaylin Braden

https://www.mcdb.ucla.edu/Research/Goldberg/HC70A_W04/pdf/Tumor_Busting_Viruses.pdf

Viruses are some of the most insidious creations in nature. They travel light: equipped with just their genetic material packed tightly inside a crystalline case of protein, they latch onto cells, insert their genes, and co-opt the cells’ gene-copying and protein-making machinery,using them to make billions of copies of themselves. Once formed, the new viruses percolate to the cell surface, pinch off inside minuscule bubbles of cell membrane and drift away, or else they continue reproducing until the cell finally bursts. In any case, they go on to infect and destroy other cells, resulting in diseases from AIDS to the common cold. Different viruses cause different diseases in part because each virus enters a cell by first attaching to a specific suction-cup like receptor on its surface. Liver cells display one kind of receptor used by one family of viruses, whereas nerve cells display an- other receptor used by a different viral family, so each type of virus infects a particular variety of cell. Cancer researchers have envied this selectivity for years: if they could only target cancer therapies to tumor cells and avoid damaging normal ones, they might be able to eliminate many of the noxious side effects of cancer treatment.

ADENOVIRUSES explode from  a cancer cell that has been selectively infected in order to kill it. The viruses can spread to and wipe out other tumor cells.

Some scientists, including ourselves, are now genetically engineering a range of viruses that act as search-and-destroy missiles: selectively infecting and killing cancer cells while leaving healthy ones alone. This new strategy, called virotherapy, has shown promise in animal tests, and clinical trials involving human patients are now under way. Researchers are evaluating virotherapy alone and as a novel means for administering traditional chemotherapies solely to tumor cells. They are also developing methods to label viruses with radioactive or fluorescent tags in order to track the movement of the viral agents in patients.

Viruses to the Rescue?

ONE OF THE FIRST INKLINGS that viruses could be useful in combating cancer came in 1912, when an Italian gynecologist observed the regression of cervical cancer in a woman who was inoculated with a rabies vaccine made from a live, crippled form of the rabies virus. Physicians first injected viruses into cancer patients intentionally in the late 1940s, but only a handful appeared to benefit. Twenty years later scientists found that a virus that causes the veterinary disorder Newcastle disease shows a preference for infecting tumor cells and began to try to enhance that tendency by growing the viruses for generations in human cancer cells in laboratory culture dishes. Although critics countered that such viruses could be exerting only an indirect effect against cancer by generally activating an individual’s immune system and making it more likely to detect and kill cancer cells, reports continued to pop up in the medical literature linking viral infection and cancer remission. In the early 1970s and 1980s two groups of physicians described patients whose lymphomas shrank after they came down with measles.

The modern concept of virotherapy began in the late 1990s, when researchers led by Frank McCormick of ONYX Pharmaceuticals in Richmond, Calif., and Daniel R. Henderson of Calydon in Sunnyvale, Calif., independently published reports showing they could target virotherapy to human cancer cells grafted into mice, thereby eliminating the human tumors. (ONYX is no longer developing therapeutic viruses, and Calydon has been acquired by Cell Genesys in South San Francisco, Calif.) [1] Both groups used adenovirus, a cause of the common cold that has been intensively explored for virotherapy. (Other viruses under study include herpes simplex, parvovirus, vaccinia and reovirus.) Adenovirus is appealing in part because researchers understand its biology very well after years of trying to cure colds and of using the virus in molecular biology and gene therapy research. It consists of a 20-sided protein case, or capsid, filled with DNA and equipped with 12 protein “arms.” These protrusions have evolved over millennia to latch onto a cellular receptor whose normal function is to help cells adhere to one another. Adenoviruses are distinct from the types of viruses usually used in gene therapy to treat inherited disorders. Gene therapy traditionally employs retroviruses to splice a functioning copy of a gene permanently into the body of a patient in whom that gene has ceased to work properly. Unlike retroviruses, however, adenoviruses do not integrate their DNA into the genes of cells they infect; the genes they ferry into a cell usually work only for a while and then break down. Scientists have investigated adenoviruses extensively in gene therapy approaches to treat cancer, in which the viruses are armed with genes that, for example, make cancer cells more susceptible than normal ones to chemotherapy.  In general, tests involving adenoviruses have been safe, but regrettably a volunteer died in 1999 after receiving an infusion of adenoviruses as part of a clinical trial to test a potential gene therapy for a genetic liver disorder.

Gene therapists have been working to tailor adenoviruses and other viral vectors, or gene-delivery systems, to improve their safety and reduce the chances that such a tragedy might occur again. It is perhaps even more essential for researchers, such as ourselves, who are investigating virotherapy to develop safer, more targeted vectors, because virotherapy by definition aims to kill the cells the viruses infect, not just insert a therapeutic gene into them. Killing the wrong cells could be dangerous. Adenoviruses bring with them characteristics that can make


VIROTHERAPISTS ARE DEVISING two main strategies to make sure their missiles hit their objectives accurately with no collateral damage. In the first approach, termed transductional targeting, researchers are attempting to adapt the viruses so that they preferentially infect, or transduce, cancer cells. The second method, called transcriptional targeting, involves altering the viruses so that their genes can be active, or transcribed, only in tumors

[2] Transductional targeting is particularly necessary because, unfortunately, adenoviruses bind more efficiently to the variety of normal tissues in the human body than they do to most tumor cells. We can reverse this pattern using specially generated adapter molecules made of antibodies that snap onto the arms of the virus like sockets on a socket wrench. By attaching carefully chosen antibodies or other molecules that selectively bind only to a specific protein found on tumor cells, we can render adenoviruses unable to infect any cells but cancerous ones. Once the antibody-bearing virus latches onto a targeted cell, the hapless cell engulfs it in a membrane sac and pulls it inside. As the sac disintegrates, the viral capsid travels to a pore in the cell’s nucleus and injects its own DNA. Soon the viral DNA directs the cell to make copies of the viral DNA, synthesize viral proteins and combine the two into billions of new adenoviruses. When the cell is full to capacity, the virus activates a “death gene” and prompts the cell to burst, releasing the new viruses to spread to other cells.
CELLS WITH VIRUSES TWO MAIN STRATEGIES are being explored for virotherapy, which is the technique of using reproducing viruses to kill tumors. In the first method, dubbed transductional targeting ( below ), scientists are attempting to engineer viruses such as adenovirus — which normally causes respiratory infections — to selectively infect and destroy only cells that have turned cancerous. They are attaching adapter molecules onto the viral outer coat proteins or directly modifying these proteins to try to prevent the viruses from entering normal cells and instead prompt them to home in 72  Adapter molecule on engineered adenovirus No infection or cell killing Receptor made only by tumor cells Targeted virus takes over cancer cell, making so many copies of itself that it kills the infected cell Cell bursts, and virus infects and kills other cancer cells Normal adenovirus receptor VIRAL DNA CELL DNA CELL DNA NORMAL CELL CANCER CELL Viral outer coat proteins  on tumor cells. [3] The second approach ( below ) involves placing a snippet of DNA called a tumor-specific promoter next to one of adenovirus’s essential genes. The promoter acts as an “on” switch that permits the gene to function only in cancer cells. The engineered viruses can enter normal cells, but they cannot reproduce and kill them. Once they enter cancer cells, however, the tumor-specific promoter lets them make millions of copies of themselves and ultimately burst the cancer cells. They can then spread to — and destroy — other tumors.  Tumor- specific promoter Promoter Infection occurs, but normal cell does not have switch to turn on viral gene. Virus cannot replicate or kill cell Cancer cell has switch to turn on viral replication genes Engineered adenovirus with tumor-specific promoter links to essential virus gene Cell bursts, and virus infects and kills other cancer cells. Transcriptional targeting generally takes advantage of ge- netic switches (promoters) that dictate how often a given gene is functional (gives rise to the protein it encodes) in a particu- lar type of cell. Although each body cell contains the same en- cyclopedia of genetic information, some cells use different chap- ters of the encyclopedia more often than others in order to ful- fill their specialized tasks. Skin cells called melanocytes, for instance, must make much more of the pigment melanin than liver cells, which have little use for the protein. Accordingly, the promoter for the key enzyme for making melanin gets turned on in melanocytes but generally is off in most other body tis- sues. In the deadly skin cancer melanoma, the gene encoding this enzyme is fully functional, making the tumors appear black. We, and others, have engineered adenoviruses that have a promoter for the enzyme adjacent to genes that are essential for the viruses’ ability to replicate. Although these viruses might infect normal cells, such as liver cells, they can reproduce only inside melanocytes, which contain the special combination of proteins needed to turn on the promoter. Researchers are currently tailoring adenoviruses with a va- riety of promoters that limit their activity to particular organs or tissues. In liver cancers, for example, the promoter for the gene α -fetoprotein — which is normally shut down after fetal de- velopment — becomes reactivated. Adenoviruses containing that same promoter hold promise for eradicating liver tumors. Sci- entists led by Jonathan W. Simons at Johns Hopkins Universi- ty have tested the approach in men whose prostate cancer re- curred following treatment with radiation. The researchers used adenoviruses that had been engineered by Cell Genesys to contain the promoter for prostate-specific antigen, a protein made in abundance by prostate tumors. They administered the virotherapy to 20 men who received varying doses of the adenoviruses. In 2001 Simons and his colleagues reported that none of the men experienced serious side effects and that the tumors of the five men who received the highest doses of the vi- rotherapy shrank by at least 50 percent.

 Other Strategies VIROTHERAPISTS MIGHT END UP combining the trans- ductional and transcriptional targeting strategies to ensure that the viruses kill only tumor cells and not normal ones. Adeno- viruses engineered to contain the promoter for the enzyme that makes melanin, for instance, can also replicate in normal melanocytes, so on their own they might cause spots of depig- mentation. And adenoviruses that are designed to bind to receptors on the surfaces of tumor cells can still invade a small proportion of healthy cells. But Is It Safe? Many approaches to virotherapy use adenoviruses, which caused a death in a clinical trial of genetherapy four years ago.

[4] IN SEPTEMBER 1999 18-year-old Jesse Gelsinger died after receiving an infusion of adenoviruses into his liver.
He had a mild form of an inherited liver disease called ornithine transcarbamylase deficiency (OTCD) and was participating in a clinical trial of a new gene therapy to use adenoviruses to ferry a corrected copy of the gene encoding OTCD into his liver cells. [5] Unfortunately, four days after an infusion of the viruses, he died of acute respiratory distress syndrome and multiple organ failure, apparently caused by an overwhelming immune reaction to the large dose of adenoviruses he had been administered as part of the trial.

[6] NOTE: Phase I tests are designed to evaluate safety in small numbers of patients. Phases II and III are intended to determine the appropriate dose and efficacy, respectively.

Although Gelsinger’s death was part of a gene therapy trial, the tragedy also has ramifications for the new field of virotherapy. Gene therapy uses crippled versions of viruses such as adenovirus to introduce a new gene into cells; virotherapy employs actively replicating viruses (which may or may not contain added genes) to kill specific types of cells. Both, however, rely heavily on adenoviruses. Gelsinger’s autopsy showed that the engineered adenoviruses had spread to his spleen, lymph nodes and bone marrow, and an examination of his records revealed that his liver function was probably too impaired for him to be a volunteer in the trial. A number of scientists have also suggested that he might have mounted such an extreme immune reaction because he had previously been infected with a naturally occurring adenovirus.  Since Gelsinger’s death, gene therapists and virotherapists alike have focused on refining adenoviruses to make them safer. But researchers are still unsure why Gelsinger reacted so violently to the adenoviral infusions: a second patient participating in the same clinical trial tolerated a similar dose of the viruses. And dozens of other people worldwide have been treated so far with adenoviruses with no serious side effects. [7] A National Institutes of Health report generated in the aftermath of Gelsinger’s demise recommends that all participants in such clinical trials be monitored closely for toxic reactions before and after the infusion of therapeutic viruses. It also stipulates that volunteers be screened for any predisposing conditions that would increase their sensitivity for the viruses. Fail-safe mechanisms would be expected to be less likely to harm normal cells.

There are no results at present, however, to demonstrate that a combination of approaches makes virus- es more targeted. A further strategy for targeting virotherapy makes the most of one of cancer’s hallmarks: the ability of tumor cells to divide again and again in an uncontrolled manner. Healthy cells make proteins that serve as natural brakes on cell division—notably, the retinoblastoma (Rb) and p53 proteins. As cells turn cancerous, however, the genes that code for one or the other of these proteins become mutated or otherwise inactivated. Certain viruses, including adenovirus, interfere with the braking mechanisms of a normal cell by making proteins that stick to and inactivate Rb or p53. They do this because they can replicate only in cells that are preparing to divide. Several research groups and biotechnology companies have engineered adenoviruses that fail to make the Rb or p53 blockers. Normal cells, which make these blockers, will stall the replication of these viruses by putting the brake on cell division. But these viruses will replicate in cells in which the Rb or p53 proteins are already disabled— cancer cells and kill them. [8] OncoVex attacks tumors in two ways. It features a modified cold sore virus that replicates inside solid tumors, causing cancer cells to die. [9] Secondly, the drug prompts the immune system to take out cancer cells. In May 2009, BioVex impressed with Phase II data on the drug in melanoma patients, showing that of 13 patients who had significant responses to the treatment, nine had signs of the cancer completely wiped out. Curiel is planning clinical trials of the approach for ovarian cancer.

Researchers are also arming therapeutic viruses with genes that make the cells they infect uniquely susceptible to chemotherapy. The technique involves splicing into the viruses genes that encode enzymes that turn nontoxic precursors, or “prodrugs,” into noxious chemotherapies. In one example, which was reported in 2002, André Lieber of the University of Washington and his co-workers designed adenoviruses to carry genes encoding the enzymes capable of converting innocuous prodrugs into the anticancer compounds camptothecin and 5-fluorouracil. The scientists engineered the viruses so that they could make the enzymes only in actively dividing cells, such as cancer cells. When they injected the viruses and the prodrugs into mice bearing implanted human colon or cervical cancer cells, they found that the viruses reproduced and spread in the tumors. Such “smart” virotherapies are the vanguard of the future. But physicians will also need to track the activity of virotherapies in a patient’s body to best assess how well the strategies are working and refine them further. Virotherapists are now teaming with radiologists to establish novel imaging technologies to easily measure how effectively a given virotherapy is replicating. The imaging strategies involve inserting a gene that governs the production of a tracer molecule into a virus or virus-infected cell. The tracer can be either a fluorescent protein that can be observed directly or one that binds readily to the radionuclides used in standard radiological imaging techniques. The fluorescent protein might work best for cancers that are accessible by an endoscope, such as cancers of the larynx. Physicians could peer into the endoscope and see exactly where the viruses and therefore, cancer cells are by looking for fluorescence. So far the approach has worked best with viruses that do not kill cells, however. Nevertheless, we are convinced that such sophisticated imaging technologies will enable scientists to draw more meaningful conclusions from future clinical trials of virotherapy.  In 1995 gene therapy pioneer W. French Anderson of the University Of Southern California School Of Medicine predicted in this magazine that “by 2000 . . . early versions of injectable vectors that target specific cells will be in clinical trials.” These trials indeed began on schedule, as well as some he could not have envisioned then. We envision a substantial role for viruses. That is, therapeutic viruses in 21st-century medicine.
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Acs 2013

Created By: Kaylin Braden

http://www.cancer.org/acs/groups/content/@epidemiologysurveilance/documents/document/acspc-036845.pdf

What Is Cancer?

[1] Cancer is a group of diseases characterized by uncontrolled growth and spread of abnormal cells. These growths are called tumors. Tumors can  interfere with the digestive, nervous, and circulatory systems, and they can release hormones that alter body function. Cancer is caused by both external factors (tobacco, infectious organisms, chemicals, and radiation) and internal factors (inherited mutations, hormones, immune conditions, and mutations that occur from metabolism). These causal factors may act together or in sequence to initiate or promote the development of cancer. [2If the spread is not controlled, it can result in death. Ten or more years often pass between exposure to external factors and detectable cancer. Cancer is treated with surgery, radiation, chemotherapy, hormone therapy, biological therapy, and targeted therapy.

Can Cancer Be Prevented?

A substantial proportion of cancers could be prevented. All cancers caused by cigarette smoking and heavy use of alcohol could be prevented completely. The American Cancer Society estimates that in 2013 about 174,100 cancer deaths will be caused by tobacco use. The World Cancer Research Fund estimates that about one-quarter to one-third of the new cancer cases expected to occur in the US in 2013 will be related to overweight or obesity, physical inactivity, and poor nutrition, and thus could also be prevented. Certain cancers are related to infectious agents, such as human papillomavirus (HPV), hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), and Helicobacter pylori (H. pylori); many of these cancers could be prevented through behavioral changes, vaccines, or antibiotics. Many of the more than 2 million skin cancers that are diagnosed annually could be prevented by protecting skin from excessive sun exposure and avoiding indoor tanning. In addition to preventing cancer through the avoidance of risk factors, regular screening tests that allow the detection and removal of precancerous growths can prevent cancers of the cervix, colon, and rectum.

Early detection of cancer, which usually results in less extensive treatment and better outcomes, can also be achieved through screening for some cancers. Screening is known to reduce mortality for cancers of the breast, colon, rectum, and cervix. A heightened awareness of changes in the breast or skin may also result in detection of these tumors at earlier stages. For complete cancer screening guidelines, please see page 60.

Who Is at Risk of Developing Cancer?

Anyone can develop cancer. Since the risk of being diagnosed with cancer increases with age, most cases occur in adults who are middle aged or older. About 77% of all cancers are diagnosed in persons 55 years of age and older. Cancer researchers use the word “risk” in different ways, most commonly expressing risk as lifetime risk or relative risk.

Lifetime risk refers to the probability that an individual will develop or die from cancer over the course of a lifetime. In the US, men have slightly less than a 1 in 2 lifetime risk of developing cancer; for women, the risk is a little more than 1 in 3. However, it is important to note that these estimates are based on the average experience of the general population and may over- or underestimate individual risk because of differences in exposure (e.g. smoking), and/or genetic susceptibility.

Relative risk is a measure of the strength of the relationship between a risk factor and cancer. It compares the risk of developing cancer in persons with a certain exposure or trait to the risk in persons who do not have this characteristic. For example, male smokers are about 23 times more likely to develop lung cancer than nonsmokers, so their relative risk is 23. Most relative risks are not this large. For example, women who have a first-degree relative (mother, sister, or daughter) with a history of breast cancer are about two times more likely to develop breast cancer than women who do not have this family history. All cancers involve the malfunction of genes that control cell growth and division. About 5% of all cancers are strongly hereditary, in that an inherited genetic alteration confers a very high risk of developing one or more specific types of cancer. However, most cancers do not result from inherited genes but from damage to genes occurring during one’s lifetime. Genetic damage may result from internal factors, such as hormones or the metabolism of nutrients within cells, or external factors, such as tobacco, or excessive exposure to chemicals, sunlight, or ionizing radiation.

How Many People Alive Today Have Ever Had Cancer?

The National Cancer Institute estimates that approximately 13.7 million Americans with a history of cancer were alive on January 1, 2012. Some of these individuals were cancer free, while others still had evidence of cancer and may have been undergoing treatment.

How Many New Cases Are Expected to Occur This Year?

[3] About 1,660,290 new cancer cases are expected to be diagnosed in 2013. This estimate does not include carcinoma in situ (non-invasive cancer) of any site except urinary bladder, and does not include basal cell and squamous cell skin cancers, which are not required to be reported to cancer registries.

How Many People Are Expected to Die of Cancer This Year?

[4] In 2013, about 580,350 Americans are expected to die of cancer, almost 1,600 people per day. Cancer is the second most common cause of death in the US, exceeded only by heart disease, accounting for nearly 1 of every 4 deaths.

Cancer Facts & Figures 2013

What Percentage of People Survive Cancer?

The 5-year relative survival rate for all cancers diagnosed between 2002 and 2008 is 68%, up from 49% in 1975-1977 (see page 18). The improvement in survival ref lects both progress in diagnosing certain cancers at an earlier stage and improvements in treatment. Survival statistics vary greatly by cancer type and stage at diagnosis. Relative survival compares survival among cancer patients to that of people not diagnosed with cancer who are of the same age, race, and sex. It represents the percentage of cancer patients who are alive after some designated time period (usually 5 years) relative to persons without cancer. It does not distinguish between patients who have been cured and those who have relapsed or are still in treatment. While 5-year relative survival is useful in monitoring progress in the early detection and treatment of cancer, it does not represent the proportion of people who are cured permanently, since cancer deaths can occur beyond 5 years after diagnosis. Although relative survival for specific cancer types provides some indication about the average survival experience of cancer patients in a given population, it may or may not predict individual prognosis and should be interpreted with caution. First, 5-year relative survival rates for the most recent time period are based on patients who were diagnosed from 2002 to 2008 and thus, do not reflect the most recent advances in detection and treatment. Second, factors that influence survival, such as treatment protocols, other illnesses, and biological and behavioral differences of individual cancers or people, cannot be taken into account in the estimation of relative survival rates. For more information about survival rates, see Sources of Statistics on page 58.

How Is Cancer Staged?

Staging describes the extent or spread of cancer at the time of diagnosis. Proper staging is essential in determining the choice of therapy and in assessing prognosis. A cancer’s stage is based on the size or extent of the primary (main) tumor and whether it has spread to other areas of the body. A number of different staging systems are used to classify tumors. A system of summary staging (in situ, local, regional, and distant) is used for descriptive and statistical analysis of tumor registry data. If cancer cells are present only in the layer of cells where they developed and have not spread, the stage is in situ. If cancer cells have penetrated beyond the original layer of tissue, the cancer is invasive and categorized as local, regional, or distant stage based on the extent of spread.

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Taber & Cheung 2010

Created By: Kaylin Braden
For centuries, viruses have been one of the greatest threats to human survival and propagation, and it has been one of medicine’s greatest challenges to create vaccines and methods to stall the onset of these viral diseases. That being said, it should come as a surprise that viruses are now being used as one of medicine’s most promising new methods to attack the next prominent threat to humanity: cancer.

Since the 1800’s, there have been case studies in which it was reported that cancer regression coincided significantly with viral infections. Dramatic reduction in the white blood cell count of patients (usually signifying an improving condition) was observed when the patients were infected by such viruses as influenza and chicken pox. Doctors and scientists at the time concluded that viruses, in certain environments, could temporarily improve a patient’s condition, especially in young children with compromised immune systems. After many years of animal and clinical research, it was found that viral infection is indeed a very potent method to treat cancer. But, at this point scientists had to use the very blunt instrument of naturally occurring viruses in their trials, which often led to subject death. (Kelly and Russel 2007)

The solution was to design the viruses and delivery systems using genetic engineering so that the immune system would let the viruses through and so that the viruses would target the desired cell type. The tools needed to achieve this goal, however, were not developed until relatively recently. Until then, science used a method called targeted evolution to encourage the propagation of mutations that would result in viruses attacking cancer cells.When recombinant DNA technology was developed, the effectiveness of virotherapy could be even more directly controlled. Today, virotherapy is showing significant effectiveness in treating many cancers and diseases in mice, and trials have even shown improvements in treating advanced melanoma in humans (Nutting 2005).

These results are too significant to be ignored, and scientists are wasting no time in developing new viruses to fight other diseases. One of the ways to solve the problems of cell targeting is to add cancer-specific binding proteins to the virus. Each type of cell has an outer membrane that acts as a selective barrier between the cell and its surroundings. All membranes are coated with proteins that are used to identify a cell and its purpose in the body. One way of thinking of these proteins is as nametags, and scientists’ job is to engineer these proteins so that viruses “know” where in the body to inactivate the innate function of cells and reproduce within them. Now that our knowledge of genetics has improved and we know that every type of cell has its own genetic marker, we can design a virus to look for the exact cell type we want it to: the cancer cell (Thirukkumaran and Morris 2009).

Advantages and Disadvantages to Virotherapy

The specificity of oncolytic vectors (cancer killing viruses) was shown by Dr. Ryan Cawood of the University of Oxford and his colleagues. In his experiment with adenovirus, Cawood was able to show that cancerous cells lack a defense mechanism that healthy cells have to prevent infection. [1 The other highlight of this research is that the viruses used inoncolytic technology can be highly infective of cancer cells with minimal risk to infect other healthy cells.

After they infect the cancer cells they have two potential methods of killing the cells. The first way involves viruses that are engineered to contain the specific anti-cancer drugs or radioactive substances to deliver a precise amount of radiation or drugs to kill the cancer cells. Another method, which this paper will focus on, is to use the innate ability of viruses to kill cells.

When a virus infects a cell, it hijacks the cell’s production system and forces the cell to make copies of the virus. Eventually the cell makes so many copies that the viruses overfills the cell and bursts through the cell membrane. Imagine overfilling a balloon with air and bursting it; this is the type violent death, called lysing, that cells undergo when infected by viruses.


[2] When contrasted with more traditional forms of cancer treatments, virotherapy is much safer and more efficient. [3] Radiotherapy and chemotherapy, which use blankets of energy to destroy the cancer cells, are extremely painful and have long-lasting side effects. Essentially, these treatments are poisoning the body, hoping to poison the cancerous regions and annihilate the tumor before the body itself is destroyed. Nearby healthy cells are destroyed, and the side effects can cause further complications in overall health.Though the methods have improved in these treatments, they are still essentially primitive and are wildly expensive. Surgery, another option, is just as imprecise, and can also incur the dangers of infection and bodily stress. Virotherapy can succeed where these methods have failed.

However, with any new miracle curein medicine, there is and always should be skepticism. The lack of comprehensive results
in human trials justifiably leads some to question the safety and efficacy of such methods. Especially when considering potentially dangerous viruses being used as oncolytic vectors, the safety of healthy tissue is a concern, since cell targeting is not perfect, and the vectors must still be kept virulent in the body to properly function. [4] Furthermore, the ethical impact present in any discussion of bioengineering must also be considered, such as the epidemiological risks of virus mutations or the spread of the oncolytic viruses to the greater population.

The research in virotherapy that is being conducted now carries with it the hope of many cancer patients. With proper and thorough research, it is possible that virotherapy could be the next mainstay of medicine, like vaccinations and penicillin before that. One of the most promising studies, by Dr. Xue Qing Lun of the Tom Baker Cancer Center and his colleagues, showed that the myxoma virus, a virus that causes skin tumors in rabbits, has the ability in mice to fight cancers cells that have been grafted with human cancer cells. In fact, the results are so significant that this treatment with the oncolytic myxoma virus almost doubled the life expectancy of the cancer afflicted mice. Even more surprisingly, three out of the five mice that were slated to die lived past their life expectancy with this treatment and were essentially “cured” of their cancer (Lun et al. 2007).

Virotherapy could very well hold the secret to treating many varieties of cancer economically and selectively. The potential for pharmacological applications in large-scale manufacturing would be irresistible to pharmaceutical companies, which should spur industry investment and advances in the field. If industry could develop and mass produce virotherapeutic tools, we may see a dramatic decrease in the cost of cancer treatment. Now, the most dangerous pathogens of human history are being used to defeat one of modern medicine’s most evasive and pernicious threats.
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Anonymous 2010

Created By: Kaylin Braden
http://familydoctor.org/familydoctor/en/diseases-conditions/cancer.printerview.all.html

Cancer
Overview

What is cancer?

The body is made up of many types of cells. Normally, cells grow, divide and then die.  [1] Sometimes, cells mutate (change) and begin to grow and divide more quickly than normal cells. Rather than dying, these abnormal cells clump together to form tumors. If these tumors are cancerous (also called malignant tumors), they can invade and kill your body's healthy tissues. [2] From these tumors, cancer cells can metastasize (spread) and form new tumors in other parts of the body. By contrast, noncancerous tumors (also called benign tumors) do not spread to other parts of the body.

There are many different types of cancer, but all cancers begin with abnormal cells growing out of control. [3] There are more than 100 different types of cancer.  The type of cancer is determined by what type of cells begin to grow abnormally and where in the body the abnormal growth occurs. The most common cancers in adults are skin cancer, lung cancer, colon cancer, rectal cancer, breast cancer, endometrial cancer, ovarian cancer and prostate cancer.
Causes & Risk Factors

Who is at risk for cancer?

Everyone has some risk for cancer. In the United States, cancer is likely to affect 1 in 2 men and 1 in 3 women at least once in their lifetime. The amount of risk you have depends on a number of factors. These factors include tobacco use, lifestyle choices (such as diet and exercise), family history and factors in your workplace and environment.

How do I know if I am at risk for cancer?

Talk to your doctor. Your doctor can help you understand your risk for cancer, especially if other members of your family have a history of cancer. Your doctor can also help you understand how your risk for cancer is affected by the following:

Using or having used tobacco products, such as cigarettes or chewing tobacco
Drinking alcohol
Having eaten a diet high in fat for much of your life
Being exposed to chemicals that can cause cancer
Being at risk for skin cancer

Depending on your age and your risk factors, your doctor may begin screening you for certain types of cancer. Screening means looking for certain cancers before they cause any symptoms. Some doctors recommend that people who are at high risk or have a family history of cancer be screened more often, or at a younger age, than people who have average cancer risks. The recommendations for screening vary for different cancers.

How does smoking and other tobacco use affect my risk for cancer?

If you smoke, quitting smoking is the single most important thing you can do for your health. Cigarette smoking is a major cause of cancers of the lung, larynx (voice box), mouth and esophagus, and it can also contribute to cancers in other parts of the body.

According to the American Cancer Society, people who quit smoking at any age live longer than those who continue to smoke. For example, smokers who quit before age 50 have half the risk of dying within 15 years compared with those who continue smoking. And the more you smoke, the more damage you do. People who smoke 2 packs or more per day are nearly 20 times more likely to develop cancer than nonsmokers.

Other forms of tobacco can also cause cancer, such as cigars, chewing tobacco and snuff. If you use tobacco products and want to stop, talk to your family doctor. He or she can help you make a plan to quit.

How does my family history affect my risk for cancer?

Unfortunately, some types of cancer seem to run in families. People of a certain race or ethnic group may also have a higher risk of some kinds of cancer.

Your doctor will ask you whether other people in your family have had cancer. If someone in your immediate family (a parent, brother, sister or child) has had cancer, you probably are at higher risk for cancer, also.

You can't change your family history, but it helps to be aware of it. If you and your doctor know that cancer tends to run in your family, you can watch more closely for the early signs of the disease. For example, if you are a woman and have a family history of breast cancer, your doctor may want you to start having mammograms more often or at a younger age.

What about factors in my workplace or environment?

There may be substances in your surroundings that can cause cancer or put you at a higher risk of developing cancer. These can include dust and vapors in the air you breathe and chemicals that touch your skin. Exposure to the sun without protection can cause skin cancer and breathing tobacco smoke (by smoking yourself or by breathing secondhand smoke) puts you at risk of lung cancer and other types of cancers.

Ask your employer if there are any materials in your workplace that can cause cancer. These may include asbestos, solvents and chemicals used for manufacturing or cleaning, smoke or fumes from burning materials and many others. Your employer should have a material safety data sheet (MSDS) for each substance that could potentially damage your health. All employers are required by law to complete these forms and you have a right to see them. Your employer should also provide safety equipment, such as a mask and protective clothing, to help decrease your exposure to any harmful materials.

Take a look at the environments you spend time in outside your workplace, as well. Too much exposure to the sun can cause skin cancer, the most common form of cancer. Try to stay out of the sun as much as you can. If you must spend time in the sun, wear protective clothing and sunscreen with an SPF (sun protection factor) of at least 15.

Breathing in smoke from a cigarette, cigar or pipe (even if you're not the person who's smoking) causes damage to your body that can lead to cancer. If you smoke, you need to quit. If someone in your family smokes, offer to help him or her quit, or ask him or her to not smoke when you are around. Cigarette smoke that clings to surfaces like carpet or clothing can also pose a risk, especially for infants and toddlers.

Diagnosis & Tests

What screening tests should women have?

Increasing age is the most important risk factor for breast cancer for most women. To help find breast cancer early, your doctor may perform a clinical breast exam (where he or she checks your breasts for lumps). Discuss the benefits and harms of a clinical breast exam with your doctor.

A mammogram is a special type of low-radiation X-ray of the breast. If you are between the ages of 50 and 75, you should have a mammogram every 2 years. If you are at high risk for breast cancer, such as a history of breast cancer in your family, your doctor may want you to have mammograms more often or at a younger age than 50. The value of mammography for average-risk women in their 40s is controversial and you should discuss the pros and cons of this with your doctor to make a decision you are comfortable with.

During a Pap smear, your doctor takes a sample of cells from your cervix to be tested for cervical cancer. Unless your doctor suggests that you need one more often, you should have a Pap smear:

Every 3 years beginning at 21 years of age and continuing until 65 years of age
Within 3 years of when you start having sex if you are younger than 21 years of age
If you are between 30 and 65 years of age and you want to have Pap smears less often, talk to your doctor about combining a Pap smear with human papillomavirus (HPV) testing every 5 years

Certain things put you at higher or lower risk for cervical cancer. Your doctor will consider these when recommending how often you should have a Pap smear.

If you're older than 65 years of age, talk with your doctor about how often you need a Pap smear. If you've been having Pap smears regularly and they've been normal, you may not need to keep having them.

If you've had a hysterectomy with removal of your cervix, talk with your doctor about how often you need a Pap smear.

If you've never had a high-grade precancerous lesion or cervical cancer, ask your doctor how often you need a Pap smear.

What screening tests should men have?

To make a decision about screening for prostate cancer, first talk to your doctor about the pros and cons of screening. Factors such as family history, age and race play a part in the risk of prostate cancer.

The National Cancer Institute, the American Cancer Society, the U.S. Preventive Services Task Force and the American Academy of Family Physicians recommend that men talk to their doctors about screening and make a decision based on the risk and potential benefits of screening, as well as their own personal values and preferences.

If you decide to have screening, your doctor will order a blood test called the PSA test. PSA is short for prostate-specific antigen. Men who have prostate cancer may have a higher level of PSA in their blood. However, the PSA level can also be high because of less serious causes, such as infection.

The AAFP recommends against prostate-specific antigen (PSA)-based screening for prostate cancer.

Treatment

Why is it important to find cancer early?

Some common cancers are easier to treat and cure if they are found early. If the tumor is found when it is still small and has not yet spread, curing the cancer can be easy. However, the longer the tumor goes unnoticed, the greater the chance that the cancer has spread. This usually makes treatment more difficult.

What are the different kinds of cancer treatment?

The three most common types of cancer treatment are surgery, radiotherapy and chemotherapy. Treatment is aimed at removing the cancer cells or destroying them with medicines or by other means.

Surgery

Surgery is a way to physically remove the cancer. Surgery can be very successful in treating some kinds of cancer, but it isn't an option in all cases. If the cancer is in the form of a malignant tumor (a tumor that spreads) but the tumor is still in one place (localized), it may be possible to safely remove the tumor and any surrounding affected tissue. Surgery may not be possible if the cancer has spread to other areas of the body or if the tumor cannot be removed without damaging vital organs, such as the liver or brain.

Different types of surgery are used to remove cancer. Some of these include:

Laser surgery. Beams of light and sometimes heat from a laser are used to target and destroy cancer cells.
Laparoscopic surgery. Very small incisions are made in the body, and the doctor uses a tiny camera to see inside your body. The camera sends signals to a video screen so that your doctor can see the tumor and your organs. The doctor uses a surgical tool to remove the tumor.
Mohs’ surgery. Layers of cancer cells are removed one at a time. Each layer is examined before the doctor removes the next layer. In this way, only the diseased layers are removed and healthy tissue remains intact.
Cryosurgery. Cancer cells are frozen and destroyed using a very cold material, such as liquid nitrogen.

Radiotherapy

Radiotherapy uses radiation—in the form of a special kind of X-ray, gamma rays or electrons—to damage cancer cells so that they can't multiply. There is usually no pain during this kind of therapy. Depending on the area that is treated, side effects from radiation damage to normal tissues may occur. Your doctor can tell you what to expect. Radiotherapy is sometimes the only treatment needed, or it may be used with other therapies. A combination of surgery and radiotherapy may be used for tumors that grow in one place.

Chemotherapy

Chemotherapy uses medicines to attack the cancer cells. The word "chemotherapy" sometimes causes a lot of fear because the side effects can be severe. However, not all people experience severe side effects. The side effects of chemotherapy can often be treated with other medicines.

Chemotherapy is usually used when the cancer has spread to other areas in the body. Chemotherapy can also be used in combination with surgery and radiation. Sometimes the tumor is surgically removed and then chemotherapy is used to make sure any remaining cancer cells are killed.

Other Treatments

Another kind of treatment is biological therapy (also called immunotherapy). This treatment is used to trigger the body's immune system to produce more white blood cells, called lymphocytes (say: limf-o-sites). Two kinds of lymphocytes can attack and kill cancer cells: T-cells and B-cells. Immunotherapy aims to boost the ability of the T-cell and B-cell lymphocytes to kill cancer. This kind of therapy can also be used in combination with surgery, radiation therapy or chemotherapy.

Hormone therapy is sometimes used to treat breast or prostate cancer, often in addition to chemotherapy or radiotherapy. Hormone therapy involves taking drugs that contain other hormones to block the effects of estrogen and testosterone, also hormones. These drugs are necessary because the hormone estrogen can make breast cancer tumors grow faster. Similarly, the hormone testosterone can make cancerous tumors in the prostate grow faster. In other cases, surgery to remove the ovaries or the testicles may be used. Removing these organs reduces the amount of estrogen or testosterone in the body.

Other specialized treatments may be available. Your doctor may talk to you about these treatments if they are an option for you.

How do I decide what treatment option to use?

Your doctor, or a team of doctors, will help you understand your options and will recommend options for treatment. You may not have a choice in the treatment. Many factors are involved, including the stage that your cancer is in, what organs are affected, and the type of cancer that you have. Some cancers, such as skin cancer, are easier to treat than others. Your age and health, as well as the potential side effects of treatment, may also be factors in how much control you have over your treatment plan.

You and your doctor will want to consider both the advantages and disadvantages of each therapy. In addition, you and your doctor will want to discuss alternative therapies in case your cancer doesn't respond to treatment.

What are clinical trials?

[4] Clinical trials are used to research new ways of treating people who have cancer. After a new medicine goes through many tests in the lab and on animals, it is tested on people who have cancer and volunteer to take part in a clinical trial. The trial helps doctors decide whether a medicine is safe and effective. It also helps determine the correct dosages that patients should receive.

Cancer trials are run differently than some other clinical trials. In other types of trials, patients taking new medicines are compared to patients who receive no medicine at all (called a placebo or "sugar pill"). It would not be ethical for doctors to give people who have cancer a sugar pill containing no medicine. So, cancer trials compare patients receiving a current medicine to patients receiving the new medicine. Doctors hope that the trial will reveal that the new medicine works better than the current one.

There are some advantages to taking part in a clinical trial. Patients who do participate may receive the newest and best medicines available. Also, patients are monitored very closely throughout the trial, so their overall health often benefits. In addition, patients who take part in a clinical trial may not have to pay for the medicine they receive. The company or organization that sponsors the trial will usually provide the medicine at no charge, and will pay for extra testing and doctor visits.

Clinical trials also come with some risks. The medicines you may receive in a clinical trial usually have not been approved by the U.S. Food and Drug Administration (FDA). The medicine may have unwanted side effects, or it may not work as well as doctors hope it will. You may have to commit more time to your treatment if you take part in a clinical trial, and you may have to have more frequent tests.

If you think you might want to take part in a clinical trial, talk to your doctor. He or she can tell you about the possible benefits and risks and can help you look for a trial. You may also want to check the National Cancer Institute's Web site (see "Other Organizations") for more information and a searchable list of clinical trials.

I sometimes don't understand what my doctor is saying. What do I do?

Tell your doctor that you don't understand. You need to be aware of what's going on at each stage of your treatment, including all the options ahead of you. Bring a close friend or relative to your appointments to act as a second set of ears and eyes on your behalf. Your companion can help advocate for you.

It may help to take notes during your appointments. Write down any questions that you want your doctor to answer. You can also record all of your conversations, and then make notes from the recording. It's important that you understand what your doctor tells you, and that your doctor is aware when you don't understand. Be honest with your doctor. Don’t hold back any information, even when answering questions about how you feel, physically or emotionally, or how well you understand what the doctor is saying.

Who does what in my treatment program?

Cancer treatment can be very complex. The kind of cancer you have, the stage that it's in, and the treatment program you go through affects the kinds of health care professionals you’ll see.

Your family physician may oversee your treatment and rehabilitation programs, and can help answer questions you have. Sometimes an oncologist may manage your treatment program, but your family physician may take over once therapy is completed. An oncologist is a doctor who specializes in treating people with cancer.

A surgeon may do the operation to remove as much cancerous tissue as possible. A pathologist will examine the tissue that is removed during a biopsy or surgery to check for signs of cancer. Radiation oncologists administer radiation treatment. The radiation oncologist is often helped by diagnostic radiologists, radiotherapy technologists and radiation physicists, who plan treatment and check the radiation dosages to ensure that treatment is as safe as possible.

Oncologists, family physicians and internists often prescribe chemotherapy medicines, hormones and other drugs. Laboratory technicians or nurses may draw your blood for tests.

Nutritionists evaluate your diet and help you plan your meals during and after treatment. Physical therapists can help you keep your muscle tone and restore your ability to move around if there are any changes to your body from treatment. Psychologists, psychotherapists and other counselors, such as clergy or social workers, can help you talk through your feelings and manage the emotional reactions to your cancer and cancer treatment. Pharmacists mix the complicated medications and check that you are getting the correct dosages.

Don't hesitate to talk to your doctor about any questions and concerns you have about your treatment. If something is on your mind, ask about it. By getting answers to your questions, you can become a more active participant in your care.

What can I do about side effects?

Cancer treatment affects every person differently. Some people have few side effects or even none at all. However, the side effects of cancer treatment make many people feel very sick.

Your doctor will tell you what kinds of side effects you might expect with your cancer treatment. He or she will also tell you which side effects are unusual and when you need to call the doctor's office.

Don't downplay your side effects. It's important to tell your doctor, members of your care team and the people around you how you are feeling. If you feel very sick, very tired or are in a lot of pain, your doctor may be able adjust your treatment or give you other medicine to help you feel better.

Will I lose my hair?

Radiotherapy to the head and some types of chemotherapy can cause people to lose their hair. Other types of treatment do not cause this side effect. If you're having chemotherapy, ask your doctor whether the drugs you're taking can cause hair loss. Losing your hair can be a difficult experience. If your doctor tells you this might happen, try to prepare yourself. Decide what you want to do if you start to lose your hair.

Some people who lose their hair during cancer treatment wear a wig or hairpiece. Others cover their heads with hats, scarves or turbans. Still others leave their heads uncovered. Do what feels right for you. Many people switch back and forth, depending on where they are, who they're with and what they're doing.

If you decide that you want to wear a wig or hairpiece, it's a good idea to pick one out before you start losing your hair. That way, you can match it to your natural hair color and texture. Some shops specialize in wigs and hairpieces for people who have cancer. You may also be able to order your wig or hairpiece over the Internet.

If you decide to shave your head or leave it uncovered, you will need to protect your skin with sunscreen, a hat or a scarf when you're outside.

If you do lose your hair during radiotherapy or chemotherapy, it will almost always grow back after you finish your treatment. However, it might be a different color or texture when it grows back.

What if I don't feel like eating?

You may not feel well enough to eat while you're getting cancer treatment. But it's important to eat as much as you feel you can. Food helps your body build new, healthy cells and also helps boost your energy level.

It may help to eat several small meals a day instead of 3 large ones. Try eating bland foods like saltine crackers, plain toast and broth. Sip water, juices and soda. Ask your doctor about whether you should take a nutritional supplement, such as Ensure. Avoid spicy foods or foods with strong odors if they make you feel nauseous. You may also find that it's easier to eat and drink lukewarm food and beverages.

Some people who have cancer (especially people who are being treated with chemotherapy) have problems with mouth soreness or sensitivity. This may make it even more difficult to eat. Try eating soft, bland food or cooked food that has been pureed in a blender. If sores develop in your mouth, tell your doctor. These sores can become infected and cause serious problems. You may want to drink through a straw to bypass mouth sores. Also, try rinsing your mouth with 1 teaspoon of baking soda dissolved in 8 ounces of water. This can help prevent mouth infections and help your mouth heal faster.

When you do feel like eating, try to get as much protein and as many calories as possible. Ask your doctor whether you need to add certain nutrients or types of food to your diet. Your doctor may want you to visit a nutritional counselor, who can help you figure out ways to get the right amount of protein, nutrients and calories. If you find you can't eat at all for more than 24 hours, talk to your doctor. He or she needs to know that you're not getting the nutrition you need.

Will I be able to work?

You may not know the answer to this question until after you've started your treatment. Some people find that the effects of cancer and its treatment make them feel so sick that they're not able to work at all. Others are able to maintain their normal schedule or adjust it to work around their treatment.

Working during treatment can help keep your mind on things other than your cancer. You may also feel better knowing that you're continuing your "normal" routine. Many people who decide to work during treatment also find that they receive a great deal of support from their employers and coworkers.

If you want to continue working during cancer treatment, explore ways to make the most of your time. Try scheduling treatments for the end of the week, so that you'll have the weekend to recover. Ask your employer about working part-time or working from home. If necessary, ask coworkers to assist you with some of your tasks or duties. They will probably be eager to help.

How will I feel emotionally during treatment?

It's normal to feel helpless, angry, scared and depressed during cancer treatment. You will probably feel all of these emotions and more while you're going through treatment. On some days, you may feel like the treatment is not worth it.

Try to find a support system that you can rely on during these times. Many people count on family members and friends for support. Other people prefer to talk to people who are also going through cancer treatment. Cancer support groups can help people who have cancer and their family members cope with the disease and its treatment. Your doctor can suggest ways to find a support group, or you may contact a local hospital or the local chapter of the American Cancer Society (check the phone book or visit their Web site). The National Cancer Institute is another resource for support group information. (See "Other Organizations.")

Keeping your mind active can also help. Try to stay busy by doing jigsaw or crossword puzzles, knitting, watching movies or playing games with friends and family. Exercise can help too, but only if you're feeling strong enough. Talk to your doctor about what physical activity is best for you.

Some research, as well as the experience of many people who have cancer and their doctors, shows that a positive outlook may improve the health of people who go through cancer treatment. This positive-thinking approach can include forming a mental picture of how well your treatment and your body's immune system are fighting the cancer (also called visualizing).

It's also important to talk to your doctor about your emotions. Depression is common during cancer treatment. If it is a problem for you, your doctor may be able to prescribe medicine to help you feel better.

Complications

Should I tell my doctor that I was treated for cancer as a child?

Yes, this information is important. Your doctor will want to know about any childhood cancer and treatment. The treatments for a childhood cancer can lead to problems later in life. These problems include obesity, brittle bones, depression, heart trouble, women's reproductive issues and a higher risk of other cancers. Up to 60% of childhood cancer survivors who are now adults have at least one ongoing or late-arising health problem.

You can work out a plan for follow-up with your family doctor. You may have to talk to your parents or your childhood doctors to get the best plan for your health care now.

Prevention

What can I do to lower my risk of cancer?

Unfortunately, some risk factors for cancer (such as family history) are out of your control. But there are things you can do each day to improve your health and lower your risk of cancer. The best ways to lower your cancer risk are to stop smoking and to maintain a healthy weight, be active and eat a healthy diet. Limiting how much alcohol you drink is also important, as is limiting your exposure to sunlight or tanning beds. If you are a cancer survivor, these same lifestyle habits can help you stay healthy.

Seeing your doctor regularly can also help. Depending on your age and medical history, your doctor will probably run tests (called screenings) to try to detect the early signs of certain cancers. For most types of cancer, the sooner the cancer is found and treatment begins, the better your chances of recovering.

Why is my weight important?

Reaching and staying at a healthy weight lowers your risk of many different cancers. Maintaining a healthy weight will also help lower your risk of other conditions, such as heart disease and diabetes. Ask your doctor what a healthy weight would be for you. If you are above a healthy weight, even losing just 5 percent to 10 percent of your current weight can help your health.
Why is being active important?

Being active on a regular basis can lower your risk of several types of cancer, including colorectal cancer and breast cancer. Exercise helps strengthen bones, build muscle and reduce body fat. It can also help improve self-esteem, and increase heart and muscle strength. Regular physical activity is also important for cancer survivors because it can help reduce tiredness and stress.

Most adults can do moderate activity without checking with their doctor first. However, if you are a man older than 40 years of age or a woman older than 50 years of age, or if you are a cancer survivor, talk to your doctor before starting an exercise program.

Try to get at least 30 minutes of activity, 4 to 6 times per week. Try to keep a medium- to high-intensity level of activity. You can become more active by adding even a small amount of activity into your daily routine. For example, try taking the stairs rather than the elevator. Go for a walk during a coffee break or during lunch.
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Fikes 2013

Created By: Kaylin Braden
http://www.utsandiego.com/news/2013/feb/11/cancer-gets-deadly-tan/

By tweaking a virus known to attack cancer, San Diego scientists have developed a clever two-in-one technique for detecting tumors and making them more vulnerable at the same time. The method was tested in mice, and it could be headed for human clinical trials in as little as a year.

Researchers at the San Diego biotech company Genelux genetically engineered the cancer-killing virus to produce melanin, responsible for skin color and tanning. Tumors infected with the virus become darker than the surrounding tissue. They become visible through optical imaging, as well as MRI, or magnetic resonance imaging.

Moreover, the melanin-darkened tumors preferentially absorb near-infrared light and covert it to heat. A two-minute exposure killed nearly all of the tumors by heating them, according to a study published Monday in the Proceedings of the National Academy of Sciences.

Human clinical trials of this therapy could begin after regulatory approvals are granted, said Aladar A. Szalay, Genelux president and CEO, and the study's senior author. The first author is Jochen Stritzker, of Genelux and the University of Würzburg, in Germany.

The virus is from a well-studied variety called vaccinia, so its safety profile is known, Szalay said. A vaccinia virus was used in the first smallpox vaccine more than two centuries ago. And Genelux is using the virus in an ongoing clinical trial that has shown preliminary evidence of safety and efficacy.

[1] Hard-to-reach tumors in places such as the brain or pancreas are among the logical choices for the therapy, Szalay said.

Eventually, the melanin technology could become a tool in the new field of "theranostics," combining therapy with diagnosis, the study said.

Attempts have been made to use melanin for cancer diagnosis and treatment. But those failed because the tumor didn't make enough melanin to be effective, Szalay said. Genelux used a virus known for making huge amounts of viral protein in the cells it hijacks, causing plentiful melanin production.

Cancer-killing, or oncolytic, viruses selectively attack solid tumors because the tumors tend to be shielded from the body's immune system, which kills the viruses elsewhere. Biotech companies such as Genelux are working to enhance such viruses so they can be safely and effectively used in people.

[2] Besides vaccina, other oncolytic viruses used in clinical trials are adenovirus, reovirus, measles, herpes simplex and Newcastle disease viruses. Conclusive proof of efficacy remains to be demonstrated.

In the existing trial, privately held Genelux is testing a viral cancer therapy called GL-ONC-1. The trial uses a cancer-killing virus, genetically engineered to produce a fluorescent protein that shows where the cancer exists.

In November, Genelux said a Phase 1/2 trial showed that the "virotherapeutic" was well tolerated when applied into the peritoneal cavity. Analysis of the peritoneal fluid showed malignant cells were infected and killed by the therapy.

Genelux was founded in 2001 to develop diagnostics and treatments for cancer and inflammatory diseases.

Solid tumors are the most difficult to treat with conventional therapies, once they have metastasized. Another biotech working with oncolytic vaccinia viruses in solid tumors, San Francisco-based Jennerex, reported last week it had achieved positive results in a clinical trial of its therapy for advanced liver cancer.

Results of the study were published in the journal Nature Medicine.

[3] Jennerex is testing JX-594, a strain of vaccinia genetically modified to kill cancer cells, stimulate an immune response against the cancer, and to reduce blood supply to the tumors by destroying blood vessels.

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