(this is a review i wrote for biology 112)
Links between cancer and viruses have been noted as early as 1912, and more clearly documented in the 1970s and 1980s when it was discovered that two patients’ lymphomas shrank when they had the measles (Nettlebeck, 2003:70). Virotherapy is a cancer treatment strategy where viruses are used to selectively kill cancer cells, and this area of study began in the late 1990s. Scientists believe there are two ways to make virotherapy effective, one is to use viruses to kill cancer cells directly, the other is to use the viruses to deliver genes to make the cancer cell more susceptible to chemotherapy.
In current research scientists prefer adenoviruses for virotherapy because the biology of this class of viruses is well understood. Other viruses that are closely studied may also be used for virotherapy in the future. Adenoviruses are not like the retroviruses used in gene therapy, that technique focuses on using the virus to to exchange a dysfunctioning gene for a functional copy. Adenoviruses are different, their genes do not become a part of the cell’s DNA structure, the genes they insert into a cell only work for a short time and begin to degrade. The goal of virotherapy is pointedly different from gene therapy in that it seeks to kill the cells it invades rather than change (without harming) the cell it invades.
While adenoviruses are useful because they are well understood, there are risks associated with their use. A patient undergoing a clinical trial for gene therapy died from the treatment with adenoviruses in 1999. While this concerns people who focus on virotherapy, they are doubly concerned because the viruses they create are being used to kill cells, not just repair them. This means that the targeting function has to be very well focused in order to kill the right cells. Another risk is highlighted by the case in 1999: immune response. Humans respond to adenoviruses with a cold or flu response. If virotherapy uses these viruses, then patients undergoing treatment are likely to respond with cold or flu-like symptoms. That means the immune system recognizes the virus because of the antibodies in the body, and the immune system mounts an attack on the viruses. This is not the ideal situation for virotherapy because the goal is for the viruses to replicate, killing off cancerous cells. Two possible solutions are to use immunosuppressive drugs to try and prevent the immune system from killing the treatment, or modify the viruses in a way that the body will not recognize them.
Targeting the appropriate cells is the greatest feat of virotherapy. Scientists are taking two approaches to this issue: transductional targeting and transcriptional targeting. In transductional targeting the virus is modified so that it prefers cancerous cells. The transcriptional strategy modifies the virus so that the genes it infects the cells with are only active in tumors.
Transductional targeting is important because adenoviruses are so successful at invading humans and binding to many types of cells. The adenovirus is a 20-sided structure with protein arms that attatch to receptors on the outside of cells. Scientists modify the structure of the virus by adding molecules onto the ends of those arms that bind only to a protein found on tumor cells. When this happens, the virus cannot bind to normal cells, it can only bind to tumor cells. Once bound to the cell, the cell’s membrane engulfs the virus, and the virus acts on the cell. The membrane sac around the virus disintigrates, and the virus travels to the nucleus, going to a pore in the nuclear envelope, and inserts its viral DNA. This viral DNA instructs the cell to make more of itself, and also make viral proteins and combine the two. When the cell is full to bursting capacity the virus activates the death gene causing apoptosis and the new viruses are released to infect new cells. One specific modification used by a group at the University of Alabama involves designing the virus to particularly target the cellular proteins integrins. This is a protein that helps cells stick to connective tissue, but cancer cells produce integrins more than normal cells when they mastecize. This method proved effective in targetting ovarian tumors in laboratory rats (Nettlebeck, 2003:71, 74).
The transcriptional strategy takes advantage of cell differentiation in the body. The virus is tailored to a specific type of cell based on certain proteins active in that type of cell. The major genetic information is the same in all cells, but the information is only turned on in cells that have a function using that information. Creating a virus able to target a particular type of tissue or organ is very important for being able to treat skin cancer or liver cancer. This strategy is being investigated for approaches to treating skin cancer and prostate cancer.
The future of virotherapy may incluse some kind of combination of the two strategies to ensure that only cancerous cells are killed. Currently the adenoviruses used still target some non-cancerous cells. This means that future virotherapy may use viruses modified to fit several checkpoints before the virus invades the cell. One key that will make virotherapy particularly useful is that cancerous cells do not undergo apoptosis. The proteins instigating cell suicide are disabled. Adenoviruses also work in cells with inhibited apoptosis pathways because “they can replicate only in cells that are preparing to divide.” (Nettlebeck, 2003:75) Adenoviruses usually have proteins that block apoptosis pathways, but some companies have manufactured adenoviruses that have no apoptosis blockers, meaning that they only work in cells that have uninhibited cell division (cancerous cells). Use of this approach is planned for ovarian cancer research.
Another method will be to use the viruses predispose cancerous cells to convert prodrugs into anticancer drugs, using the virus as a tool to facilitate more effective chemotherapy. The goals to achieve more effective therapy will be to adequately trace what the viruses are doing, and where they are going. Work is done with radiologists to be able to see where viruses are replicating. The goal is to add a tracer molecule to the virus that can be observed so that we can “see” where the viruses are. This approach works best with viruses that do not kill the cells, but scientists may be able to find some indications of how the mechanisms are working.
After the publication of this article in Scientific American, there have been several studies pointing to the advancement of virotherapy. Sunamura et al used adenoviruses to target pancreatic cancer cells by targeting cells deficient in the proteins p53 and RB(necessary for apoptosis). Their results were cancer cell death and tumor prevention. It is believed that because pancreatic cancers have a tendency for abnormal p53 and RB pathways that the virotherapy will be effective in most pancreatic cancers. (Sunamura, 2004)
Another group looked at the use of virotherapy to kill benign or malignant brain tumors (meningiomas). Preliminary research showed that one specific modified adenovirus, Ad.d24 was effective in supressing outgrowth and killing outgrowth of brain tumors. (Grill, 2005)
The Psiron company of Australia has been doing work on virotherapy targetting melanoma and ovarian cancer. The company’s Phase I clinical trials for both melanoma and ovarian cancer are slated to run this year. (Sheon, 2005)
These examples show the current areas being explored in research for virotherapy. This is a therapy that could provide a new venue of treatment for cancer, which is especially promising for cancers such as melanoma which are particularly difficult to treat with traditional chemotherapy.