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Eradication of brain tumor stem cells with an oncolytic adenovirus.

Jiang et al. Discov Med. 2010 Jul;10(50):24-8.

Philosophically, tumor cells have an advantage to humans in the “War on Cancer”. That is, the tumors have the ability to rapidly mutate, so that when drugs are given to fight the tumor, the tumor can “mutate around” the drug and become resistant. This occurs in several ways: a) the tumor starts expressing drug efflux pumps, such as the multi-drug resistance (MDR) protein that actively transports chemotherapeutics out of cancer cells; b) the tumor mutates the kinase or molecular target that the drug is inhibiting; and c) the tumor increases expression of other oncogenes that are not inhibited by the drug.

One interesting method of dealing with the problem of tumor mutation is to use agents against the tumor that are actively mutating. One approach has been the use of viruses that have a selective ability to infect tumors and to kill them. These are called “oncolytic” viruses. One of the most well-known oncolytic virus is the Reovirus, which only replicates in cells that express high concentrations of the oncogene RAS. This virus is in clinical trials by the Canadian company Oncolytics.

Delta-24-RGD is an oncolytic adenovirus that is capable of infecting glioma cells and preferentially inducing their death. It is being developed at the Brain Tumor Center, The University of Texas MD Anderson Cancer Center and is the subject of an ongoing Phase I clinical trial in the treatment of patients with therapy-resistant glioma.

One of the key issues surrounding any cancer therapeutic is whether the treatment is targeting tumor stem cells, or only the tumor progeny cells. This is very important because tumor stem cells are usually resistant to chemotherapy or other interventions that require cells to be metabolically-active and hyperproliferating. The majority of tumor cells are metabolically-active and fast multiplying, these cells are usually destroyed by conventional drug approaches, however, subsequent to their destruction the tumor stem cells exit quiescence and start making a new tumor. This has been one of the primary reasons for the poor success rate of cancer therapeutics that are currently under development.

In the current paper scientists found that the Delta-24-RGD virus is capable of infecting and causing death of glioma stem cells. This is a very important finding because it implies the possibility of attaining tumor cure by administration of such an oncolytic virus. Other advantages of the oncolytic virus approach is that the process of tumor cell death likely releases numerous antigens which cause activation of systemic immunity towards micrometastasis. Unfortunately one of the drawbacks of cancer therapy using oncolytic viruses is that the host develops an immune response to the virus which does not allow for long term continual administration. Patients interested in this treatment should contact Dr. Jiang at .

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