What is the deal with cytomegalovirus in glioblastoma?
For over a decade now, my research group has been investigating the possible association and role of human cytomegalovirus (CMV) in glioblastoma. I’ll be frank with you, this has been a rough road. Our initial observations were published in 2002 in the Journal of Cancer Research. To my surprise, there was no apparent interest in this area until I received a phone call from researchers at Duke University around 2004. They had tried to identify CMV in glioblastoma, because, as innovator’s in the world of immunotherapy for cancer, they were looking for a target that would be specific for the tumor that was not in the rest of the body’s cells.
For immunotherapy, the best potential target would be something that is nonself, such as a virus. In any event, Dr. Duane Mitchell came to my laboratory and learned how to perform the staining techniques to identify CMV in glioblastoma’s. During that same period of time we had several meetings with experts from around the world in CMV virology. I proposed to these experts that the virus might be involved in glioblastoma. Most of these investigators met this with skepticism. However, two of these investigators, Dr. Robert Kalejta at the University of Wisconsin, and Dr. Timothy Kowalik at the University of Massachusetts went back to their laboratories and independently investigated this proposed association. I believe they were somewhat shocked to find that they indeed could identify CMV DNA, RNA and proteins in over 90% of the glioblastoma specimens they tested. Also, at the Karolinska Institute in Stockholm Sweden, my colleague Dr. Cecelia Soderberg-Naucler, independently validated our findings. Furthermore she and her associate in neurosurgery at the Karolinska Institute proposed a clinical trial using the well tolerated oral antiviral drug valganciclovir, also known as Valcyte. They treated patients in a prospective randomized clinical trial with Valcyte for glioblastoma in addition to radiation and chemotherapy.
Unfortunately, the endpoint of their clinical trial was whether or not there was significant change in tumor volume after 6 months of treatment. Most neuro-oncologists will tell you that it is difficult to determine who is responding to any type of therapy for glioblastoma after just 6 months. Since the imaging at 6 months did not show a clear difference, they then opened the clinical trial results and allow patients who were on a placebo to switch over to the Valcyte.
They subsequently followed all the patient’s who had been on Valcyte for any length of time, and performed a retrospective analysis to determine whether length of time on Valcyte was associated with improvement in survival. There results were striking and were published in the New England Journal of Medicine as a letter, which is a very brief report. They showed that patients who are on Valcyte from the beginning of their treatment had a median survival of nearly 5 years. This is remarkable for glioblastoma, yet it must be taken in the context of a retrospective analysis of a previous study. This retrospective analysis received much interest but also serious criticism in the scientific community. It accelerated the debate as to whether CMV is involved in glioblastoma and irritated many neuro-oncologists who now had to field questions from patients and families about the use of a drug that was not approved for glioblastoma, based on a poorly designed retrospective study. It should be noted that I personally tried for over 15 years to have pharmaceutical companies provide drug for a clinical trial that could be performed definitively, and to date they have not agreed to provide a drug in the United States for such a trial.
Nevertheless, with respect to the fundamental biology of glioblastoma, the possibility that CMV plays a role in initiating and/or promoting the disease remains a serious question that needs to be answered. It is difficult to get these answers because there appears to be some unusual biology going on with respect to CMV in these tumors. Normally, when a human cellular gene is present, it is present in 100% of cells. The RNA that is made from this gene is usually present in a very high fraction of cells as well. Proteins derived from this RNA can usually be detected easily. In the case of CMV in glioblastoma, we now believe that the virus is in a semi-latent form with very low level of viral DNA present. We also believe that the viral DNA that is present may only be a subset of the glioblastoma cells. We have evidence that an important subset of glioblastoma cells called glioblastoma cancer stem cells may be the host cells for the virus. The cells may represent only 0.1% of the total tumor cells. It’s difficult however to explain the fact that we often see the viral proteins and a high percentage of the tumor cells. We are doing our best to explain these discrepancies and this may have to do with the fact that the virus produces proteins that are highly stable and are not degraded and can be passed from a grandparent tumor cell down to the multiple progeny tumor cells.
I certainly cannot give a definitive yes or no answer as to whether the virus is present in all glioblastomas and whether it is a cause or even a promoter of these tumors. Nevertheless, we have published from this laboratory multiple peer review journal articles that show evidence of the viral genes and proteins with the appropriate controls. Sometimes we have difficulty finding these in tumors. Other laboratories seem to have similar results. Some laboratories publish high percentage of their tumors being positive for CMV while others cannot seem to detected based on varying methods. One of the most confounding issues is the fact that a widely regarded definitive type of test called next generation sequencing, in which the the tumor DNA or RNA is sequenced millions of times to find evidence of any gene, has to date shown no evidence of CMV in these tumors.
How can you square this fact with the fact that we frequently find evidence of the viral proteins in tumors. I’m sorry, I don’t have a good answer for that at this point. We are in discussions with other investigators about some type of potential viral cofactor or some type of unusual biology.
The goal of my laboratory at this point is to use techniques such as next generation sequencing and protein mass spectroscopy to show absolutely and unequivocally that the viral genes and proteins are present in the tumors. We are getting preliminary evidence that these incontrovertible techniques are doable. We hope to answer this question once and for all, by using such techniques that do not rely on any type of potential bias.
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All content provided on this blog is for informational purposes only. The owner of this blog makes no representations as to the accuracy or completeness of any information on this site or found by following any link on this site. The owner will not be liable for any errors or omissions in this information nor for the availability of this information. The owner will not be liable for any losses, injuries, or damages from the display or use of this information.