Saturday, May 31, 2008

Human cytomegalovirus and glioblastoma

The timing of news about these related topics is interesting.

Common Virus May Serve As Target For Vaccine In Fight Against Deadly Brain Tumors (5/16/08)
A type of herpes virus called human cytomegalovirus (CMV) is found in up to 80 percent of Americans, though the virus normally produces very few clinical symptoms, is dormant, and usually undetectable in most people. However, more than 80 percent of patients newly diagnosed with the brain cancer glioblastoma multiforme (GBM) exhibit detectable CMV in their blood as well as in their tumors. The Duke team thought this might provide an opportunity to target brain tumors by going after the virus.

"Previous work has demonstrated the activation of this virus in patients with GBMs, so we took it one step further and tested a vaccine, in a small group of patients, that seems to show some efficacy in stalling the recurrence of these deadly tumors," said Duane Mitchell, M.D., Ph.D., a Duke researcher and lead investigator on the study. "We knew there was a connection between this virus and the brain cancer, and we were hoping to take advantage of that connection to treat one by treating the other."

The fact that glioblastoma multiforme and human cytomegalovirus occur together doesn't automatically mean that the latter "causes" the former, in the way that human papilloma virus (HPV) is known to cause cervical caner. Indeed, the fact that CMV is endemic, while GBM isn't, means that the story has to be more complicated. (The Wikipedia article even cites research (from 2003) that did not find a link between GBM and viral infection.)

However, the fact that a vaccine based on CMV seems to have some effect on GBM, means the relationship has to be more than fortuitous:
There were 21 patients enrolled in the trial, and the vaccine appears to have delayed the re-growth of tumors from a typical six to seven months after surgery to more than 12 months. Early results also show a lengthened overall survival among GBM patients, from about 14 months with standard treatment to greater than 20 months.

This still doesn't prove that CMV "causes" GBM. For instance, the tumor environment of GBM may simply be more supportive of the virus. But just having CMV more prevalent in GBM tumors makes it possible for a vaccine to work, because the vaccine causes the immune system to target cells that contain CMV.

Here's some other recent research that addresses the relationship. In fact, it shows just how CMV is tumorigenic.

Virus Mimics Human Protein To Hijack Cell Division Machinery (5/8/08)
Viruses are masters of deception, duping their host's cells into helping them grow and spread. A new study has found that human cytomegalovirus (HCMV) can mimic a common regulatory protein to hijack normal cell growth machinery, disrupting a cell's primary anti-cancer mechanism.

Writing in the May 9 issue of Science, researchers from the University of Wisconsin-Madison and Harvard Medical School report that a viral protein, called UL97, masquerades as a normal regulatory enzyme to modify a tumor-suppressing protein in human cells. Unlike the normal enzyme, which can be switched on and off by the cell as needed, the viral stand-in lacks an off switch and evades cellular control. The findings represent a previously unknown way that viruses can cause uncontrolled cell growth and division.

But this still doesn't address the question of why, if CMV is in 50% to 80% of the population, GBM is so rare. Or, indeed, why GBM is the only sort of cancer with which CMV seems to be associated. Whatever the relaltionship really is, it's apparently somewhat tenuous.

Update 6/4/08:

Here's another news report on the vaccine that just appeared. There will probably be more, since the results sound pretty encouraging.

Vaccine doubles brain cancer survival time
A vaccine that more than doubles the survival time of patients with the most common and aggressive form of brain cancer has been developed by scientists.

Early results from clinical trials suggest patients who received the vaccine lived for nearly three years after being diagnosed with glioblastoma multiforme.

Update, 7/16/08: More recent news story: Does Herpes Cause Brain Cancer? (7/3/08)

Further reading:

Phosphorylation of Retinoblastoma Protein by Viral Protein with Cyclin-Dependent Kinase Function – Research article in 5/9/08 Science about tumorigenicity of CMV

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Anonymous iayork said...

The data aren't available (presented at a meeting, rather than published) and the press release is the usual incoherent marketing department babble, so we don't actually know what's going on here. But I'm puzzled by the "vaccine" line.

If these people have really developed a vaccine against human cytomegalovirus then they've accomplished something -- as an afterthought byproduct -- that intense effort, or decades of work, by specialist vaccine and virological groups has not done. Herpesviruses in general, and CMV in particular, are notoriously difficult vaccine targets.

I suspect -- trying to translate from "marketing" to "science" -- that the group is using CMV antigens in a tumor vaccine, which is somewhat different and may be more practical.

In general, I think it's more likely that the arrow of causation is pointing the other direction. Most likely CMV grows especially well in the tumor, so that the tumor causes the virus infections; it's less likely (from what we understand about CMV) that the virus causes the tumor. I suspect that the research team feels the same way and the marketing department has kludged up the story.

Need the paper before I can tell, though.

6/04/2008 07:52:00 AM  
Blogger Charles Daney said...

I suspect -- trying to translate from "marketing" to "science" -- that the group is using CMV antigens in a tumor vaccine, which is somewhat different and may be more practical.

I agree, Ian, and I was trying to suggest that in the post. To be more clear, for others reading these comments, the way that vaccines work is they stimulate the immune system to react when protein fragments ("antigens") are encountered. In this case, the antigens are from CMV, but because the CMV is in the tumor cells, the immune system goes after those.

Since the people doing the vaccine work are from the Duke U. brain tumor center, I think they deserve a lot of credence.

I've just added a new news reference to the vaccine work, which was presented a few days ago at the ASCO conference.

6/04/2008 11:28:00 AM  

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