Fixing VHL

Question:

In Ariel’s Story in the May 2009 issue of VHLFF, she says: “A person with VHL is lacking the von Hippel-Lindau tumor suppressor gene; this gene produces a protein that helps to control cellular growth.  Without this gene, and hence, without the protein, tumors are predisposed to grow in places rich with blood vessels, like the brain, eyes, spine, pancreas, adrenal gland, and kidneys.”

If the problem is the lack of the VHL protein, couldn’t we simply make VHL protein and inject it into the tumor? or take it as a supplement?

-- Curious in Michigan

Response:

People with VHL actually have quite a bit of VHL protein in most cells of the body.  Everyone has two copies of the VHL gene.  In a person with VHL, there is one tiny misspelling in one copy of the gene, but the second copy is correct and makes good VHL protein (abbreviated pVHL).  If that second copy becomes disabled for some reason, a tumor may begin to form.  It may take years for the tumor to get to a size where we can even see it on the best scan. 

The pVHL is present in most cells, but missing from these tumor cells.  So in theory if we could add some pVHL back into the cells of the tumor, we should be able to reverse tumor growth.  However, this is not possible with today’s technology.  The protein is very unstable outside the cell, so even preparing it to inject would be very difficult.  And we do not have the technology today to deliver it inside the cell, where it would need to be.  Furthermore, the protein turns over every 1-2 days: normally you make more inside the cell.  But as a therapy, we would need to deliver new pVHL inside the cell every 1-2 days.  If we had the technology to do this, we could solve lots of medical problems, not just VHL.

Dr. William G. Kaelin of the Dana-Farber Cancer Research Institute in Boston refers to this as the “holy grail” of medicine.  There is a great deal of experimentation going on to find a delivery mechanism to accomplish this.  Perhaps one day through nanotechnology or some such thing we will have the capability to do it.  But today, we simply don’t have the technology needed to do it.

What is more feasible with today’s technology is controlling some of the “downstream” proteins.  When there is too little pVHL, there is too much HIF, which makes too much vascular endothelial growth factor (VEGF), which in turn stimulates the growth of new blood vessels.  There are known ways to control HIF and VEGF, a category of drugs known as angiogenesis inhibitors (drugs that inhibit the creation of new blood vessels). This is the primary mechanism of drugs such as Bevacizumab (Avastin), Sunitinib (Sutent), Ranibizumab (Lucentis), and others being tried in clinical trials with VHL.  There are another twenty or more such drugs “in the pipeline,” somewhere in the development process.  As we move forward, they are getting more “specific” and with fewer side effects.  As Dr. Kaelin once described it to me, classic chemotherapy is rather like using a sledge hammer.  What we really want is a tweezers to get right to the very spot and do the job carefully, with least damage to surrounding tissues, and with fewest side effects.

The research continues!

As printed in the VHL Family Forum 17:3, October 2009. For permission to reprint, please contact VHL Family Alliance, editor@vhl.org. Further information is available from the VHL Family Alliance, info@vhl.org.