On Thursday we drove into the countryside to a medieval abbey nestled in the rolling green hills, surrounded by wheat fields and lush woodlands. Fifty monks still live in this enormous complex, but one large wing has been renovated to form a modern conference center with all the conveniences. We entered through ancient walls into a stone foyer, and proceeded to a modern auditorium with comfortable chairs and modern audio-visual equipment.

After Dr. Opocher and Joyce Graff welcomed everyone, Dr. William Kaelin of Boston introduced the first session, "New Advancements in VHL Proteomics." Proteomics1 is the process of annotating the genome. We may know the letter sequences that form the genes, but we don’t yet understand just what all this means. We are moving from the VHL gene sequence to the protein it encodes and the functions of this protein in the cell and in the body.

*Dr. Maha Kecem came from Tunisia where she works with two VHL families.*

So far we know that VHL combines with elongin B and elongin C, CUL-2 and Rbx1 to form an E3 ubiquitin ligase complex known as VEC, a kind of garbage-collector machine. This machine can attach to any of a number of other proteins in the cell in order to lower their levels in the cell, or "degrading" them,

clearing them out, in order to function as an "off" switch for the function of these other proteins. When they are needed they are produced. When they are no longer needed, VHL is supposed to degrade them and turn off their function. If the VHL protein is not there to perform this function, they can continue to function – a normal function but now out of control – and a tumor can ensue.

A number of these proteins are being studied, in hopes of finding a "target" for a drug to work on. Perhaps by manipulating the levels of one of these other proteins we can effectively replace the function of VHL. Three primary angiogenic factors – VEGF, PDGF, and TGF-alpha – are all being studied for other cancers. In addition, it is clear that VHL plays a role in the body’s response to changes in the levels of available oxygen and how the cell processes oxygen. It does this through its binding with HIF-1 and other substances. The scientists presented their work with these chemical processes, studying them in the lab as well as in animals.

VHL is highly conserved in evolution. Many animals have a VHL gene quite similar to our own, including the drosophila fruit fly and the worm, as well as guinea pigs and mice. Dr. Tien Hsu of South Carolina and Dr. Harry Drabkin from Denver described their work with drosophila. Smaller animals go through many generations in a short time, allowing us to see effects more rapidly. Dr. Laura Schmidt of the U.S. National Institutes of Health described their work in creating a "mouse model" -- a mouse with a kind of VHL sufficiently similar to the human VHL disease that they can use it to test out therapies.

Dr. Kaelin remarked that it takes examination of the same problem from many different perspectives in order to form a complete understanding of a complex issue like pVHL function. There is something unique about the way VHL works that loss of one of the things in the picture does not make the same outcome. There is something special about the VHL protein itself. We need other models – fly, worm, and mouse – to help us see the problem fully.

The VHL protein also seems to have a regulatory effect upon the orderly differentiation and dispersion of cells, the orderly creation of microtubules, and orderly processing of a variety of mechanisms in the cell. In the absence of the VHL protein, these cells proliferate in a haphazard manner.

The development and availability of in vivo models for VHL – drosophila, worm, and soon mouse – provide us with greater ability to observe the normal and aberrant processing of these substances by the cell, with and without pVHL.

Dr. Neumann’s group presented their findings about the genetic causes of pheochromocytomas. So far there are at least six different genes which can cause a pheo. Why so many? In studying the functions of these various genes we will eventually get to the problem. Dr. Opocher’s group found that people with VHL who have pheos often also have a particular change in chromosome 1. Similarly, Dr. Thomas Böhling of Finland showed that in the group he studied, people with VHL who have CNS hemangioblastomas often also had a change at chromosome 6q, and Dr. Hiltrud Brauch of Stuttgart showed that a change in the MDR1 gene raised the risk of having renal cell carcinoma.

*Richard Hbud, Lone Sunde and Thomas Rosenburg from Denmark*

There is evidence that some modifier genes exist, influencing the effects of VHL by raising or lowering the odds of getting particular kinds of tumors (e.g. loss of 6q may influence toward CNS tumors, and alteration of MDR1 may influence toward renal tumors). These conditions help to explain why different people in the same family will have entirely different experiences of VHL.

People in VHL Type 2 families (with pheos) tend to be at somewhat higher risk of pancreatic neuroendocrine tumors (PNET). Careful monitoring is needed to ensure that any PNET are detected early and that metastatic disease can be avoided.

*Joke Jansen, Naim and Hetty Berisha from the Netherlands. Naim is originally from Kosovo*

Dr. Catherine Stolle of the University of Pennsylvania moderated a session on Genotyping. Genotyping is not easy. Methods vary from one lab to another. Finding known VHL mutations in clinically diagnosed patients is one challenge, finding large-size alterations in people with ambiguous diagnoses is much more challenging. The ability of the diagnostic lab varies considerably. It is clear from studies done in countries with higher rates of detection that there are many people (8-25%) with a single VHL-associated tumor who will likely have a germline mutation. Rates of new mutation are very significant (15-25%) and rates of mosaicism are small but significant (1-2%).

Then came the clinical presentations. Dr. Hartmut Neumann studied the use of PET scanning to find where the pheochromocytoma is hiding in the body. He found that 18F DOPA PET is a highly sensitive and specific procedure for detection of pheochromocytomas and has potential as the functional imaging method of the future. MRI got essentially the same results, but requires more skilled interpretation. PET scanning is still not widely available, but might be sought out in the case of an elusive pheo.

Dr. Edward Oldfield of the U.S. National Institutes of Health showed some compelling data on the natural history, or growth patterns, of CNS hemangioblastomas. It is important to understand that most hemangioblastomas never develop into clinically significant tumors. More symptoms are caused by the cyst than by the tumor itself. The ability to forecast which of these very small tumors might be about to form a cyst would help us select targets for therapy before the damaging "mass effect", the pressure, begins to build. It is also important to advise patients and physicians of the large numbers of small tumors that may be seen on increasingly finer quality scans, in order to sustain hope and work toward appropriate treatment. It’s not a matter of how many tumors you have, it’s how big they are.

Dr. Alessandra Murgia described her VHL clinical program at the University of Padua. A clinical care center that serves as a resource for differential diagnosis, clinical collaboration and technical support to local physicians can make a tremendous impact on appropriate clinical care for people with VHL.

Dr. Kathlyn Marsot-Dupuch described her studies of ELST in France. Because an ELST can occur even where there is normal hearing function, they are reviewing the 1997 NIH recommendations to use auditory screening as a way of determining who needs to have focused temporal bone imaging study. She feels that ELST should probably be considered as a major clinical criterion for VHL diagnosis in the same way as hemangioblastoma.

Dr. David Gross from Israel presented his encouraging results using halofuginone to inhibit the growth of pheo cells in vitro, in a dish in the lab. Dr. Richard talked about the mixed results he received using SU5416 with three patients. While none of the tumors regressed, it did cause edema in the eye to disappear, improving vision. The likelihood is that it will take more than one drug to constrain the growth of VHL tumors because of the multiple influences that promote them.

In the general discussion we talked a bit about some of the key questions for which there should be better answers:

- Should we have a more practical set of screening guidelines? Is it reasonable to recommend an MRI annually, when the reality is that it will not often be economically feasible to do so?

- What is the right age to begin monitoring children? The French now begin regular screening at age 4. They are seeing symptoms earlier because of DNA diagnosis -- they are looking earlier and with better imaging capabilites than ever before.

We will visit these questions in greater depth as we revise the Handbook over the next year.

The German and Spanish affiliates of the VHL Family Alliance described their experiences in creating their groups, deciding what to talk about, getting people together in meetings, in chat rooms, or in e-mail discussions on the internet. There is much energy and organization going on in Europe, much of it driven by Gerhard Alsmeier, our International Volunteer of the Year, and by our energetic new affiliate in Spain.

There were also fifteen poster presentations, with new contributions by teams in Hungary, Spain, and Croatia. Attendees came from six continents!

*Hartmut Neumann, M.D., violin, Klaus-Martin Kreusel, M.D., piano*

It was not all hard work. On Friday afternoon we toured the Abbey, an impressive self-supporting community. Later we went to dinner at the Air Museum in San Pelagio, near Padua, where Dr. Neumann gifted us with his traditional violin serenade after dinner, with Dr. Klaus-Martin Kreusel from Berlin accompanying him on the piano.

Lella Guerra, our contact person in Italy, held a meeting for the Italian families on Saturday afternoon where they drafted a constitution for an Italian Affiliate. Sunday fifteen of us met in Abano Terme for a European Leadership meeting of VHLFA, sharing ideas for forming groups and collaborating across Europe and around the globe.

As ever, it was hard to say goodbye. This community and the bonds we have formed among researchers, clinicians, patients, and families is a rich and rewarding group that honors and respects the power of the community as a whole. The most important message we can bring you from Padua is a message of hope. There is a global community of brilliant scientists and doctors working to find the answer to this puzzle and to make life better for all of us. Arrivederci -- ‘til we meet again -- perhaps in Cleveland in October?

More photos from Padua

As printed in the VHL Family Forum 10:2, June 2002. For permission to reprint, please contact VHL Family Alliance, editor@vhl.org.

This conference was supported in part by a grant from the U.S. National Cancer Institute, Bethesda, Maryland.