- All cells have defective VHL
- Difficult to deliver gene to all cells (not yet developed)
- Targeting is a major hurdle (multiple tumors)
- Germline therapy is very controversial
Conclusions:
At this time, gene therapy may not be the answer for VHL
To prevent inheritance, may do in vitro selection of embryos
To treat tumors, may use anti-angiogenesis, anti-VEGF, anti-HIF-1 directed therapy
Function of the VHL protein
VHL is a disease that has multiple clinical manifestations
The VHL gene makes a protein that has multiple functions within the cell
Many puzzle pieces are beginning to come together
Understanding the multiple functions of the VHL protein, and figuring out how its tumor-suppressor function works, is like solving a complicated puzzle.
The good news is that many of the important puzzle pieces are already in place.
What we know so far
The VHL gene has been identified and shown to be an important tumor suppressor gene.
The protein is known and being studied to determine its function.
The disease can be diagnosed accurately clinically.
New Pieces to the Puzzle Emerge
We heard about the determination of the molecular structure of the VHL protein
Structure Predicts Function
VHL seems to be a protein with two parts (domains) that come together.
Most of the common mutations of VHL fall within one of these domains where VHL binds another protein complex with multiple functions.
VHL - ElonginC - ElonginB
Most VHL mutations destabilize or destroy this complex.
What we have learned about the Function of VHL
Very exciting results were presented here that characterize the VHL protein complex as analogous to a multiprotein complex (SCF-E3 Ubiquitin protein Ligase complex)
Why is this important?
Because these results provide key evidence for a new function for VHL
VHL May be a Molecular Adaptor Protein
VHL functions like an analogous protein that links very important proteins to the multi-protein VHL complex
Then these proteins are targets for destruction in the cell.
Thus, this function could normally prevent proteins from acting throughout the cell cycle or at inappropriate times in development.
Which Proteins might bind to VHL for destruction?
This is a key question. One of the most exciting news presented here is that the VHL protein binds to the Hypoxia Inducible Factor (HIF-1) protein.
This is important because HIF-1 is activated in the cell when oxygen levels are low (a condition called hypoxia).
HIF-1
HIF-1 has been shown to activate a number of important genes that are important in vascularization of tumors during hypoxic conditions.
Normally, then, VHL might target HIF-1 for destruction so that HIF-1 would not continually activate these genes.
What about in VHL disease?
VHL might not be able to target HIF-1 for destruction, thus HIF-1 would constantly activate genes required for vascularization.
This could be a possible mechanism to explain the high degree of vascularization in VHL tumors.
If HIF-1 could be inactivated, then perhaps the small tumors in VHL would not grow as well.
New Research Directions
One of the most important tasks ahead will be to determine the proteins that VHL targets for destruction.
Also, it will be important to tie together other aspects of VHL function with its tumor suppressor activity.
Controlling Tumorigenesis in VHL (beginnings of new tumors)
VHL mice deficient in VHL protein have been developed (VHL-/-) The mice die during placental vasculogenesis.
This is important because it suggests that VHL must be critical for normal vascular development.
VHL +/- mice do not develop tumors.
A VHL homologue has been discovered in the fruit fly.
VHL Tumorigenesis Models
Efforts are underway to construct a conditional VHL knockout in mice in which VHL is absent only in the kidney.
This could be very useful to understand kidney tumor initiation and to test gene therapies.
New Mutation and Mosaicism
see June newsletter
Finding all VHL Mutations
Dr. Catherine Stolle and Dr. Alessandra Murgia have a very high success rate in finding VHL mutations (~100%)
They are willing to share!
Ask about the "hit rate" of the lab you are using.
If you already know the mutation, it’s less important
If it’s a question of differential diagnosis, go for the best possible lab.
Genotype/Phenotype Alignments
Presentations from study groups in many countries depicting the variations among their families
Type 1, Type 2 distinctions
Recommendation is still to do screening for all manifestations of VHL
Cannot with confidence rule out particular tumors in some genotypes
Clinical Trials
Informed consent
ASK QUESTIONS
Brochure available from NIH
Consider both short and long-term consequences
DON’T FORGET THE TISSUE BANK
You can participate in helping research
