Dr Andrew Wilner (Host): This is Better Edge, a Northwestern Medicine podcast for physicians. I'm your host, Dr. Andrew Wilner, Associate professor of neurology at the University of Tennessee Health Science Center, and division director of neurology at Regional One Health in Memphis, Tennessee. Joining us today from The Von Hippel Lindau Disease Program at Northwestern. We have three distinguished guests, Dr. Brittany Szymaniak, genetic counselor and instructor of urology, Dr. Rimas Lukas, associate professor of neurology in the division of neuro-oncology, Dr. Niraj Shenoy, Associate professor of Medicine in the division of hematology and oncology and pathology. Welcome, Dr. Szymaniak, Lukas and Shenoy.

Dr Niraj Shenoy: Thank you.

Dr Brittany Szymaniak: Hi. Thanks for having us.

Dr Rimas Lukas: Thank you, Dr. Wilner.

Dr Andrew Wilner (Host): Yes. Thanks for joining. To get started, Dr. Shenoy, let's start with you. Tell us about Von Hippel Lindau Disease or VHL?

Dr Niraj Shenoy: All right, so the von hippel lindau disease, it's a genetic disorder due to defects in the vhl gene. And it is manifested by characteristic tumors and multiple organs. And so specifically these tumors are hamangio blastomas in the central marrow system, particularly in the cerebellum and spinal cord retinal heman, blastomas, ple cell renal cancers in the kidneys, often multiple and bilateral. Pancreatic neuroendocrine tumors, feocromocitomas, and much less commonly end lymphatic sac tumors.

And often these patients can also manifest with cysts in multiple organs in the kidneys, pancreas, and in the liver. They typically, patients typically present in the third or fourth decade of life, and that is because they've inherited usually one defective allele from one of their parents. And pathology usually develops when the wild dipole la is also affected by a mutation or a deletion or epigenetic silencing. And so when the, when both of these eleals are compromised, that's when, pathology develops in terms of, tumor formation.

Dr Andrew Wilner (Host): Thank you, Dr. Shenoy. I'm a practicing neurologist and frankly I can't remember whether I've ever seen a patient with this disorder. Is it rare?

Dr Niraj Shenoy: It is The incidence is estimated to be one in is it 35,000, around 35,000 live births. And so it is a reasonably rare disease, but we are seeing these patients a little more commonly right now, and that is largely due to the approval of a drug that we've had that happened last year which has been a really exciting development for these patient.

Dr Andrew Wilner (Host): All right. We're gonna get to that, the treatment in a little while. But Dr. Szymaniak, Dr. Shenoy mentioned that VHL is a genetic condition. I know it was described more than a hundred years ago, but when did they figure out the genetic part?

Dr Brittany Szymaniak: Oh, you're stumping me with the question. I'm not sure if Dr. Shenoy, Dr. Lukas would know but off the top of my head, I'm not sure what year exactly the gene was discovered, but the idea is that this gene is a tumor suppressor. So just like Dr. Shenoy described, When we have one allele that's compromised, that's putting a patient one step closer to actually developing some type of tumor or cancer. And so when the second allele has some type of mutation, then we actually see disease presenting.

But what's important to note about VHL is that, like Dr. Shenoy mentioned, this is typically inherited from a parent so dominant, but about 20 to 25% of the time we can see the, this is actually a brand new genetic change in one of our patients that was not inherited. from a Parent. So this can actually make sometimes identifying patients more complicated because we don't see that there's this very strong pattern of VHL type of cancers that we, or tumors that we would typically anticipate.

Dr Andrew Wilner (Host): If I suspected this in a patient, would it be because they have one tumor or would they have a lot of them all at the same time? And the second part of my question is how do I make the diagnosis? Is it a blood test or is it a clinical diagnosis or do I need some tissue?

Dr Brittany Szymaniak: Yeah, so typically because. This is gonna be a mutation present in every cell of this patient's body, we typically see people presenting with more than just one tumor or cancer. And Dr. Shenoy mentioned, typically with the kidney cancer, it tends to be bilateral. We tend to see multi focused cancers presenting. Back before we actually had good genetic testing, we had clinical criteria that we used, but now really the gold standard is to be able to do blood testing to actually get germline results for a patient. Or if we think that this is a de novo mutation or a new mutation, we might actually need to do a skin punch biopsy to identify that this could be mosaic for a patient.

Dr Andrew Wilner (Host): Now I have a feeling if I did a blood sample and sent it to my lab, I would just sit there on the counter and probably wouldn't get processed. They have to send it somewhere?

Dr Brittany Szymaniak: Yeah. So I would say that the vast majority of hospitals do not have in-house germline testing. So usually it's going to be independent clinical genetic testing laboratories that will be performing this type of testing.

Dr Andrew Wilner (Host): Dr. Lukas do you do that kind of testing at your hospital, or do patients have to get tested and then come to the Northwestern program? How does that work?

Dr Rimas Lukas: Yeah I think it's interesting because the workflow for patients with VHL or suspected VHL can come from a number of different directions, and you as a neurologist, actually maybe one of the first people to see these patients because, one of the most classic manifestations is somebody coming into your ER or into your clinic with neurologic symptoms associated with increased intercranial pressure. Imaging is performed, an abnormality is noted in the posterior fossa. That raises for, at least for myself, suspicion for hemangio blastoma.

And then they undergo surgical intervention to relieve that pressure, relieve that lesion, which can usually be completely cut out if the pathology comes backas hemangio Blastoma. I think it's important to be aware that it could be VHL related. And you know about 50 or so percent of Heman blastomas in the nervous system are gonna be sporadic. So not related to VHL, but that means half of them will be. And if there's, factors that start to make you a little bit worried, so the patient's younger maybe something else was seen on the imaging study, it, I think warrants further evaluation for VHL.

At our institution, we'll typically do the histopathology, so looking under the microscope of the tumor itself. We'll also do the next generation sequencing of the tumor which universally in a hemaniog blastoma will show VHL mutation. Now that doesn't mean that the person has VHL, it just means that gene is mutated within the hemangio blastoma. We'll also do DNA methylation profiling, so looking at some of those epigenetic features that Dr. Shenoy had alluded to.

And then I'll pass the baton to Dr. Szymniak and she will then coordinate the genetic testing for that patient to confirm the germline presence of VHL mutation. And I think being able to package the whole thing together is really important. And one of the reasons why is people can slip through the cracks. So they see you as the neurologist. You say, Oh, you have this tumor, the neurosurgeon cured you of it, you're done. Let's call it a day. Nothing to worry about. And the last thing we want is for that same young individual then to get renal cancer that subsequently metastasizes and nobody paid attention to it, or they get retinal angios that lead to blindness.

And I think we work really hard to make sure that none of that falls through the cracks. And it's the cancer genetics counseling team that really serves as the linchpin to, to allow people to get to the right subspecialty physicians with experience in VHL within our program.

Dr Andrew Wilner (Host): Dr. Szymaniak, we just learned that this disease tends to present in the twenties and thirties, which is for a lot of people it's childbearing years. Probably it's important for those people to know whether they are carrying this gene or not. How does that work at your program there, in terms of genetic counseling and testing?

Dr Brittany Szymaniak: . Yeah. Like Dr. Lukas mentioned, we can sometimes see patients at different, points in their care. So sometimes it's the situation that they've already had genetic testing. This is something that's been known about it in the family for a long time. So we talk through options when it comes to family planning because most patients and even some providers don't know that we actually have the ability to do testing on embryos as part of the IVF process. Now not everybody can necessarily afford to go through something like that, but we talk through options when it comes to how can we actually do testing for families to figure out what they would want to do in terms of possibly passing this on to any future children.

But if it's the situation that somebody has not had genetic testing yet, then we're going through that whole process of figuring out for them and then being able to have a better idea of what risk could be for other relatives. And so it's really important for us to be able to identify these patients because then not only are we getting them in for screening when we need to, where we already know that their kids are gonna be at risk and we're already gonna be able to start screening for them when it's appropriate. Versus potentially having somebody come in, like Dr. Lukas mentioned presenting with symptoms already because we didn't actually know that they had VHL.

Dr Andrew Wilner (Host): Would one of you like to give an example of a recent patient and how it goes through the, your program?

Dr Rimas Lukas: I think I had already mentioned the scenario where somebody comes in with the neurologic symptoms. But another one that was alluded to a moment ago is the scenario where somebody has a known diagnosis of VHL or maybe their family member does. Their brother has known VHL, they undergo the genetic testing, and then it turms out they also have that mutation present. In that type of scenario, what would typically happen is they'd see Brittany in the clinic. She would confirm that the presence of that mutation.

We'd make sure we have the full documentation of what the story of this individual is, have a good understanding of their family tree with regards to the presence or absence of tumors of various sorts, and then make sure that they have the appropriate screening done. Classically for us that appropriate screenings can include central nervous system imaging, meaning taking a look with a MRI scan of the brain and the spine neurological exam, which is where I would come into play. And ideally we find nothing. And if that's the case, then that's great.

And if we do find something, Most of the time in VHL, one of the things I wanna stress to patients and families is that we can usually be pretty conservative with regards to our therapeutic management. Meaning we can just keep an eye on things often and then just check and double check and triple check over time to ensure that the abnormalities that are present are not growing, that they're not causing any symptoms. And hopefully that continues indefinitely. And then if something does happen, then we'll address it. And our cLassic tools have been surgery, but now we have some other things that we can also use.

In addition to that, they would meet with Dr. Shenoy, for example, and he would keep an eye on the renal manifestations, etcetera, and address those if needed. We'd have them evaluated by ophthalmology in ophthalmologists with specific experience in VHL. E NT with Audiometry to look for those endo lymphatic sac tumors that can cause decrease in hearing scanning kind of top to bottom to make sure that there is no abnormal. What's nice for us is that the VHL Alliance has a delineated recommendation of screening procedures. So we keep people on track and then address things as they as symptoms develop.

Dr Andrew Wilner (Host): Okay, so it sounds like if a patient does have the gene but is otherwise asymptomatic, that at a minimum they're gonna have a fairly extensive systemic screening on an annual basis?

Dr Rimas Lukas: Overall, yes. And certain types of scans, it's every two years, etcetera. And so that makes it complex with regards to how to keep the parts of the puzzle together. And that's why I think it's helpful to have an organized program because for me, my job becomes so much easier. When I have confidence that everything else is under good control or that somebody is keeping a watch on these other aspects, even if they are, having problems that arise. And so then I can make my recommendations regarding the central nervous system disease, whether that's recommending somebody be seen by neurosurgery or whether recommending they initiate a systemic therapy with a much greater degree of confidence.

Dr Andrew Wilner (Host): Thanks for that Dr. Shenoy, we know that VHL is currently incurable. Are there any new treatment options that make all of this screening really worthwhile?

Dr Niraj Shenoy: Yeah we were just, alluding to this new medication called Belzutifan. Which was approved by the FDA last year and specifically for cancers associated with the VHL disease. And the approvals for three approval was for three specific cancers. The clear cell renal cancer, which is what the study was powered to detect. It was a phase two open label single arm study which was published, but it was a registrational study. Which was published in the N JME last year, which showed impressive response rates and different cancers associated with VHL. Response rates of 49% in clear cell renal cancer, 30% in heman, neuroblastoma, and Upwards of 75% for pancreatic neuroendocrine tumors.

And so the data was strong enough to gain approval for all of these three malignancies associated with VHL. And which is great because you don't wanna be in a position where, patients have a particular, say for example, VHL patients, MA who manifested without clear cell renal disease. If the approval was only specifically for rcc, those patients would not have benefited. And the FDA rightly deemed that the response rates were impressive enough across the cancers and gave the approvals for these three malignancies. So there are very few VHL patients who would not really meet that criteria.

Perhaps, the two Cs who have just fear cytomas may not qualify. But most of these patients have one of these three cancers, clear cell renal cancers or hemangio blasnomas or pancreatic neuroendocrine tumors and would qualify for this medication. But then it's not that all of these patients need these medication and need this medication . We recently wrote this paper and which has been accepted in neuro-oncology, so it's a bit of a self promotion over here, but , we, so we've gone over the details of the disease and this medication and certain clinical practical considerations in terms of the patient selection, monitoring and the adverse effect profile, etcetera.

And because this drug was just recently approved the real world experience is relatively, it's relatively new. But this particular medication going back to the biology when your VHL is affected so VHL, it's a tumor suppressive protein, which is a part of a complex that functions as something called a ubiquitin ligase. And it regulates these proteins called hypoxia, invisible factors. There are two major isoforms, the hypoxia invisible factor two and one. And the HIF two has been shown to be the dominant bronchogenic isoform. And Belzutifan is a small molecule inhibitor of HIF two of her won't go into the depths of the biology.

How it, essentially it causes a it breaks a dimerization of HIF two alpha with its partner and what these hypoxia invisible factor proteins do is they enhance the transcription of genes involved in angiogenesis and rewiring of metabolism. So it ties into the hypoxia pathway. So essentially these cells which are affected by this visual disease think that they're under a hypoxic stress, and it's something that we call a pseudo hypoxic phenomenon. And they upregulate genes that help these cells adapt to. A low hypoxia, a low oxygen environment, even if your oxygen environment is normal.

And this chronic pseudo hypoxic state resulting in the upregulation of angiogenesis and rewiring of metabolism results in these hypervascular tumors that are characteristic of the VHL disease. And really with belzutifan, we are going at the trunkal aspect of the pathogenesis which is, what has resulted in these impressive response rates.

Dr Andrew Wilner (Host): Oh that's an explanation. And it makes it makes sense. And I'm gonna throw something out as a non-expert would there be any role for taking low dose, belzutifan as a prophylaxis say a regular basis to prevent these tumors from growing. Has anyone looked into that?

Dr Rimas Lukas: Yeah, so at this point in time, we don't have any data to support that being of benefit. And I think as Dr. Shenoy had mentioned, it's. Being sorted out now in real time as we all collectively gain experience with this drug. And that, trying to figure out who the optimal patients are for treatment. And I think in general, the consensus thus far is those who have multiply progressive tumors that are symptomatic. That's your ideal patient for it. But there is some variability and there's a number of different factors that need to be weighed.

We don't know what the optimal duration of therapy is. We don't know in some ways what the optimal dosing schedule. Do you take breaks or not. And at this point, again, there is no definitive evidence that if you're nice and stable and nothing's going on, that you would benefit from a low chronic dose of the drug.

Dr Andrew Wilner (Host): Okay? But you're thinking about it?

Dr Rimas Lukas: These are all important questions that we're weighing and trying to sort out it. And I think from a practical perspective, it's stuff that's not really easy to model in preclinical settings in animals. You know what happens 10 years down the line or 30 years down the line, you can't replicate the mouse.

Dr Andrew Wilner (Host): Yep. There are all limitations. That's fair. Dr. Lukas, any final recommendations for providers managing patients with VHL?

Dr Rimas Lukas: I would say that, one, have a suspicion for it when you come across the patient who has the heman blastoma or the patient who you're seeing with the stroke and gets pan scanned and has a bunch of cysts in the pancreas or has a little lesion in the liver. So it's something to be suspicious of. And then I understand that there is value in making sure that there's a comprehensive evaluation so things don't slip through the cracks. And I guess last bit is that there is a lot of hope on the horizon with the advent of a new regulatory approval for a systemic therapy.

So this is the exciting thing for us that we haven't seen. We have to just cut away and burn away at these tumors for a long time, at least in the central nervous system. And now we have something that can address multiple lesions all at once. And, hopefully we'll continue to have advances in this field that will be driven by the preclinical science.

Dr Andrew Wilner (Host): Oh, that's terrific. Is there anything else any of you would like to add?

Dr Niraj Shenoy: I'd just say that over the last three decades, the research in this field, on this pathway, would not have been possible had it not been for multiple groups and the 2019 Noble Prize in Medicine Physiology was awarded to Dr. Kalin Samanza and Radcliffe for work related to this pathway. Dr. Samanza had discovered the hypoxy visible Factor one protein, and Dr. Kalin and Radcliffe's groups identified the regulatory mechanisms, between VHL and the HIF. So very well-deserved Nobel there and had it not been for their work and the scientists at UT Southwestern who identified that the HIF two isoform could be targeted with small molecule inhibitors, it would've been we would not have been here.

It's credit to these groups and years of focused research in this. That we are where we are. And going back to when the gene was first isolated, it was 1993. And that happened at the NCI in collaboration with the University of Birmingham. So it's interesting, it's actually a century after the disease was first, I guess described as penicular vascular growth in the retina, is when the gene was clothed. And since 1993, Three decades of research, focused research has got us to where we are. So we are standing on the shoulders of these giants in the.

Dr Andrew Wilner (Host): Yes, Exactly. Thank you Dr. Szymaniak, Lukas and Shenoy. Thank you for this very informative discussion about Von hippel lindau disease and for joining me on Better Edge.

Dr Brittany Szymaniak: Thank you.

Dr Andrew Wilner (Host): To refer your patient or for more information, head to our website at breakthroughsforphysicians.nm.org/neuro to get connected with one of our providers. And that wraps up this episode of Better Edge. A Northwestern Medicine Podcast for physicians. I'm your host, Dr. Andrew Wilner. Thank you for listening.