Mass. General Cancer Center, Medical Oncologist, Dr. Othon Iliopoulus, MD talks about a new drug that shrinks tumors of Von Hippel-Lindau disease, or VHL.
Interview conducted by Ivanhoe Broadcast News in 2022.
What is VHL?
ILIOPOULOS: VHL is the acronym from the name of two physicians, Von Hippel and Lindau. Lindau was a Swedish pathologists, Von Hippel was a German ophthalmologist. And they were the first ones that made the connection with patients that they have hemangioblastoma. Some specific tumors in the brain have also this tumors in the back of the eye and kidney cancer. And they described clinically for the first time the disease at the mid 1800s.
How uncommon is it?
ILIOPOULOS: It’s a rare disease. It’s categorized as a rare disease. One out of 35,000 births have VHL, which is about half of the frequency of cystic fibrosis. Patients with VHL know, though they live a long life and you end up having many adults that they’re having it.
Is it a genetic condition?
ILIOPOULOS: It’s a genetic condition. You inherit it either from the father, from the mother. In a very small percentage it happens the novel as we call it, at birth, but it’s an inherited disease.
At about what time does it start to present? Is this a disease that people start to see in their teens, their twenties, mid adulthood?
ILIOPOULOS: It has three waves. It has three waves if we want to describe it. The earliest wave can start around years 2 or 3 of life. And it only manifests with hemangioblastomas of the retina. Retina is the lining of the back of our eye. The way with- the membrane that makes as see. And with rare tumors that connect to VHL, which is called pheochromocytomas. The second wave, and nothing else happens until you reach 10 or 11 years old. The second wave is around 10, 11, 9-11, that people may develop this very particular and signature brain tumor, which is called hemangioblastoma. And the third wave is towards the mid-end of adolescence, that the people they have the disease develop a possibility to have renal carcinomas. Now, all these things are cumulative, like you continue to have these risks for all these diseases. Kidney cancer, hemangioblastoma of the brain or the retina, pheochromocytoma, pancreatic neuroendocrine tumors throughout your whole life.
Is it potentially fatal?
ILIOPOULOS: If not treated it’s fatal, because these tumors grow, they can metastasize, they are cancerous and you can die from cancer. Hemangioblastomas are not cancerous are-, somebody ironically could say benign lesions with strict scientific terms, but these are space-occupying tumors within a closed box, which is our brain. And therefore people can die from an untreated hemangioblastoma.
Because it’s affecting the lining in the back of the eyes, it affects vision?
ILIOPOULOS: Absolutely. Unfortunately, at the beginning before we know very well about the disease in natural history, there are many people that they lost their vision because these tumors either grow in the optic nerve and therefore destroy it, or they end up destroying the lining of the eye, the retina, and if left untreated, they can lead in complete loss of vision.
What have been the treatments historically till now? Is it a surgical treatment?
ILIOPOULOS: It is a surgical disease. Before August of 2021, this was a surgical disease and the surgical approach shifted dramatically, even during the years that I deal with VHL, early at the ’70s or ’80s, people were removing the kidneys even prophylactically, which of course you understand, send people to hemodialysis and had a lot of morbidity. Then with time we realize that we can observe the tumors in the kidneys without removing them until they grow to three centimeters. So I had many patients here at the MGH that they were running around with three or four, two-and-a-half centimeters kidney cancers in each kidney, which appear paradoxical, but our attention shifted into preserving the kidney. We know that these tumors cannot give metastasis, which is a problem, unless they reach the three centimeters. Hemangioblastoma has been always a surgical disease. The neurosurgeons will do a craniotomy. The ophthalmology with laser of the tumors in the eye, if they were in permissive positions because not everything can be lased in the eye. And the abdominal surgeons would do a big operation taking out the head of the pancreas, half of the stomach and the intestine unblock, as we say, when the tumors appeared. So before August of 2021, it was a purely surgical disease.
What happens in August 2021?
ILIOPOULOS: August 2021 what happen is that many years of efforts and research and study of the biology of the disease in the bench as basic scientists culminated in the approval of a drug by the FDA. And this drug has been approved- actually it’s the first indication of this drug was approved by FDA. These patients with VHL disease and renal cell carcinoma, or hemangioblastoma, or neuroendocrine tumors of the pancreas.
What is the drug and what does it do?
ILIOPOULOS: The chemical name of the drug is called Belzutifan, the marketing name is called Welireg. This is a drug developed initially by Peloton and then commercialized by Merck. And to get to what the drug does, allow me to take a step back and say what is the problem with the VHL tumors. VHL tumors suppress our genes, the specific gene that it is destroyed by mutation. So a change in the DNA in the people that they have the disease. When you lack VHL in the cell, there is a protein in APOE gene that’s called HIF standing for hypoxia-inducible factor. And this protein goes rogue completely and it turns the cell into a cancer cell. So it’s a classic example of a gas and a brake in a car, you destroy the brake which is the VHL and the gas it can be a stopper. So this is a drug that essentially stops very effectively the function of HIF. The way that it does it, is that it is like a small key. HIF cannot work by itself in the cell, it has to partner with another protein. And there is a great crystallographer down from Texas Richard Brooch, who about 10 years ago took a picture of these two partners tangled together. And then what happen is Peloton and Merck developed this drug, which essentially is a key that goes into the cleft between these two molecules and breaks it apart, and then destroys the partnership and destroys the consequences of having these molecules to undergo the cell.
So, will it be FDA-approved it in August of 2021?
ILIOPOULOS: Yes, FDA-approved it in August of 2021.
How is it administered? Is it an oral pill?
ILIOPOULOS: It’s an oral medication. You take three pills together once a day and this is it.
How quickly can it work?
ILIOPOULOS: This is a very good question. In kidney, cancers works a little bit slowly. In contrast to our classic chemotherapy that we give to the patients who wait the results immediately, it may take up to six months to give us the results. And the results can be due a prolonged period of time. The hemangioblastoma is a different story. We were very surprised from the beginning to see that hemangioblastoma patients had a quite rapid response. We enter many patients to the clinical trial in MTH because we have a comprehensive clinical care center designated by the beach that aligns in the MTH, and we follow more than 300 patients over 20 years now. So we were able to enter patients that they had both kidney cancers and hemangioblastomas and several of them also have pancreatic neuroendocrine tumors. And it was very surprising because hemangioblastoma it worked surprisingly fast. At the beginning, we thought that it works within three months. Later on when we decided to image the brain of this people little bit earlier, turns out that it can work within six weeks and give significant clinical results.
What is the implication after having something for the first time that can this much?
ILIOPOULOS: This is a real game changer. This is a miracle. It’s not a miracle that because cures VHL disease, but it sets a completely different approach. It creates the possibility for a completely different approach. Instead of operating repeatedly the brain of the patients, which is even in the best hands, and procedure which is not pleasant and even in the best hands it has a degree of morbidity and potentially mortality. We can treat the patients and save them from having the craniotomy. Currently, I have out of the trial, 20 patients that they’re treated off trial commercially with a prescription of earlier that they have hemangioblastomas. And I did not have any progression for disease. And I had the automatic clinically improvement and the radiographic improvement. So it is clearly a game changer. Everybody suspects or is afraid that at some point we may have progression of the disease. In some point, it was every targeted therapy, we may have a resistance to the medication- the medication, but there is no question that it dramatically changed the quality of life of these patients.
Can you tell me a little bit about Ashley’s case?
ILIOPOULOS: Ashley’s a lovely young lady. It’s an amazing individual. I met Ashley, I think it was the last 10 or 12 years. Ashley has VHL and suffer a lot of consequences of the disease. She had kidney cancer since she had surgeries, but mostly she suffered from hemangioblastomas. She lost her vision at the very early stage of life because of retinal hemangioblastomas. And despite the fact that she lost her vision and she had to go to all these doctors visits, Ashley is one of the most positive, upbeat, and visionary persons that I’ve met. She finished the speech pathology. She works as a speech pathologist. She coaches people that they have some limitations, visual or other type of limitations. I never- I would never forget the day that you came to the clinic and- and she said that she spent the weekend very actively. And I said, what did you do? She says, we went for a hike for two days. The limitation of losing her vision did not stop Ashley from doing anything. She had two craniotomies because of her hemangioblastomas. And the second one was not uncomplicated. She had a clot in one of the veins of the brain, despite the fact that it was performed by outstanding surgeon with a log experienced the disease, the natural history, or having continuous operations. She didn’t have any neurological consequences of this. But then she developed a third tumor. And she even avoided to talk about her early symptoms because she was afraid that she was going to have another operation. And when she arrived in the clinic, it was very clear. It’s got the big 3.5 centimeters tumor in a closed space like our brain, in a critical position that blocks the functions of the brain is very dramatic. She had headaches, she felt horrible, she could not walk straight, she had nausea in all the symptoms of the big tumor in the brain. I treated her with high-dose steroids. And that was before the drug is approved. Actually during the transition that we’re expecting the FDA results. I treat her with high-dose steroids and then other medications that we thought it might help. She was really hanging back cliff. She was on her way for surgery.
I was going to ask you, if she’d had two, the second one was tough. She’s not looking forward to a third, but she had no option at that point.
ILIOPOULOS: That’s right. She was going into surgery according to the classic ways of treating VHL.
So instead, the drug became approved. Can you tell me what you saw in her after she started taking the drug?
ILIOPOULOS: She had a dramatic response to the drug. She was the first patient that I treated with this medication commercially. And essentially, it was almost a very gutsy thing to do because she was in such a condition that a lot of people advice that she goes to surgery, that they did not have time to treat her with the medication. But we have made already the observation that the responses may be very rapid. So I offered her the possibility. She really like this option and didn’t want to go through a craniotomy. And we started this medication. Within three weeks, she was off the high-dose steroids, off the other medication and her symptoms improved immediately. And the first MRI that followed in six weeks showed that the tumor had shrunk from 3.5 centimeters to 1.6 to three. And in the end of the three months, the tumor was 2.5 centimeters. If you take the numbers, is not exactly half.
END OF INTERVIEW
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