Dr. Eric Jonasch, a professor of genitourinary medical oncology at MD Anderson Cancer Center in Houston, is also the director of the von Hippel Lindau (VHL) Clinical Center, which focuses on managing the care of people with a rare genetic disorder called von Hippel-Lindau (VHL) syndrome (sometimes referred to as von Hippel-Lindau disease or simply as VHL). People with VHL syndrome develop tumors and cysts in different parts of the body. These growths, made from newly formed blood vessels, are typically non-cancerous but can cause serious or life-threatening complications as they grow in size.
Those with VHL also have an increased risk of developing a type of kidney cancer called clear cell renal cell carcinoma, as well as pancreatic cancer. If these tumors aren’t controlled, they can metastasize, and spread to distant organs in the body.
There is currently no approved therapy to systematically treat VHL, said Jonasch. He has led several clinical trials evaluating the use of drugs that were approved by the FDA to treat kidney cancer as a way to possibly control VHL lesions, including renal cell carcinoma tumors. His latest trial shows promise as an alternative approach to surgery to treating kidney cancer and other cysts and tumors that can develop with VHL.
Jonasch spoke with HealthCentral by phone, explaining what his research means for improving the management of VHL and kidney cancer.
What is VHL syndrome and how does it develop in patients?
VHL is a rare autosomal dominant disorder, meaning that you just have to have one mutation in your two chromosomes for this to manifest itself. About 80 percent of individuals with VHL disease have a mother or father who was diagnosed with VHL disease. So, a lot of kids will be diagnosed relatively early because they’ll go through genetic testing to rule in or rule out the 50 percent chance that they have inherited it from their parent.
The remaining 20 percent of individuals who develop VHL don’t have a parent with VHL. They develop it during the creation or very early division of the embryo. This mutation can happen spontaneously during early development, which results in a defect in most cells throughout the body, including the reproductive organs. So, this starts a new generation of individuals with VHL disease.
What are the symptoms of VHL and how does it affect individuals?
Starting in young adulthood, VHL can cause blood vessel-rich tumors to grow in various areas of the body, which can cause damage by occupying space, although they are usually not cancerous.
In the absence of close surveillance, the most noticeable symptoms would involve the eye. Non-cancerous tumors called retinal capillary hemangioblastomas can cause displacement of retina and loss of vision. Similar lesions can develop in the cerebellum and the spine, which can cause balance problems, headaches, or other neurological issues.
Another symptom of VHL can be the development of pheochromocytomas, non-cancerous growths in the adrenal glands, which can result in blood pressure variations and other uncomfortable symptoms.
VHL disease can also cause cysts or cancers to develop in the pancreas.
Why do so many people with VHL get kidney cancer? What are the challenges doctors have when treating kidney cancer in patients who have VHL?
Roughly 50 percent of people with VHL will develop kidney cancer; it is the most common cancer that can develop from VHL. Patients inherit the first missing or defective VHL gene, and their second VHL gene gets lost or broken at a higher rate than in other people, although we’re not sure why. Once you lose two VHL genes, the possibility of developing kidney cancer increases dramatically.
In addition, the age of clear cell renal cell carcinoma onset for an individual with VHL could be much younger than that of non-VHL patients, which is typically around age 60. A person with VHL disease can develop multiple carcinomas of the kidney, sometimes as young as in their 20s and 30s. And they are at risk for getting cancer in both kidneys, which is unusual for non-VHL patients. Many people can do well with just one functioning kidney, but it’s more serious if both kidneys aren’t working. The patient would need dialysis or a kidney transplant to survive. This is a key difference which makes management of VHL cases quite challenging.
How is kidney cancer in VHL patients currently treated?
We typically watch a tumor until reaches a 2- to 3-centimeter range and we then start planning to remove it as it approaches or exceeds 3 centimeters. Before it reaches this size there’s very little chance it will metastasize.
The traditional approaches would either be partial nephrectomy, where we’re removing the tumor and as little of the kidney as possible, or ablation, such as cryoablation or radiofrequency ablation, freezing or heating to kill the cancer cells while causing minimal damage to the surrounding kidney. We avoid removing the whole kidney or both kidneys if at all possible, to preserve as much kidney function as we can, possibly preventing or delaying the need for dialysis or a transplant. This is fundamentally the same treatment for non-VHL patients with clear cell renal cell carcinoma. But we haven’t found an alternative treatment for VHL disease beyond observing the patient and offering surgery when a tumor becomes too large. We are looking for drugs or other systemic treatments because tumors can return even after surgery, and repeated surgeries have negative effects on the organ systems involved.
What areas have your clinical trials focused on and what results have you seen?
There have been a number of drugs developed to treat metastatic kidney cancer based on our biological understanding of what a normal VHL gene does. VHL downregulates the factors in the cells that would result in unbridled blood vessel development. So with a mutated VHL gene, you basically have a cell that is essentially saying “I’m lacking oxygen, please build me more blood vessels.”
The blood vessels built by kidney cancers have vulnerabilities that would then be targetable. There are therapies to block the receptors that spur blood vessel development, which have been FDA-approved since 2005 for renal cell carcinoma.
What we’ve done is to test these agents in individuals with VHL to see whether or not they can provide benefit. We’ve published three studies. The most recent one was published in The Lancet Oncology where we are looking at pazopanib, an antiangiogenic agent which inhibits the growth of blood vessels that support tumor growth. We looked at 31 individuals with VHL disease.
What we’re doing is taking a drug that was approved by the FDA to treat renal cell carcinoma, and seeing if it’s effective in a group of individuals with this rare disorder which includes renal cell carcinoma, but other growths as well.
There were a lot of positives in this trial. We saw shrinkage to renal cell carcinomas; there was a response in 52 percent of the renal cell carcinomas. But we also saw that the drug might be inducing some toxicity, and that is of concern.
VHL can cause cysts and tumors in the pancreas and brain. We saw that pancreatic cysts dramatically decreased in size, and we saw modest shrinkage of hemangioblastomas in the brain, but also saw toxicities in the brain. We saw two individuals who developed bleeding in the brain, which is relatively rare in the absence of the therapy, so that may be a major caution that we may be inciting fragility of those blood vessels in the brain.
Pazopanib can be considered as an option for individuals with VHL disease where surgery is not a reasonable option. We are looking to develop agents with even greater effectiveness and potentially lower toxicity rates. A potential candidate is the Peloton PT2977 drug.