Living with a genetic disorder that calls for regular monitoring, appropriate treatment and emotional support calls for a multidisciplinary team that works together to coordinate patient care. Those diagnosed with von Hippel-Lindau (VHL) disease have a resource for that complete and coordinated care in Roswell Park Comprehensive Cancer Center, which was recently named a VHL 

“We are honored to partner with Roswell Park Comprehensive Cancer Center in providing the first VHL Clinical Care Center for patients and families in Western New York. Roswell Park’s reputation for excellence and dedication to providing holistic, coordinated and knowledgeable VHL care make them an invaluable resource for the VHL community,” says Chandra Clark, MEd, VHLA Executive Director. “We look forward to the life-changing impact that this collaboration will make in the lives of patients and families affected by VHL.”

A rare hereditary condition, VHL occurs as tumors that can appear in up to 10 areas in the body. While all people are born with two copies of the VHL gene, an altered copy can lead to the growth of cysts and tumors. The disease appears differently in each person — tumors can grow unpredictably over time and cause life-changing problems due to location and size. Though most tumors are noncancerous, patients with VHL have a high risk of developing kidney cancer as well as tumors of the adrenal gland and pancreas.

Because VHL can affect so many different organ systems, it takes numerous experts across multiple disease sites and disciplines to keep track of a patient’s care plan. Roswell Park takes this comprehensive and personalized approach. A patient navigator helps guide patients through the steps needed for attentive surveillance to monitor any new or changing tumors, ensuring that those patients are seen by the necessary specialists.

“VHL is complex, and our staff at Roswell Park are well equipped to provide the best care possible to these patients,” says 

, a urologic oncologist at Roswell Park. “We are proud to be able to provide these resources — from our clinical genetics service to kidney cancer experts — for anyone who finds themselves diagnosed with the disease.”

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Those diagnosed with von Hippel-Lindau disease have a resource for that complete and coordinated care in Roswell Park Comprehensive Cancer Center, which was recently named a VHL Clinical Care Center by the VHL Alliance.

Roswell Park Is First Site in Region Named a Resource for Patients With Rare Genetic Disease

A woman in her 20s with von Hippel-Lindau (VHL) syndrome was undergoing routine surveillance for the inherited condition, when a dramatically enlarged hemangioblastoma in her spinal cord was detected.

Surprisingly, she didn’t have symptoms. Even still, the surgery was able to be successfully completed to avoid spinal cord compression. Had her disease not been monitored so routinely, it is unclear whether surgical intervention would have still been an option.

“That, to me, was a really dramatic presentation, and one that I didn't expect, but one for which I'm very grateful that we had surveillance as an option,” Kim E. Nichols, MD, director of the Cancer Predisposition Division at St. Jude Children’s Research Hospital told 

. “It’s a great example of the importance of surveillance and intervention [in VHL].”

It may sound complicated, said Nichols, but having a VHL diagnosis shouldn’t consume a patient’s life. In fact, monitoring through routine screenings is one of the most important components of care for patients with the inherited condition, which puts them at an increased risk for developing tumors.

“It's really important that people recognize the importance of monitoring, to follow through with surveillance, but also not to let that dictate their lives. Patients with VHL are no different than anyone else,” said Nichols. “They may have to have additional tests, but it's all meant to keep them healthy and it's a very important thing to do. Don't let it cause great anxiety because, ultimately, the outcomes are excellent. You just have to be a little bit more careful about caring for yourself.”

VHL disease is defined as a rare, inherited disorder that causes tumors and cysts to grow in specific areas of the body, including the brain, spinal cord, eyes, inner ear, adrenal glands, pancreas, kidney, and reproductive tract.

 Although many of these cases are benign, others can develop malignant tumors.

 gene mutation, and symptoms do not appear until young adulthood.

“VHL syndrome is a relatively rare genetic syndrome; it's thought to affect about 1 in every 35,000 to 36,000 individuals,” said Nichols. “Of course, this includes adults as well as children. In the United States, there are probably around about 10,000 people with VHL syndrome; around the world, it is about 200,000 [people], so not very many, as you can appreciate.”

Patients with VHL are also at an increased risk of presenting with rare types of tumors, including hemangioblastoma and pheochromocytomas.

“These can occur in children; they can occur at any time during the life course of an individual’s [life], from patients as young as infancy to toddlerhood, all the way up into the older years,” explained Nichols.

However, those with VHL syndrome have an increased risk of certain types of other cancers, such as clear cell renal cell carcinoma (RCC) and neuroendocrine tumors of the pancreas. Approximately 70% of patients with VHL end up developing RCC by the age of 60 years and it is the leading cause of death.

While prognosis for children with VHL-associated disease is “excellent,” according to Nichols, the challenge and essential component of care for these patients is surveillance, as the tumors can slowly grow and impinge on organs.

“They can cause problems that way. For example, there is a rare tumor type called an endolymphatic sac tumor; this is a benign tumor in the portion of the ear that helps you to hear, and these tumors can be very small,” Nichols explained. “However, if they press on the auditory structures in the wrong way, you can end up with deafness. Therefore, prognosis from a life-expectancy perspective is very good, but you have to be very careful about organ dysfunction due to the presence of these tumors.”

Intervention strategies generally involve surgery, or, if it is a retinal hemangioblastoma, then laser therapy, cryotherapy, or heat therapy may be applied to the small tumor, said Nichols, who added that the surgeries are very precise so as to not cause any damage to the surrounding organ(s).

FIGURE 1: The full list of von Hippel-Lindau Clinical Care Centers in the United States

 for effective therapies designed to target VHL disease–associated RCC comprise immunotherapy, HIF-2α inhibitors, and potentially CDK4/6 inhibitors.

 According to preliminary data, HIF plays a critical role in VHL tumor suppressor protein–defective tumor formation.

Transplantation is another approach that has been tested. Transcriptional upregulation of hERV-E in clear cell RCC is driven by HIF2, and therefore, recognition of an hERV-derived antigen by allogenic T cells leads to disease regression.

 In a trial of patients with metastatic clear cell RCC, 48% of patients had a disease response following allogeneic stem cell transplant.

 (formerly MK-6482) has been gaining traction in patients with VHL disease–associated RCC. In an open-label, phase 2 study (NCT03401788) that was presented during the 

, investigators tested the efficacy of belzutifan, a potent, selective, small molecule inhibitor, in patients with VHL disease who have at least 1 measurable RCC tumor, did not receive prior systemic anticancer therapy, did not have metastatic disease, and had an ECOG performance status of either 0 or 1.

The results comprised 61 adult patients who received 120 mg of oral belzutifan once daily until disease progression or intolerable toxicity. Results showed that treatment with the agent led to a confirmed objective response rate (ORR) of 27.9% (95% CI, 17.1-40.8), which included 17 partial responses (PRs).

 Eight patients (13%) achieved an unconfirmed PR. Responses in central nervous system, retinal, and pancreatic lesions, were also reported.

Additional data showed that 43 patients (70.5%) achieved stable disease with the HIF-2α inhibitor, and the median duration of response had not yet been reached (95% CI, 11.9-62.3). Notably, most of the patients on the trial (86.9%) experienced a reduction in the size of their target lesions, and the 52-week progression-free survival (PFS) rate was 98.3%.

Regarding safety, any-grade treatment-related adverse effects (TRAEs) occurred in 96.7% of patients. TRAEs were mostly grades 1/2 (83.6%), consisting primarily of anemia (86.9%), fatigue (52.5%), and headache (36.1%). Grade 3 TRAEs were reported in 9.8% of patients and were primarily fatigue (4.9%) and anemia (3.3%).

FDA granted a breakthrough therapy designation to belzutifan

 for the treatment of patients with VHL disease–associated RCC who have nonmetastatic tumors of less than 3 centimeters, unless immediate surgery is necessitated, based on the phase 2 data.

The TKI pazopanib (Votrient) in hydrochloride formulation was tested in a phase 2 trial of adult or pediatric patients with VHL syndrome (NCT01436227).

 Treatment was given daily for 6 months until disease progression or unacceptable toxicity. Data showed that the ORR was 42% (n = 13/31), and 23% (n = 7/31) chose to stay on treatment after 6 months. The safety profile was similar to what has been reported with pazopanib in prior trials. Overall, the findings warrant further investigation in this landscape.

“Many of the tumors, particularly these hemangioblastomas, but also the RCCs in patients with VHL are very vascular tumors,” Nichols noted. “Any drugs that can interfere with, or reduce, blood vessel formation have potential to be of benefit in patients with VHL.”

These therapeutic efforts have proven to be an exciting advance on the horizon, but Nichols remains focused on surveillance—especially for the pediatric population.

“Right now, for kids, we mostly monitor; we try to pick up tumors at the earliest, smallest, and most successfully treatable stages,” said Nichols. “In the future, maybe we will have medications like [belzutifan] where we can even prevent the tumors from occurring. That's my goal.”

Various institutions are driving efforts to spotlight VHL and not only provide personalized, optimal care for patients with the condition, but to make progress on improving outcomes through innovative research efforts.

In September 2020, the VHL Alliance designated St. Jude Children’s Research Hospital as a von Hippel-Lindau Clinical Care Center, and is the first and only recognized 

 These centers are committed to providing “outstanding, holistic, coordinated care” for patients with VHL

 and have been established to provide ongoing care for local patients, meet the specialty care needs of those who must to travel to the center, and serve as a local resource for patients in college or who are traveling.

“We brought together all of the experts who take care of patients with VHL—for example, surgeons and neurologists, nephrologists and oncologists,” concluded Nichols. “Our goal is that by bringing everyone together, we could provide a source of information and serve as a resource to individuals who live in the St. Jude catchment area who have VHL or might need to be evaluated and monitored for it. Many of the communities in this area are relatively underserved, so we wanted to try to make ourselves available to the families in this area and to provide expertise for anyone who might have VHL syndrome.”

 The full list of von Hippel-Lindau Clinical Care Centers globally

VHL syndrome. National Cancer Institute. 

van Leeuwaarde RS, Ahmad S, Links TP, and Giles RH. Von Hippel-Lindau syndrome. 

. 2015. http://www.ncbi.nlm.nih.gov/books/NBK1463.

Kaelin WG. New therapies for kidney cancer based on studies of the Von Hippel-Lindau tumor suppressor gene. Presented at: IKCS 2020 Virtual Experience; November 6-7, 2020; Virtual.

Kim WY, Kaelin WG. Role of VHL gene mutation in human cancer. 

. 2004;22(24):4991-5004. doi: 10.1200/JCO.2004.05.061

Takahashi Y, Harashima N, Kajigaya S, et al. Regression of human kidney cancer following allogeneic stem cell transplantation is associated with recognition of an HERV-E antigen by T cells. 

 2008;118(3):1099-1109. doi:10.1172/JCI34409

Jonasch E, Donskov F, Iliopoulos O, et al. Phase II study of the oral HIF-α inhibitor for Von Hippel-Lindau disease–associated renal cell carcinoma. 

. 2020;38(suppl 15):5003. doi:10.1200/JCO.2020.38.15_suppl.5003

Srinivasan R, Donskov F, Iliopoulos O, et al. Phase II study of the oral HIF-2α inhibitor MK-6482 for Von Hippel-Lindau (VHL) disease-associated clear cell renal cell carcinoma (ccRCC): update on RCC and non-RCC disease. 

 2020;31(suppl 4):S1158. doi:10.1016/j.annonc.2020.08.2255

Jonasch E, McCutcheon IE, Gombos DS, et al. Pazopanib in patients with von Hippel-Lindau disease: a single-arm, single-centre, phase 2 trial. 

. 2018(10):1351-1359. doi: 10.1016/S1470-2045(18)30487-X

Pazopanib hydrochloride in treating patients with von Hippel-Lindau syndrome. Clinicaltrials.gov. Updated September 19, 2011. Accessed February 15, 2021. 

St. Jude recognized as clinical care center for rare von Hippel-Lindau syndrome. News release. St. Jude Children’s Research Hospital. September 30, 2020. Accessed February 15, 2021. 

Clinical Care Centers Directory. VHL Alliance. January 13, 2021. Accessed February 15, 2021. 

VHL disease is defined as a rare, inherited disorder that causes tumors and cysts to grow in specific areas of the body, including the brain, spinal cord, eyes, inner ear, adrenal glands, pancreas, kidney, and reproductive tract. 

VHL Disease: Monitoring Is Imperative, But Research Efforts Are Gaining Ground

Recent research for effective therapies designed to target von Hippel-Lindau (VHL) disease–associated renal cell carcinoma (RCC) is pointing to a future with the paradigm that comprises immunotherapy, HIF-2α inhibitors, and potentially CDK4/6 inhibitors, according to William G. Kaelin Jr, MD, who delivered the keynote address during the IKCS 2020 Virtual Experience.

“You can start to dream what an eventual kidney cancer curative combination will look like. I suspect that it will contain a VEGF inhibitor, an immune checkpoint inhibitor, maybe a HIF-2α inhibitor, maybe a CDK4/6

 inhibitor, [and] maybe even a MET inhibitor,” said Kaelin, the 2019 Nobel Laureate in Physiology or Medicine, Sidney Farber Professor of Medicine, Dana-Farber Cancer Institute and Harvard Medical School, and an investigator at Howard Hughes Medical Institute. 

RCC is arising more often in patients with VHL, said Kaelin, who added that inactivation of VHL is not sufficient for renal carcinogenesis, even if it is an initiating event. In sporadic clear cell RCC, however, VHL inactivation is the initiation event and should be targeted. HIF2 inhibition, he explained, is both necessary and sufficient for VHL tumor suppression (pVHL).

“We think HIF-2 is the driver, or oncoprotein, in VHL–associated renal cell carcinoma cells and, if anything, HIF-1 seems to act as a tumor suppressor and is frequently lost in such tumors,” Kaelin said.

Though initially believed that p53 was an important target in these patients, research has shown that an intact p53 pathway is not essential for clear cell RCC HIF2-dependence, and 

 knockout doesn’t alter PT2399 sensitivity of OSRC2 cells. 

“We no longer think p53 status is a biomarker for HIF2 

In preclinical models, a first-generation HIF-2α compound, PT2399,

 led to decreased HIF-dependent mRNAs, decreased proliferation, and decreased tumor growth by 

homozygous negative (-/-) kidney cancer cells. Moreover, tumor formation by some VHL-/- kidney cancer cell lines were not inhibited by PT2399, despite pharmacodynamic response. 

“These are all [pull-]down assays—decrease, decrease, decrease,” Kaelin said. “You would worry whether these effects were really on-target or off-target.”

HIF-2 inhibitors however do not generate responses in all patients, and to avoid resistance, Kaelin emphasized the importance of synthetic lethality. VHL -/- RCC he added, is hypersensitive to the MET ligand hepatocyte growth factor/scatter factor in RCC, emphasizing that MET depletion preferentially kills VHL-/- cells. 

A number of TKIs are indicated for RCC treatment, such as bevacizumab (Avastin), sunitinib (Sutent), sorafenib (Nexavar), axitinib (Inlyta), pazopanib (Votrient), cabozantinib (Cabometyx), and lenvatinib (Lenvima). However, their use as single agents does not lead to responses in all patients, and in those who do, they eventually relapse.

For example, the dual MET/VEGF inhibitor cabozantinib demonstrated an improvement in overall survival (OS) compared with everolimus (Afinitor), with a median OS of 21.4 months (95% CI, 18.7–not estimable) with cabozantinib and 16.5 months with everolimus (95% CI, 14.7-18.8), leading to a 34% reduction in the risk of death (HR, 0.66; 95% CI, 0.53-0.83; 

However, Kaelin said these data were “a bit unsatisfying; it could be that cabozantinib is a better VEGF inhibitor than the VEGF inhibitors that patients had failed on previously.”

Other synthetic lethality methods are through CRISPR-based lethal screens and utilizing CDK4/6, Kaelin added, which is synthetically lethal with VHL and appears to be HIF-independent. In an orthotopic VHL-/- kidney cancer mouse model, the CDK4/6 inhibitor palbociclib (Ibrance) was found to prolong survival, he said.

When used in combination with the HIF-2α inhibitor PT2399, data showed that the regimen synergistically suppresses VHL -/- cell growth in HIF2-sensitive cell lines, leading to more investigations of this approach. Additionally, the use of palbociclib suppressed orthotopic xenograft growth alone and in combination with PT2399.

“I think we might learn something from our friends in the world of breast cancer, because they already learned that combining tamoxifen with a CDK4/6 inhibitor is a good thing to do, and maybe that’s because when you add an ER agonist you lower cyclin D1 transcription, and cyclin D1 is then the partner for CDK4/6, which you’re now going to inhibit with a small molecule. Maybe we can do something analogous in kidney cancer by combining PT2399 with a CDK4/6 inhibitor at least for those tumors that are still HIF2 dependent.”

Beyond its potential use in combination with HIF-2a inhibitors, CDK4/6 inhibitors could also be used as a way to enhance immunotherapy in solid tumors.

Transplantation could also be an intriguing approach to target this population. Additional data have shown that transcriptional upregulation of hERV-E in clear cell RCC is driven by HIF2, and therefore recognition of an hERV-derived antigen by allogenic T cells leads to disease regression.

 Following allogeneic stem cell transplant, 48% of patients with metastatic clear cell histology had a disease response.​ 

The most recent data, presented at the 2020 ASCO Virtual Scientific Program, showed that the HIF-2a inhibitor MK-6482 led to favorable efficacy and tolerability in patients with VHL disease–associated RCC.

In this open-label, phase 2 study (NCT03401788), investigators evaluated the efficacy of MK-6482, a potent, selective, small molecule HIF-2α inhibitor, in patients with VHL disease who have at least 1 measurable RCC tumor, did not receive prior systemic anticancer therapy, did not have metastatic disease, and had an ECOG performance status of either 0 or 1.

Data comprised 61 adult patients who received 120 mg of oral MK-6482 once daily until progression or intolerable toxicity. Results showed that treatment with the agent led to a confirmed objective response rate (ORR) of 27.9% (95% CI, 17.1-40.8), which comprised 17 partial responses (PRs).

 Eight other patients (13%) experienced an unconfirmed PR. Responses were also seen with central nervous system, retinal, and pancreatic lesions.

Forty-three patients (70.5%) achieved stable disease with the HIF-2α inhibitor. Additionally, the median duration of response had not yet been reached (95% CI, 11.9-62.3). Notably, most of the patients on the trial (86.9%) experienced a reduction in the size of their target lesions. At 52 weeks, the progression-free survival (PFS) rate was 98.3%.

With regard to safety, any-grade treatment-related adverse effects (TRAEs) occurred in 96.7% of patients. TRAEs were mostly grade 1 or grade 2 (83.6%) and primarily anemia (86.9

%), fatigue (52.5%), and headache (36.1%). Grade 3 TRAEs were reported in 9.8% of patients and were primarily fatigue (4.9%) and anemia (3.3%).

Based on these data, the FDA granted a breakthrough therapy designation to MK-6482 for the treatment of patients with VHL disease–associated RCC who have nonmetastatic tumors of less than 3 centimeters, unless immediate surgery is necessitated.

The HIF-2α inhibitor also showed promising single-agent activity in patients with heavily pretreated clear cell RCC. An ORR of 24% and a disease control rate of 80% was observed in the 55 patients enrolled in the dose-escalation/expansion cohort.

 The ORR consisted of 13 confirmed PRs. Additionally, the median PFS for the total population was 11.0 months. At 12 months, 49% of patients remained progression free.

Kaelin WG. New therapies for kidney cancer based on studies of the Von Hippel-Lindau tumor suppressor gene. Presented at: IKCS 2020 Virtual Experience; November 6-7, 2020; virtual.

Cho H, Du X, Rizzi JP, et al. On-target efficacy of a HIF-2α antagonist in preclinical kidney cancer models. 

. 2016;539(7627):107-111. doi:10.1038/nature19795

Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal cell carcinoma. 

. 2015;373(19):1814-1823. doi:10.1056/NEJMoa1510016

Nicholson HE, Tariq Z, Housden BE, et al. HIF-independent synthetic lethality between CDK4/6 inhibition and VHL loss across species. 

. 2019;12(601):eaay0482. doi:10.1126/scisignal.aay0482

Goel S, DeCristo MJ, Watt AC, et al. CDK4/6 inhibition triggers anti-tumour immunity. 

. 2017;548(7668):471-475. doi:10.1038/nature23465.

Takahashi Y, Harashima N, Kajigaya S, et al. Regression of human kidney cancer following allogeneic stem cell transplantation is associated with recognition of an HERV-E antigen by T cells. 

Srinivasan R, Donskov F, Iliopoulos O, et al. Phase II study of the oral HIF-2α inhibitor MK-6482 for Von Hippel-Lindau (VHL) disease-associated clear cell renal cell carcinoma (ccRCC): update on RCC and non-RCC disease. 

 2020;31(suppl 4):S1158. doi:10.1016/j.annonc.2020.08.2255

Choueiri TK, Plimack ER, Bauer TM, et al. Phase I/II of the oral HIF-2α inhibitor MK-6482 in patients with advanced clear cell carcinoma (RCC). 

. 2020;38(suppl 6):611. doi:10.1200/JCO.2020.38.6_suppl.611

Recent research for effective therapies designed to target von Hippel-Lindau disease–associated renal cell carcinoma is pointing to a future with the paradigm that comprises immunotherapy, HIF-2α inhibitors, and potentially CDK4/6 inhibitors.

VHL-Associated Cancers | Articles

Roswell Park Is First Site in Region Named a Resource for Patients With Rare Genetic Disease

VHL Disease: Monitoring Is Imperative, But Research Efforts Are Gaining Ground

Future of VHL Disease–Associated RCC Bright, With Immunotherapy and HIF-2α, CDK4/6 Inhibitors Part of Ongoing Research