(UroToday.com) Von Hippel-Lindau (VHL) syndrome is a rare, inherited disorder that causes tumors and cysts to grow in various parts of the body. Patients with VHL syndrome have an increased risk of certain types of cancer, especially kidney cancer and pancreatic cancer. The signs and symptoms of von Hippel-Lindau syndrome usually do not appear until young adulthood. Some of the manifestations of VHL include:
- Eye (retinal hemangioblastoma 60%)
- CNS (hemangioblastoma cerebellum 40-70%, spine 13-50%)
- Kidney (cysts and RCC 25-60%)
- Pancreas (cysts, neuroendocrine tumors 9-17%)
- Pheochromocytoma / paraganglioma 10-20%
- Ear (endolymphatic sac tumors 10-25%)
- Epididymis 25-60%/broad ligament 10% cystadenoma
The VHL Alliance and its Clinical Advisory Council have published clear surveillance recommendations for VHL patients (Table 1).
VHL patients carry a germline mutation of the VHL tumor suppressor gene. A total of five-hundred different pathogenic germline mutations have been identified in families with VHL disease1. The VHL protein interacts with elongins B, C, and Cullin-2 to form the VBC complex, an E3 ubiquitin ligase. This complex mediates ubiquitin-mediated degradation. Biallelic inactivation of VHL most likely underlies the basis of carcinogenesis in VHL disease. Reintroduction of the VHL function can reverse some effects of inactivation. VHL inactivation can cause HIF-dependent and HIF-independent effects, as shown in figure 1.
Figure 1 - VHL protein functions: HIF independent and HIF dependent2:
HIF is a heterodimeric transcription factor consisting of an unstable α and a stable β subunit. Different HIFα genes have been identified. HIF1α and HIF2α do not appear to be completely identical. Post-natal inactivation of HIF1α and HIF2α leads to differing phenotypes. The two proteins are also differentially expressed in VHL lesions, where immature cells show exclusive activation of HIF2α in contrast to frank tumors that show activation of both HIF2α and HIF1α3. The HIF-dependent proteins are involved in oxygen sensation and regulation and include genes involved in the uptake and metabolism of glucose, angiogenesis, control of extracellular pH, mitogenesis, and erythropoiesis.
PT285 and PT2399 are selective HIF2α inhibitors with no effect on HIF1α. They prevent DNA binding and HIF2α transactivation of downstream targets. They also suppress tumor growth.
NCT02293980 is a phase 1, dose-escalation trial of PT2385 tablets in patients with advanced clear cell renal cell carcinoma, showing promising findings with adequate safety profile4.
Another study is an abstract that was presented in this SUO 2020 meeting, the NCT03401788: A phase 2 study of Belzutifan for the treatment of VHL disease-associated renal cell carcinoma (nk-6482-004)5. This trial involved 61 patients with a minimum of 60 weeks of follow-up. The safety profile was quite promising, and the objective response rate was favorable as well (Table 2).
Table 2 – Objective response rate in the NCT03401788 trial5:
Lastly, Dr. Maranchie ended her talk by mentioning that CDK 4/6 inhibition has been shown to be synergistic with HIF2α antagonism. Combined treatment with the CKD 4/6 inhibitor palbociclib + PT2399 showed greater anti-cancer activity than either agent alone6.
Presented by: Jodi Maranchie, MD, FACS, Associate Professor of Urology at the University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center- Shadyside, Pittsburgh, Pennsylvania
Written by: Hanan Goldberg, MD, MSc, Assistant Professor, Urology Department, SUNY Upstate Medical University, Syracuse, NY, USA, @GoldbergHanan during the 2020 Society of Urologic Oncology Annual Meeting – December 2-5, 2020 – Washington, DC
1. Nordstrom-O'Brien M, van der Luijt RB, van Rooijen E, et al. Genetic analysis of von Hippel-Lindau disease. Human mutation 2010; 31(5): 521-37.
2. Gläsker S, Vergauwen E, Koch CA, Kutikov A, Vortmeyer AO. Von Hippel-Lindau Disease: Current Challenges and Future Prospects. OncoTargets and therapy 2020; 13: 5669-90.
3. Vortmeyer AO, Tran MG, Zeng W, et al. Evolution of VHL tumourigenesis in nerve root tissue. The Journal of pathology 2006; 210(3): 374-82.
4. Courtney KD, Infante JR, Lam ET, et al. Phase I Dose-Escalation Trial of PT2385, a First-in-Class Hypoxia-Inducible Factor-2α Antagonist in Patients With Previously Treated Advanced Clear Cell Renal Cell Carcinoma. Journal of Clinical Oncology 2018; 36(9): 867-74.
5. Srinivasan R DF, IIiopoulos O, et al. . Oral HIF-2α inhibitor MK-6482 for Von Hippel-Lindau (VHL) disease–associated clear cell renal cell carcinoma: evaluation of RCC and non-RCC disease. 2020 Society of Urologic Oncology Annual Meeting (virtual) December 3-5, 2020 Abstract 10.
6. Nicholson HE, Tariq Z, Housden BE, et al. HIF-independent synthetic lethality between CDK4/6 inhibition and VHL loss across species. Science Signaling 2019; 12(601): eaay0482.