Background

Belzutifan is transforming the management of individuals with von Hippel-Lindau (VHL)

disease. However, its real-world efficacy and safety outside clinical trials remain poorly

characterised. The pivotal trial that led to its approval included only 61 patients, limiting

our understanding of how patient-specific factors, such as VHL mutation type, age, sex,

and co-morbidity, affect treatment response and toxicity.

Additionally, no robust quality-of-life (QoL) data exist to quantify how Belzutifan improves

patient well-being or how side effects, such as anaemia, impact daily life. Moreover,

mechanisms of response and resistance remain undefined; a more detailed

understanding is crucial for optimising treatment strategies and may have broader

relevance to targeting the VHL-HIF axis in other solid cancers beyond the VHL disease

setting.

UK VHL Systemic Therapy Forum and TRACERx Renal Study

We have established a UK VHL Systemic Therapy Forum, a national network of VHL

specialists and medical oncologists who prescribe Belzutifan. This group aims to:

• Share clinical experiences and develop treatment guidelines.

• Facilitate collaborative research into real-world outcomes and safety

Study Design and Data Collection

Within the TRACERx Renal protocol at The Royal Marsden Hospital, in collaboration

with Imperial College Hospitals, St. George’s, Guy’s & St Thomas’, and Barts Health

NHS Trust,

This research will provide critical real-world insights into Belzutifan’s effectiveness and

toxicity while advancing our understanding of resistance mechanisms in VHL disease with wider relevance to patients with cancer.

An overview from Professor Drake:
“Our research endeavours focus on the intricate understanding and treatment of von Hippel-Lindau (VHL) disease. We’re diligently amassing patient-specific specimens, notably tissue fragments that retain the tumour microenvironment’s vital characteristics. These fragments are pivotal in replicating the disease’s complexity. Our objective is to delve into the molecular mechanisms involved when VHL patients undergo Belzutifan therapy. By scrutinizing how Belzutifan functions across diverse tissues affected by VHL, we aspire to personalize treatment approaches and potentially influence therapeutic strategies for related conditions like renal cell carcinoma. We’re deeply appreciative of the generous support from VHL UK/Ireland, and this research holds immense promise for revolutionizing VHL disease treatment at a molecular level.”

The 100K genomes project is a world-leading genomics study performed in the UK that has provided more than 100,000 whole genome sequences on individuals with a variety of rare diseases and cancers (including more than 1,000 kidney tumours). We are analysing the genetic alterations in VHL and other kidney genes in order to better classify the genetic variations in these genes. The results from these studies will make an important contribution to international efforts to improve genetic diagnosis of VHL disease and related disorders. *The initial grant award was for £40,000 and an additional grant award of £20,000 was made March 2021 to continue the work.

The VHL Alliance published in its Summer 2022 Newsletter an overview:

 ALTERATIONS IN THE ELOC GENE MAY CAUSE VHL DISEASE By Dr. Amit Tirosh, Sheba Medical Center.

“The diagnosis of von Hippel-Lindau disease (VHL) can be based on genetic testing or a combination of the typical manifestations. About 5% of VHL patients have a clinical VHL diagnosis, while lacking a positive result on a genetic test.
The VHL protein, the actual biological machinery encoded by the VHL gene, works in a complex with two other proteins called Elongin B and Elongin C, the latter encoded by the ELOC gene. A recent study by Andreou and others, led by the renowned Prof. Eamonn Maher from the UK, that was published in the journal Human Molecular Genetics, reported on a patient with VHL disease, with no variant identified in the VHL gene, but rather a variant in the ELOC gene. This finding makes “biological” sense and is further supported by scientific evidence from non-hereditary kidney cancer. The importance of this finding is in the possibility of diagnosing VHL based on variants in genes other than the VHL gene. Further research is needed to learn more”

The Human Molecular Genetics article published is:

Elongin C (ELOC/TCEB1)-associated von Hippel–Lindau disease cite 1.

It contains a detailed description of one patient with the specific ELOC Gene variant NM_005648.4(ELOC):c.236A>G (p.Tyr79Cys). The patient has a clinical diagnosis of VHL with no VHL Gene variant.  The article describes the detailed analysis of the 100,000 Genome Project data and the finding that this variant was also absent from the germline of 78,195 participants including 1,336 individuals with RCC. Of these 1,336 individuals identified 8 had a candidate pathogenic ELOC somatic variant.

At the end of the article discussion:
“Currently, we would suggest that testing of ELOC should be performed in patients with suspected VHL disease but without an identifiable VHL mutation. The clinical course of ELOC-mutated RCC is variable (21); however, based on existing data, we would propose that individuals with a pathogenic germline variant should be managed as per VHL disease (40). While the emphasis of VHL management is primarily early diagnosis and treatment, the mechanistic similarities between VHL- and ELOC p.Tyr79Cys-associated tumours suggest that treatment with HIF-2α antagonists, such as bezultifan, may be a therapeutic option for ELOC-mutated tumours.”

The data of the 1,336 individuals with RCC was analysed in this further article

Frequency of pathogenic germline variants in cancer susceptibility genes in 1336 renal cell carcinoma cases cite 2.

From the abstract:

“Whole-genome sequencing data on 1336 RCC participants and 5834 controls recruited to the UK 100 000 Genomes Project, a nationwide multicentre study, was analyzed to identify rare P/LP short variants (single nucleotide variants and insertions/deletions ranging from 1 to 50 base pairs) and structural variants in 121 CSGs.”

1. _{Human Molecular Genetics, Volume 31, Issue 16, 15 August 2022, Pages 2728–2737, https://doi.org/10.1093/hmg/ddac066}

2. _{Human Molecular Genetics, Volume 31, Issue 17, 1 September 2022, Pages 3001–3011, https://doi.org/10.1093/hmg/ddac089}

Some snippets taken from the project description.
Saturation genome editing (SGE)is a method that allows us to assay thousands of genetic variants in their endogenous genomic context. SGE was used previously to assay 3,893 SNVs in BRCA1 for functional effects at the mRNA and protein level in human HAP1 cells2. “Function scores” derived for each variant were highly accurate at distinguishing established pathogenic variants, indicating SGE data can aid clinical variant interpretation. Watch this YouTube video about SGE used for BRCA1.
Using SGE on VHL variants to produce a systematic genotype-phenotype map of VHL would prove useful for adjudicating which variants are pathogenic. Furthermore, by using multiple assays to study all possible coding variants, we will gain insights into how disruption of the gene’s distinct molecular functions correlates with clinical presentation.

This Grant Award was made possible from the fundraising by Charles White in 2020

This project was successfully completed in July 2024 with the publication of results in Nature Saturation genome editing maps the functional spectrum of pathogenic VHL alleles. This was announced in a press release from the Crick Institute.