VHL/HIF and VEGF inhibitors in clear cell renal cell carcinoma

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Published: 4 Nov 2020
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Dr Toni Choueiri - Dana-Farber Cancer Institute, Boston, USA

Dr Toni Choueiri speaks to ecancer about his keynote lecture at the virtual ENA 2020 about VHL/HIF (and VEGF) inhibitors in renal cancer at the ENA virtual meeting 2020.

He starts with explaining the role of VHL/HIF and VEGF inhibitors in clear cell renal cell carcinoma. Then he talks of the main points his lecture aimed at and how important it was that another biomarker was being used for targeted therapy.

He says before we were using cytokine inhibitors but now VHL/HIF inhibitors can also be used which will open new avenues for translational research.

Dr Choueiri finishes it by stating how these new developments can affect the future of clear cell renal cell carcinoma treatment.

This is one of the main things where we transitioned 15-20 years ago from using old cytokines, interleukin-2 and interferon to targets downstream of VHL, downstream of HIF2 by targeting VEGF and the VEGF receptor. Very, very important – kidney cancer is an angiogenic tumour defined by VHL alterations which lead to an upregulation of angiogenesis through VEGF and many other factors. So people in the ‘90s were testing these drugs and luckily they decided to test them in kidney cancer. So definitely they are crucial, it’s a VEGF driven tumour in the large part.

I had the chance, next to Sir Peter Ratcliffe, to present the other keynote talk going through the landmark studies and advancements in kidney cancer overall with a focus on the VHL/HIF/VEGF axis, rather than a particular part by itself or any original research. It was a synthesis of the whole field.

What were the highlights from your keynote?

We went through some biology initially with VHL and the intermediate step which is HIF, then targeting VEGF and the VEGF receptor and all the advances and the advancement in survival with these drugs. Now back upstream with drugs that target HIF2 now that are starting to gain traction with manageable side effects and activity that we’re seeing. So I provided an overview of the field and how we’re going to go in the next five years in kidney cancer.

I think there is room to be optimistic i you see the survival. I quoted one Cochrane review from 2005 that looked at 6,800, 6,900 patients with metastatic RCC on trial, the median survival at 13 months. This is doubled or tripled with VEGF targeted therapy and when you introduce immune checkpoint inhibitors most of the trials that are reading now with combinations they don’t achieve a median survival, it’s not reached. We have to look at the one year and two year survival. So it’s refreshing to see that.

I think other targets are very, very important to continue investing in. HIF2 inhibitors are very, very important and they’re coming. I think another way also to look at the field is to continue investing in biomarkers despite that today we still don’t have a biomarker specifically in renal cell cancer. But there’s a new platform, new ways to look at biomarkers, new comprehensive biomarker analysis that hopefully will shed light into the biology and into mechanisms of response.