Renal Cell Carcinomas

Tim Humphrey and Kirsten Lopez

Updates from the research team

Kirsten is making excellent progress in her characterization of RITA, a drug which specifically targets SETD2-deficient kidney cancer cells incredibly effectively.

With your continued support, we are hopeful that we will determine its targeting mechanism, and perform some preclinical work, which we hope to write up for publication over the coming year.

Professor Tim Humphrey

My name is Kirsten Lopez and I recently finished a PhD in Oncology at the University of Oxford.

I first learned about UCARE in 2016 when my supervisor Tim Humphrey and I applied for a research grant that would help support me as I worked on my PhD project, which is about how to target kidney cancers where a specific gene has been lost or mutated.

The enzyme that is produced by this gene acts on proteins called histones, which package DNA into compact bundles within the cell. Modifications on histones play an important role in controlling which genes are active or inactive without affecting the sequence of the DNA and is one example of the phenomenon known as epigenetics. The gene my lab is interested in is lost in a substantial number of kidney cancers and with around 12,000 new cases diagnosed each year, we’re hopeful that finding a way to target this loss will be able to help many patients.

The way I looked into this was by testing thousands of compounds on cancer cells where our gene of interest was deleted using a gene editing technology called CRISPR. I found a couple of promising compounds that specifically killed these cells and investigated what these drugs were doing differently when our gene was missing.

Thanks to the 3-year funding I got from UCARE, I was able to making significant progress on this project with the aim of publishing it in a high-impact journal this year.

At the moment, I am exploring various molecular pathways that could explain the mechanism of action of the compounds I identified. I am deeply grateful to UCARE for sponsoring my education and supporting me and other scientists as we continue to discover new and better ways to treat kidney cancer.

Kirsten Lopez

Renal cell cancer (RCC) is relatively common in the UK, with 12,000 cases diagnosed annually. While advances in the treatment have been made, this disease still accounts for 4,000 deaths in the UK each year.

We have recently made significant advances in understanding how renal cancers can be specifically killed.

We identified a drug (AZD1775) that kills cells that are unable to modify (methylate) histone H3 (a protein which DNA is wrapped around). Loss of this histone modification (H3 lysine 36 trimethylation) is observed in ~20% of primary and ~60% of metastatic clear cell renal cell carcinomas. As this drug has little effect on normal cells, cancer cells carrying these mutations can be specifically targeted. This approach to treat cancers with these mutations has now entered clinical trials.

To extend these findings we have screened more than 2,000 compounds for those that specifically kill cells in which SETD2 was deleted, but do not affect identical cells carrying this gene. From this, we identified two further compounds that specifically target SETD2-deficient cancer cells.

We plan to study whether these drugs work through the same or different mechanisms to the drug we have previously identified (AZD1775). Further, we plan to screen a library of 1,600 drugs already approved for patient treatment to identify those which also kill SETD2-deficient cancer cells.

Using this approach we hope to identify complementary ways by which to target kidney cancers, which could have considerable clinical benefit.

Pictured are Tim Humphrey and Kirsten Lopez.