Renal Cell Carcinomas

Tim Humphrey and 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.