University of North Carolina (UNC) Lineberger Comprehensive Cancer Center has discovered a new potential therapeutic target for clear cell renal cell carcinoma (RCC), the most common form of kidney cancer. The new target is a protein called ZHX2, which over-accumulates in cells and helps to turn on signals involved in cancerous growth.
Approximately 90% of cases of clear cell RCC involve a genetic mutation or alteration that causes an important tumour suppressor gene called VHL to lose its function and leads to an overabundance of blood vessels that feed tumours. ZHX2 is a downstream effect of this genetic mutation.
Since patients can show little response, or become resistant, to US Food and Drug Administration’s (FDA) approved drugs that work by blocking the signals involved in abnormal blood vessels, the researchers at UNC Lineberger decided to search for new targets.
UNC Lineberger School of Medicine associate professor of medicine and genetics William Kim said: “In the last decade or more, we’ve had quite a number of major treatment advances in kidney cancer. There are nearly a dozen FDA-approved treatments now for this disease, but many of them are similar. Studies like this are important because they delineate the underlying biology of kidney cancer and identify novel, distinct pathways to develop drugs against.”
The scientists created a screening technique to discover molecules that may drive cancer when VHL loses its function. They found that kidney cancer cells lacking VHL often had more ZHX2. When researchers eliminated ZHX2 from the cells this inhibited cancer cell growth, invasion and spread.
UNC Lineberger School of Medicine assistant professor Qing Zhang said: “VHL is the most important tumour suppressor in clear cell renal cell carcinoma. There are extensive reports showing that from initiation to tumour progression to metastasis — during the whole process of kidney cancer development – VHL plays a central role. It is important to understand how the VHL loss contributes to kidney cancer, and how we can therapeutically target the downstream effects of this loss in kidney cancer.
“If you lose VHL, you will accumulate lots of this ZHX2 protein, which will turn on signals that promote kidney cancer. This protein could be a potential therapeutic target used to treat kidney cancer on its own or in combination. The next step is to try to figure out how we can target it therapeutically.
“We wanted to understand, once VHL is lost, what else in kidney cancer cells is promoting oncogenesis? Therapeutically speaking, we’re trying to understand how we can target these novel signalling pathways, once we identify them.”
The research was supported by the US Department of Defense Careers Development Award, UNC Lineberger’s Cancer Research Fund and the National Career Institute.