ZHX2 Protein Could Offer New Treatment Strategy for Kidney Cancer

July 20, 2018

Scientists at the Comprehensive Cancer Center Cancer Center of the University of North Carolina have discovered a potential therapeutic target for kidney cancers that have a common genetic change. Scientists have known that this genetic change can lead to an overabundance of blood vessels, which help to nourish the tumors. Their latest discovery shows a new potential route of cancer-driving.

More than 90 percent of the most common type of kidney cancer has a genetic change that leads to the loss of an important tumor suppressor gene called VHL. In a study published in the journal Science the researchers identified a new downstream effect of this genetic modification that helps counteract kidney cancer: They discovered that a protein called ZHX2's accumulates in these cells and helps to transform on other signals involved in cancerous growth. Their findings suggest that ZHX2 is a potential new therapeutic target for renal cell carcinoma clear, which is the most common type of kidney cancer.

"If you lose VHL, you will accumulate a lot of this ZHX2 protein, which will light up the signals that promote kidney cancer," said Qing Zhang, PhD, UNC Lineberger, an assistant professor at the University of New York. UNC School of Medicine Department of Pathology and Laboratory Medicine and Pharmacology. "This protein could be a potential therapeutic target used to treat kidney cancer alone or in combination; the next step is to try to understand how we can target it therapeutically."

Clear cell carcinoma of renal cells is the most common type of kidney cancer, accounting for about 70 percent of all cases, the researchers report. About 90 percent of patients with clear cell renal cell carcinoma have genetic mutations or alterations that cause them to lose the function of VHL. When VHL function is gone, cells can accumulate signals that trigger the growth of blood vessels.

"VHL is the most important tumor suppressor in renal cell carcinoma," said Zhang. "Many reports show that from initiation to tumor progression into metastasis – throughout the developmental process of kidney cancer – VHL plays a central role: it is important to understand how VHL loss contributes to kidney cancer, targeting the downstream effects of this loss in kidney cancer. "

There are drugs approved by the US Food and Drug Administration that block the cellular signals involved in the abnormal production of blood vessels – which is an effect downstream of the loss of VHL. the standard of care for renal cell carcinoma clear cells. Patients may show little response to these drugs or may develop resistance, so Zhang and his colleagues wanted to look for other targets that accumulate in cells without VHL function that help drive abnormal cancerous growth .

"We wanted to understand VHL is lost, what else in kidney cancer cells promotes oncogenesis?" Zhang said. "Therapeutically, we are trying to understand how we can target these new signaling pathways once we identify them."

Researchers have created a screening technique to discover new molecules that could help drive cancer when VHL is lost. This led them to determine that kidney cancer cells lacking VHL usually had more ZHX2. By eliminating ZHX2 from their laboratory models, they inhibited the growth of cancer cells, the invasion and spread of cancer. In addition, they saw that he was involved with signals that can help cancer cells to grow.

William Kim, MD of UNC Lineberger, said that there have been major advances in the treatment of kidney cancer. However, additional treatments are needed to reach more patients with metastatic disease.

"The vast majority of kidney cancers have mutations in the VHL, making it a very important gene to study," said Kim, an associate professor of medicine and genetics at the School of Medicine from the UNC. "Over the last decade or more, we've had a number of major advances in the treatment of kidney cancer. There are currently about a dozen FDA-approved treatments for this disease, but many Among them are similar, they delineate the underlying biology of kidney cancer and identify new distinct pathways for developing drugs against. "