Discovery of kidney cancer driver could lead to new treatment strategy

July 19, 2018, UNC Lineberger Comprehensive Cancer Center

University of North Carolina Lineberger Comprehensive Cancer Center scientists have uncovered a potential therapeutic target for kidney cancers that have a common genetic change. Scientists have known this genetic change can lead to an overabundance of blood vessels, which help feed nutrients to the tumors. Their latest finding shows a potential new cancer-driving pathway.

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

"If you lose VHL, you will accumulate lots of this ZHX2 protein, which will turn on signals that promote kidney cancer," said UNC Lineberger's Qing Zhang, Ph.D., an assistant professor in the UNC School of Medicine Department of Pathology & Laboratory Medicine and Pharmacology. "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."

Renal cell clear cell carcinoma is the most common type of kidney cancer, accounting for about 70 percent of all cases, researchers report. Approximately 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 the function of VHL is gone, cells can accumulate signals that trigger blood vessels to grow.

"VHL is the most important tumor suppressor in clear cell renal cell carcinoma," Zhang said. "There are extensive reports showing that from initiation to tumor 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."

There are U.S. Food and Drug Administration-approved drugs that block cell signals involved in abnormal blood vessel production—which is a downstream effect of VHL loss—that are part of the standard of care for clear cell . Patients can show little response to these drugs or can develop resistance, so Zhang and his colleagues wanted to search for other targets that accumulate in cells lacking VHL function that help to drive the abnormal cancerous growth.

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

The researchers created a screening technique to discover new molecules that might 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 , invasion and the cancer's spread. In addition, they saw that it was involved with signals that can help cancer grow.

UNC Lineberger's William Kim, MD, said there have been major advances in the treatment of kidney cancer with the development of molecularly-targeted therapies and immune-based treatments. However, additional treatments are needed to reach more patients with metastatic disease.

"The vast majority of kidney cancers have mutations in VHL, so it makes it a very important gene to investigate," said Kim, who is an associate professor of medicine and genetics in the UNC School of Medicine. "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."

Explore further: New models of kidney cancer may drive immunotherapy research

More information: "VHL substrate transcription factor ZHX2 as an oncogenic driver in clear cell renal cell carcinoma" Science (2018). science.sciencemag.org/cgi/doi … 1126/science.aap8411

Related Stories

New models of kidney cancer may drive immunotherapy research

June 9, 2017
University of North Carolina Lineberger Comprehensive Cancer Center scientists have developed preclinical laboratory models of the two most common types of kidney cancer, an advancement that may aid in the evaluation of novel ...

Kidney cancers caught stealing genes from other cell types in order to spread

June 7, 2018
A study has identified how kidney cancers may develop the ability to spread around the body by hijacking genes from other cell types and 'stealing' their functions.

Link between HPV and cancer after kidney transplant

May 30, 2018
The European Cancer Stem Cell Research Institute at Cardiff University has shed light on the link between skin cancer development and kidney transplants, highlighting the importance for clinicians to monitor transplant patients ...

FDA clears Pfizer drug for advanced kidney cancer

January 27, 2012
(AP) -- The Food and Drug Administration has approved a new Pfizer drug for patients with advanced kidney cancer that has spread to other parts of the body despite treatment with at least one previous drug.

Study uncovers genetic differences for kidney cancer that may contribute to survival disparity in African-Americans

March 30, 2016
A University of North Carolina Lineberger Comprehensive Cancer Center-led study has identified genetic differences in tumors of African-Americans with the most common type of kidney cancer compared with whites.

Researchers find new target for kidney cancer therapy

November 10, 2014
Cincinnati Cancer Center (CCC) researchers have discovered that a membrane channel, Transient Receptor Potential Melastatin 3, or TRPM3, promotes growth of kidney cancer tumors, and targeting this channel therapeutically ...

Recommended for you

Scientists discover new method of diagnosing cancer with malaria protein

August 17, 2018
In a spectacular new study, researchers from the University of Copenhagen have discovered a method of diagnosing a broad range of cancers at their early stages by utilising a particular malaria protein that sticks to cancer ...

Researchers find pathways that uncover insight into development of lung cancer

August 17, 2018
Lung cancer is the leading cause of preventable cancer death. A disease of complex origin, lung cancer is usually considered to result from effects of smoking and from multiple genetic variants. One of these genetic components, ...

Developing an on-off switch for breast cancer treatment

August 17, 2018
T-cells play an important role in the body's immune system, and one of their tasks is to find and destroy infection. However, T-cells struggle to identify solid, cancerous tumors in the body. A current cancer therapy is using ...

Pregnant? Eating broccoli sprouts may reduce child's chances of breast cancer later in life

August 16, 2018
Researchers at the University of Alabama at Birmingham have found that a plant-based diet is more effective in preventing breast cancer later in life for the child if the mother consumed broccoli while pregnant. The 2018 ...

Scientists discover chemical which can kill glioblastoma cells

August 15, 2018
Aggressive brain tumour cells taken from patients self-destructed after being exposed to a chemical in laboratory tests, researchers have shown.

Three scientists share $500,000 prize for work on cancer therapy

August 15, 2018
Tumors once considered untreatable have disappeared and people previously given months to live are surviving for decades thanks to new therapies emerging from the work of three scientists chosen to receive a $500,000 medical ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.