Researchers Find New Target for Kidney Cancer Therapy

CINCINNATI—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 could lead to more treatments for a disease, which currently has few treatment options.

A membrane channel is a family of proteins that allows the movement of ions, water or other solutions to pass through the membrane. 

These findings are being published in the Nov. 10, 2014, edition of the journal Cancer Cell. 

"Metastatic clear cell kidney cancer is largely incurable, and existing treatments for the disease are only minimally effective,” says Maria Czyzyk-Krzeska, MD, PhD, senior author of the study, member of the CCC and the University of Cincinnati Cancer Institute and professor in UC’s Department of Cancer Biology. "Our team found a new target in kidney cancer known as TRPM3. TRPM3 is increased in 60 percent of kidney clear cell carcinomas where it promotes growth of tumors by stimulating intracellular pathways that initiate autophagy—a quality control process in cancer cells that also generates intracellular nutrients.

"During tumor growth, cancer cells become addicted to autophagy as a source of nutrients. Moreover, autophagy contributes to chemotherapy resistance in kidney cancer. The new target we’ve identified regulates kidney cancer cell autophagy.” 

The experiments were conducted using animal models, human cell cultures and tumor specimens. The researchers analyzed expression of the channel, its effect on tumor growth and on autophagy and how regulation of autophagy contributed to tumor growth.  

"Our discovery of a TRPM3 stimulated network in the regulation of autophagy and kidney cancer growth could lead to use of the channel as a new actionable target in renal cancer. Indeed, there are already FDA-approved TRPM3 inhibitors on the market, so this is quite promising,” Czyzyk-Krzeska says.

Co-investigators on this research include cancer biology faculty members and former fellows including Daniel Hall, Nicholas Cost (who is currently assistant professor of Urology at the University of Colorado Medical Center, Denver), Shailaja Hedge, Emily Kellner, Olga Mikhaylova, Yiwen Stratton, Birgit Ehmer, William Abplanalp, Raghav Pandey, and David Plas; CCHMC bioinformatics faculty member Jacek Biesiada; Christian Harteneck from the University of Tübingen, Tübingen, Germany; and Jarek Meller from UC’s Departments of Environmental Health and Bioinformatics. 

This work was funded by the National Institutes of Health (CA122346, CA133164 and CA168815), a Veterans Affairs Merit Award and a UC Center for Environmental Genetics Award (P30-ES006096).