Researchers have uncovered a novel way to potentially target clear cell renal cell carcinoma (ccRCC), a predominantly incurable disease for which patients have limited treatment options.
Researchers have uncovered a novel way to potentially target clear cell renal cell carcinoma (ccRCC), a predominantly incurable disease for which patients have limited treatment options. The target is TRPM3 (transient receptor potential melastatin 3), a membrane channel that can promote renal cell tumors.
TRPM3 is a calcium-permeable nonselective cation channel and is expressed on different cell types.
The results are published in a recent issue of the journal Cancer Cell.
Current ccRCC therapies include those that target angiogenesis, tyrosine kinase receptors as well as the mTOR pathway, but all are only temporarily and partially effective in controlling the disease.
"Our team found a new target in kidney cancer known as TRPM3. TRPM3 is increased in 60% 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,” said lead author Maria Czyzyk-Krzeska, MD, PhD, of the Cincinnati Cancer Center (CCC) and professor at the University of Cincinnati Cancer Institute.
In their study, Czyzyk-Krzeska and colleagues show that TRPM3 stimulates autophagy-a way for cells to generate nutrients by breaking down the components of the cell’s cytoplasm. While autophagy can function to suppress tumor growth during the initial phase of cancer, during rapid tumor growth, tumor cells can become reliant and addicted to autophagy as a nutrient source. Autophagy is also a mechanism of resistance to some cancer therapies, and particularly, has been shown to be a way renal tumor cells become resistant to chemotherapy treatment. Previous studies have shown that cancer cells have distinct ways to maintain autophagy that are not utilized by noncancerous cells.
The authors also found that extracellular calcium ions can contribute to ccRCC growth by stimulating autophagy and note that hypercalcemia is well documented as a paraneoplastic syndrome that occurs in ccRCC.
The authors used human cell cultures and tumor samples from patients, as well as animal models to conduct their studies.
"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,” said Czyzyk-Krzeska.
There are already FDA-approved TRPM3 inhibitors on the market known as fenamates--a parent structure for nonsteroidal anti-inflammatory drugs.