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New Drug Combinations Block Kidney Cancer in Culture and Mouse Models

By BiotechDaily International staff writers
Posted on 20 May 2013
Image: Senior author Dr. John Copland (Photo courtesy of the Mayo Clinic).
Image: Senior author Dr. John Copland (Photo courtesy of the Mayo Clinic).
Drugs that block the activity of the enzyme Stearoyl-CoA desaturase-1 (SCD1) repress the growth of kidney cancer cells in culture and in mouse models of the disease.

SCD1, which is overexpressed in most kidney cancer samples, is a key enzyme in fatty acid metabolism responsible for forming a double bond in Stearoyl-CoA. This is the way that the monounsaturated fatty acid oleic acid is produced from the saturated fatty acid stearic acid. The ratio of stearic acid to oleic acid has been implicated in the regulation of cell growth and differentiation through effects on cell membrane fluidity and signal transduction.

Investigators at the Mayo Clinic (Jacksonville, FL, USA) worked with a drug that had been designed to block the activity of SCD1 in clear cell renal cell carcinoma (ccRCC), which accounts for almost 85% of kidney cancer cases in the United States.

The investigators examined patient normal and ccRCC tissue samples and cell lines for SCD1 expression. Genetic knockdown models and targeted inhibition of SCD1 through the use of the drug A939572 were analyzed for growth, apoptosis, and alterations in gene expression using gene array analysis. Models of combined therapy using A939572 and the tyrosine kinase inhibitors (TKI) sunitinib and pazopanib, and the mTOR inhibitor temsirolimus were evaluated.

Results published in the May 1, 2013, issue of the journal Clinical Cancer Research revealed increased SCD1 expression in all stages of ccRCC. Both genetic knockdown and pharmacologic inhibition of SCD1 decreased tumor cell proliferation and induced apoptosis in vitro and in vivo. Upon gene array, quantitative real-time PCR, and protein analysis of A939572-treated or genetic SCD1 knockdown samples, induction of endoplasmic reticulum stress response signaling was observed, which suggested a mechanistic mechanism for SCD1 activity in ccRCC. Furthermore, application of A939572 (25% inhibition when applied alone) combined with temsirolimus inhibited tumor growth by 60%–70% in vitro and in vivo.

“There is a clear need for new therapies for this common cancer. With very few exceptions, patients inevitably become resistant to all available treatments,” said senior author Dr. John Copland, professor of cancer biology at the Mayo Clinic.

“We found it [A939572] to be incredibly specific to cancer cells in laboratory mice treated with the agent,” said Dr. Copland. “But these are early days in the testing of this agent for cancer. The synergy between the drugs [A939572 and temsirolimus] was very striking, suggestive of significant clinical benefit in patients.”

Related Links:
Mayo Clinic



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