Blocking Fatty Acid Synthesis Kills Some Forms of Brain Cancer

A possible therapeutic approach to treat rapidly growing tumors is to inhibit the synthesis of the fatty acids they require for formation of new membranes and as an alternative energy source.

Investigators at the University of California, Los Angeles (USA) worked with the most common form of brain cancer, glioblastoma. This is one of the most difficult to treat cancers with the median survival for patients of from only 12 to 18 months.

The investigators focused their attention on the master regulator of fatty acid synthesis, sterol regulatory element-binding protein 1 (SREBP-1), which is in turn controlled by signaling from the epidermal growth factor receptor (EGFR). Although nearly 50% of glioblastomas develop because of overexpressed or mutant EGFR, clinical trials testing EGFR inhibitors have not been particularly successful, with only about 10 to 15% of patients responding.

In the current study, the investigators used genetic and pharmacologic approaches to identify the signaling pathways that EGFR uses to activate SREBP-1. They reported in the December 15, 2009, issue of the journal Science Signaling that glioblastomas with overexpressed or mutant EGFR were more dependent on fatty acid synthesis than cancers lacking these characteristics. Breaking the link between EGFR and SREBP-1 in these tumors caused the cancer cells to self-destruct.

"This suggests an important link between cancer progression and fatty acid synthesis and has raised the idea that targeting fatty acid synthesis could be an effective way to block cancer growth," said senior author Dr. Paul Mischel, professor of pathology and laboratory medicine at the University of California, Los Angeles.

"We found that EGFR signaling does activate the master regulator SREBP-1 to increase the amount of fatty acids in the cells," said Dr. Mischel. "We also were able to uncover the molecular circuitry linking EGFR with increased fatty acid synthesis. This is exciting because it identified a previously undescribed EGFR-controlled metabolic pathway and suggests new treatment approaches for EGFR-activated glioblastomas and perhaps other cancers with amplified signaling. We hope that interrupting fatty acid synthesis will kill tumor cells and spare the normal cells, decreasing treatment side effects."

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