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Targeting brain cancer cell metabolism may provide new treatment
Date:12/15/2009

up" with other cellular processes for tumor development and progression.

As part of a Phase II clinical trial for EGFR inhibitor Tykerb, Mischel and his team at UCLA performed an analysis of brain tumor tissue before and after the drug was given to see what it did to cell signaling. They also decided to examine the tissue to determine whether EGFR was activating a master regulator in the cell called SREBP-1 that governs fatty acid synthesis. They also studied these processes in glioblastoma cell lines and in an animal model.

Mischel used genetic and pharmacologic approaches to identify the signaling pathways the EGFR uses to activate SREBP-1 and looked for targets for therapeutics. In addition, the team explored whether amplified or mutated EGFR signaling makes glioblastomas more dependent on fatty acid synthesis. If so, they asked, would inhibiting that synthesis, either by blocking activation of SREBP-1 or blocking a downstream fatty acid synthase enzyme, kill the EGFR-bearing tumors?

"We found that EGFR signaling does activate the master regulator SREBP-1 to increase the amount of fatty acids in the cells," Mischel said. "We also were able to uncover the molecular circuitry linking EGFR with increased fatty acid synthesis."

Most importantly, Mischel said, the team found that amplified EGFR signaling does make glioblastoma cells more dependent on fatty acid synthesis and interrupting that synthesis results in massive cell death in EGFR-bearing tumors, but not in tumors with little EGFR signaling.

"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," Mischel said. "We hope that interrupting fatty acid synthesis will kill tumor cells and spare the normal cells, decreasing treatment side effects."

There are drugs in development that block fatty ac
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Contact: Kim Irwin
kirwin@mednet.ucla.edu
310-206-2805
University of California - Los Angeles
Source:Eurekalert

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