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Potential Weapon against Brain Tumors – Stop Them from Fattening Up

For release: Tuesday, February 23, 2010

Two new studies reveal that some kinds of glioblastoma – an aggressive and deadly brain tumor – thrive and spread by turning up their production of energy-rich fat molecules.  Finding ways to cut off this energy supply may lead to effective treatments against glioblastoma.

The research shows that glioblastomas need an internally generated supply of fatty acids, which are components of body fat and a vital source of energy within all cells.  Most fatty acids are derived from food, but they can also be produced – or synthesized – within cells.  According to the new studies, the growth of some brain tumor cells depends on an increased synthesis and use of fatty acids. 

“In the future, fatty acid inhibitors could be used to supplement other targeted brain tumor therapeutics and potentially provide a more effective means to kill the tumor cells, rather than just slowing or temporarily arresting tumor growth,” said Jane Fountain, Ph.D., a program director at the National Institute of Neurological Disorders and Stroke (NINDS).

Few studies to date have examined the role of fatty acid metabolism in brain cancer.  The new research was funded in large part by NINDS and the National Cancer Institute (NCI).  It follows a jointly sponsored NCI-NINDS workshop on Cancer Cell Metabolism, held in July 2009 in Rockville, Maryland,where participants agreed there is a need to understand the contribution of cell metabolism to brain cancer growth.

One study* connects the growth of glioblastoma cells to fatty acid synthesis and to a protein called the epidermal growth factor (EGF) receptor.  Mutations affecting the EGF receptor are known to be present in about half of all glioblastomas.  However, the EGF receptor regulates many cell pathways, and understanding which ones influence tumor growth has been a challenge.

“Blocking fatty synthesis deals a serious blow to glioblastoma cells that have a mutated EGF receptor,” said Paul S. Mischel, M.D., the study’s senior author and a professor of pathology and pharmacology at the David Geffen School of Medicine, University of California Los Angeles.

Dr. Mischel’s study took advantage of an ongoing clinical trial of lapatinib, a drug that inhibits EGF receptors.  The trial is testing whether lapatinib can help prevent the spread of glioblastoma cells and make them easier to remove by surgery.  The patients have their tumors biopsied prior to receiving lapatinib, and then undergo surgery after a 7-10 day course on the drug.

Dr. Mischel’s team examined tumor samples from nine patients, before and after treatment with lapatinib.  After treatment, the tumors showed the expected decrease in EGF receptor activity.  The tumors also showed a decrease in the activity of SREBP‑1 (sterol regulatory element-binding protein 1), a master switch that controls the synthesis of fatty acids.  Experiments on glioblastoma cell lines allowed the researchers to trace a more complete pathway – from EGF receptor to SREBP-1 to the enzymes that make fatty acids.  They also showed that compounds with an inhibitory effect on SREBP-1 or other steps in fatty acid synthesis were effective at killing glioblastoma cell lines.

The other study** shows that a protein called ACSVL3 helps power the growth of glioblastomas.  The ACS (acyl-CoA synthetase) proteins are needed to “activate” fatty acids for different uses, such as building complex fats or releasing their stored energy. 

“It wasn't that we were studying brain tumors and decided to investigate ACS proteins, but the other way around,” said Paul A. Watkins, M.D., Ph.D., a research scientist at the Kennedy Krieger Institute and professor of neurology at the Johns Hopkins University in Baltimore. 

Dr. Watkins was interested in the possible role of ACSVL3 in X-linked adrenoleukodystrophy, a disease where fatty acids accumulate in the brain.  When he learned that a colleague had found a possible association between ACSVL3 and cancer, he investigated further and discovered that levels of the protein skyrocket in glioblastomas.  His team also found they could suppress the growth of tumor cell lines by using a technique called RNA interference to suppress the level of ACSVL3.

Further research will be necessary before fatty acid synthesis inhibitors can be evaluated in patients with glioblastoma, Dr. Mischel said.  Meanwhile, efforts are underway that will enable a search for small-molecule inhibitors of ACSVL3, said Dr. Watkins.

Dr. Mischel’s study was published in Science Signaling.  It received additional support from the Brain Tumor Funders’ Collaborative; the lapatinib trial is supported by NCI’s Adult Brain Tumor Consortium.

Dr. Watkins’ study was published in Cancer Research. Additional support came from the National Institute of Child Health and Human Development (NICHD), the National Brain Tumor Society and the American Brain Tumor Association.

– By Daniel Stimson, Ph.D.

*Guo D et al.  “EGF receptor Signaling Through an Akt-SREBP-1–Dependent, Rapamycin-Resistant Pathway Sensitizes Glioblastomas to Antilipogenic Therapy.”  Science Signaling, December 15, 2009, Vol. 2 (101), p. ra82.

**Zhengtong P et al.  “Acyl-CoA Synthetase VL3 Knockdown Inhibits Human Glioma Cell Proliferation and Tumorigenicity.” Cancer Research, December 15, 2009, Vol. 69 (24), p. 9175.

Last Modified March 1, 2010