Targeting brain cancer cell metabolism may provide new treatment

December 14, 2009

Inhibiting fatty acid synthesis in brain cancer cells may offer a new option to treat about 50 percent of deadly glioblastomas that are driven by amplified signaling of the epidermal growth factor receptor (EGFR), according to a first-of-its-kind study by researchers at UCLA's Jonsson Comprehensive Cancer Center.

Rapidly dividing cancer cells require fatty acids for the formation of new membranes. The fatty acids also provide an alternative energy source for the cancer cells, and may be important for regulating cell signaling, said Dr. Paul Mischel, a professor of pathology and laboratory medicine and senior author of the study, which appears in the Dec. 15 issue of the journal Science Signaling.

While healthy cells take up the fat they need to function through the blood stream, the cancer cells prefer to be autonomous of the body and convert glucose for the fatty acids they need to multiply out of control.

"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 Mischel, a Jonsson Cancer Center researcher. "Understanding the molecular links between oncogenes such as EGFR and the process by which simple sugars such as glucose are converted to fatty acids could lead to new treatments. It could also potentially be used to identify the subsets of patients most likely to benefit from treatment targeting fatty acid biosynthesis."

Although about half of glioblastomas involve amplified and mutated EGFR, which is clearly playing a role in the development and progression of the disease, clinical trials testing EGFR inhibitors have not been successful, with only about 10 to 15 percent of patients responding, Mischel said. The cancer, it appeared, finds a way to work around the inhibitor. Something more had to be going on. Previous studies have suggested that EGFR signaling needs to "team 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 acid synthesis, mostly targeted at weight loss, but they also disrupt other important enzymes and may cause toxicity in cancer patients. Mischel hopes this study will prompt drug companies to develop new therapies that target key points in the molecular circuitry linking EGFR with increased fatty acid synthesis.

"The current treatments we have now only modestly extend lives and are far from long-term disease suppression," Mischel said. "New strategies are absolutely essential. A drug that prevents tumors from making their own fatty acids could potentially provide a more effective way to treat the 50 percent of patients with EGFR-bearing glioblastoma."
-end-
About 10,000 new cases of glioblastoma are diagnosed each year. The median survival for patients is 12 to 18 months.

UCLA's Jonsson Comprehensive Cancer Center has more than 240 researchers and clinicians engaged in disease research, prevention, detection, control, treatment and education. One of the nation's largest comprehensive cancer centers, the Jonsson center is dedicated to promoting research and translating basic science into leading-edge clinical studies. In July 2009, the Jonsson Cancer Center was named among the top 12 cancer centers nationwide by U.S. News & World Report, a ranking it has held for 10 consecutive years. For more information on the Jonsson Cancer Center, visit our website at http://www.cancer.ucla.edu.

University of California - Los Angeles

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.

More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.

New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.

American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.

Read More: Cancer News and Cancer Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.