Navigation Links
Targeting cholesterol to fight deadly brain cancers
Date:9/15/2011

Blocking the uptake of large amounts of cholesterol into brain cancer cells could provide a new strategy to battle glioblastoma, one of the most deadly malignancies, researchers at UCLA's Jonsson Comprehensive Cancer Center have found.

The study, done in cells lines, mouse models and analysis of tissue from brain cancer patients, uncovered a novel mechanism by which the most commonly activated oncogene, the mutated epidermal growth factor receptor (EGFR), overcomes normal cell regulatory mechanisms to feed large amounts of cholesterol to the brain cancer cells, said Dr. Paul Mischel, a professor of pathology and laboratory medicine and molecular and medical pharmacology, a Jonsson Cancer Center researcher and senior author of the study.

The study appears Sept. 15 in Cancer Discovery, the newest peer-reviewed journal of the American Association for Cancer Research. It shows that EGFRvIII, common in glioblastoma, promotes the import of cholesterol into cancer cells by up-regulating its cellular receptor, the LDL receptor, promoting rapid tumor growth and survival.

There are at least three ways by which cells normally tightly control their cholesterol levels - synthesis, import and efflux, or pumping out the cholesterol, Mischel said.

"Our study found that the mutant EGFR hijacks this system, enabling cancer cells to import large amounts of cholesterol through the LDL receptor," Mischel said. "This study identifies the LDL receptor as a key regulator of cancer cell growth and survival, and as a potential drug target."

Mischel and his colleagues hypothesized that targeting the LDL receptor for destruction could result in strong anti-tumor activity against glioblastoma. They showed that a drug that activates the nuclear Liver X Receptor, a critical regulator of intracellular cholesterol that ensures appropriately balanced levels, degraded the LDL receptor in tumor cells bearing EGFR mutations, potently killing the cancerous tumors in mice.

About 45 percent of glioblastoma patients have cancers driven by mutated EGFR, so the findings have the potential to help almost half of those diagnosed with this aggressive malignancy. EGFR also is mutated in a number of other cancers, indicating that these findings may have relevance for other malignancies.

"This study suggests a potential therapeutic strategy to treat glioblastoma, and potentially a broader range of cancer types," Mischel said.

In a previous study, Mischel showed that inhibiting fatty acid synthesis in brain cancer cells may offer an additional option to treat those with mutated EGFR. Rapidly dividing cancer cells also require these fatty acids to form new membranes and provide energy for the cells. Mischel and his team found the same cell signaling pathway is at work in fatty acid synthesis and the import of cholesterol into cancer cells.

"That was a surprise here, this ghastly trick of the cancer cells," Mischel said. "The same mutation is coordinately regulating both the cholesterol and fatty acid synthesis mechanisms."

Going forward, Mischel and his colleagues will do more preclinical studies that could lead to clinical trials of drugs that activate the Liver X receptor.

Glioblastoma is the most common brain malignancy and one of the most lethal of all cancers, killing most of those diagnosed within 12 to 15 months despite aggressive treatment. It is also one of the most chemotherapy- and radiation-resistant cancers. New treatments are desperately needed, Mischel said.

"This study uncovers a novel and potentially therapeutically targetable tumor cell growth and survival pathway, which could result in more effective treatments for patients," he said.

Mischel's findings are the result of a collaboration with Dr. Peter Tontonoz, a Howard Hughes Medical Institute investigator and a professor of pathology and laboratory medicine at UCLA, Dr. Timothy Cloughesy, professor of neurology and director of neuro oncology at UCLA's Jonsson Comprehensive Cancer Center, and Dr. Deliang Guo, an assistant professor of radiation oncology at the Ohio State University Comprehensive Cancer Center.


'/>"/>
Contact: Kim Irwin
kirwin@mednet.ucla.edu
310-206-2805
University of California - Los Angeles Health Sciences
Source:Eurekalert

Related medicine news :

1. Targeting innate immunity in malaria
2. Targeting PTEN may prevent skin cancer
3. Targeting the Ewing sarcoma family of tumors
4. Latest data from Cedars-Sinai vaccine study supports immune targeting of brain tumors
5. Study confirms safety, cancer-targeting ability of nutrient in broccoli, other vegetables
6. NIH grant for the move toward clinical trials targeting the lysosomal storage disease MPSIIIB
7. Targeting top 911 callers can trim cost, improve patient care
8. Cancer-targeting investigational nanoparticle receives FDA IND approval for first-in-human trial
9. New program targeting whole-person health care gets major grant
10. Targeting nicotine receptors to treat cognitive impairments in schizophrenia
11. Scientists announce new advance with potential for future cancer targeting
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:10/13/2017)... ... 13, 2017 , ... Ellevate Network, the leading network for professional women, brought ... gender equality at their inaugural Summit in New York City in June. The event ... audience of over 3 million. To watch the Mobilize Women video, click here ...
(Date:10/13/2017)... ... October 13, 2017 , ... Coveros, ... Development, has been awarded a contract by the Center for Medicare and Medicaid ... to accelerate the enterprise use of Agile methodologies in a consistent and high ...
(Date:10/12/2017)... ... October 12, 2017 , ... CitiDent and San ... using cutting-edge Oventus O2Vent technology. As many as 18 million Americans are ... cessation in breathing. Oral appliances can offer significant relief to about 75 percent ...
(Date:10/12/2017)... , ... October 12, 2017 , ... The American College ... to Carol Friedman, PhD, FACMI, during the Opening Session of AMIA’s Annual Symposium in ... , In honor of Morris F. Collen, a pioneer in the field of medical ...
(Date:10/12/2017)... ... October 12, 2017 , ... HMP , a leader in ... 2017 Folio Magazine Eddie Digital Award for ‘Best B-to-B Healthcare Website.’ Winners were announced ... 2017. , The annual award competition recognizes editorial and design excellence across a range ...
Breaking Medicine News(10 mins):
(Date:10/2/2017)... 2, 2017 The Rebound mobile app is poised ... reverse the tide of prescription drug addiction. The app empowers ... intake and stepping down their dosage in a safe, controlled ... December 2017; the first 100,000 people to sign up will ... http://www.rebound-solution.com/ ...
(Date:9/27/2017)... MIAMI , Sept. 27, 2017  Commended for their ... recent notable awards. Ranked as number one in the South ... ninth time in Inc. 5000 yearly list, the national specialty ... CEO, Armando Bardisa will soon be honored by ... Set to receive his award ...
(Date:9/25/2017)...  EpiVax, Inc., a leader in the fields ... announced the launch of EpiVax Oncology Inc., a ... cancer vaccines. EpiVax has provided $500,000 in seed ... technologies to the new precision immunotherapy venture. Gad ... as Chief Executive Officer. Gad brings over 25 ...
Breaking Medicine Technology: