Modification of tumor suppressor affects sensitivity to potential GBM treatment

August 13, 2012

Despite years of research, glioblastoma, the most common and deadly brain cancer in adults, continues to outsmart treatments targeted to inhibit tumor growth.

and have long understood that a called the or EGFR is altered in at least 50 percent of patients with glioblastoma. Yet patients with glioblastoma either have upfront or quickly develop resistance to inhibitors aimed at stopping the protein's function, suggesting that there is another signalling pathway at play.

Researchers from the Ludwig Institute for , the University of California, San Diego (UCSD) and Los Angeles (UCLA) and the University of São Paulo, Brazil published their findings on a mechanism that defines these types of resistance in the August 13 online issue of Proceedings of the National Academy of Sciences.

Previous research suggested that PTEN, a tumor suppressor gene, may be turned off in some cancer patients, disabling its function and potentially causing the resistance to EGFR inhibitors. "We asked ourselves, how is PTEN being modified? What is altering its function?," said Frank Furnari, PhD, corresponding author and Ludwig senior investigator based at UCSD.

The researchers focused on one type of modification called phosphorylation, the process by which some proteins are turned on and off. They mapped the sites where PTEN was changed or phosphorylated and subsequently developed an antibody that would recognize the PTEN protein when it was phosphorylated.

The team then put the antibody to the test. Together with Suely Marie, MD, at the University of São Paulo, they first evaluated a large series of clinical samples from patients with glioblastoma and found that the presence of phosphorylation was associated with shortened survival. Then with Paul Mischel, MD, at UCLA, they examined samples from a completely different series of patients who were EGFR positive and did not respond to EGFR-inhibitor treatment. The results confirmed that patients with modified PTEN had resistance to EGFR inhibitors.

"We think this modification of PTEN may become a useful marker to determine if a patient will respond or not to a growth factor receptor inhibitor," added Furnari. "If you can prevent phosphorylation, our studies showed that you have created a scenario where EGFR inhibitors will work better."

The team identified two enzymes responsible for turning off the brakes of PTEN – the fibroblast growth receptor and SRC family kinases. By understanding how these enzymes disable the suppressor function of the gene, scientists may be able to target different molecules that can intervene to stop resistance.

"The more we understand, the better we can conceive of ways to restore PTEN function in tumor cells and stop resistance to EGFR inhibitors in patients with glioblastoma," said lead author, Tim Fenton, PhD, who conducted this research while at the Ludwig Institute at UCSD and is currently at the University College London Cancer Institute.

According to Paul Mischel, who has since moved from UCLA to become a Ludwig member based at UCSD, "The study outcomes provide a potentially clinically targetable . The findings enable us to move forward to identify and develop small molecule inhibitors for eventual use in combination with inhibitors for the treatment of glioblastoma and other cancers."

Explore further: The right combination: Overcoming drug resistance in cancer

Related Stories

The right combination: Overcoming drug resistance in cancer

June 1, 2012
Overactive epidermal growth factor receptor (EGFR) signaling has been linked to the development of cancer. Several drug therapies have been developed to treat these EGFR-associated cancers; however, many patients have developed ...

Targeting cholesterol to fight deadly brain cancers

September 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 ...

How brain tumors invade

December 12, 2011
Scientists have pinpointed a protein that allows brains tumors to invade healthy brain tissue, according to work published this week in the Journal of Experimental Medicine.

Recommended for you

Vitamin C may encourage blood cancer stem cells to die

August 17, 2017
Vitamin C may "tell" faulty stem cells in the bone marrow to mature and die normally, instead of multiplying to cause blood cancers. This is the finding of a study led by researchers from Perlmutter Cancer Center at NYU Langone ...

Outdoor light at night linked with increased breast cancer risk in women

August 17, 2017
Women who live in areas with higher levels of outdoor light at night may be at higher risk for breast cancer than those living in areas with lower levels, according to a large long-term study from Harvard T.H. Chan School ...

Scientists develop novel immunotherapy technology for prostate cancer

August 17, 2017
A study led by scientists at The Wistar Institute describes a novel immunotherapeutic strategy for the treatment of cancer based on the use of synthetic DNA to directly encode protective antibodies against a cancer specific ...

Toxic formaldehyde is produced inside our own cells, scientists discover

August 16, 2017
New research has revealed that some of the toxin formaldehyde in our bodies does not come from our environment - it is a by-product of an essential reaction inside our own cells. This could provide new targets for developing ...

Cell cycle-blocking drugs can shrink tumors by enlisting immune system in attack on cancer

August 16, 2017
In the brief time that drugs known as CDK4/6 inhibitors have been approved for the treatment of metastatic breast cancer, doctors have made a startling observation: in certain patients, the drugs—designed to halt cancer ...

Researchers find 'switch' that turns on immune cells' tumor-killing ability

August 16, 2017
Molecular biologists led by Leonid Pobezinsky and his wife and research collaborator Elena Pobezinskaya at the University of Massachusetts Amherst have published results that for the first time show how a microRNA molecule ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.