Featured Research

from universities, journals, and other organizations

Modification of tumor suppressor affects sensitivity to potential GBM treatment

Date:
August 13, 2012
Source:
Ludwig Institute for Cancer Research
Summary:
Biologists and oncologists have long understood that a protein called the epidermal growth factor receptor or EGFR is altered in at least 50 percent of patients with glioblastoma. Yet patients with glioblastoma either have upfront resistance or quickly develop resistance to inhibitors aimed at stopping the protein's function, suggesting that there is another signalling pathway at play.

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

Biologists and oncologists have long understood that a protein called the epidermal growth factor receptor or EGFR is altered in at least 50 percent of patients with glioblastoma. Yet patients with glioblastoma either have upfront resistance 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 Cancer Research, 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 pathway. The findings enable us to move forward to identify and develop small molecule inhibitors for eventual use in combination with EGFR inhibitors for the treatment of glioblastoma and other cancers."


Story Source:

The above story is based on materials provided by Ludwig Institute for Cancer Research. Note: Materials may be edited for content and length.


Journal Reference:

  1. Tim R. Fenton, David Nathanson, Claudio Ponte de Albuquerque, Daisuke Kuga, Akio Iwanami, Julie Dang, Huijun Yang, Kazuhiro Tanaka, Sueli Mieko Oba-Shinjo, Miyuki Uno, Maria del Mar Inda, Jill Wykosky, Robert M. Bachoo, C. David James, Ronald A. DePinho, Scott R. Vandenberg, Huilin Zhou, Suely K. N. Marie, Paul S. Mischel, Webster K. Cavenee, and Frank B. Furnari. Resistance to EGF receptor inhibitors in glioblastoma mediated by phosphorylation of the PTEN tumor suppressor at tyrosine 240. Proceedings of the National Academy of Sciences., August 13, 2012 DOI: 10.1073/pnas.1211962109

Cite This Page:

Ludwig Institute for Cancer Research. "Modification of tumor suppressor affects sensitivity to potential GBM treatment." ScienceDaily. ScienceDaily, 13 August 2012. <www.sciencedaily.com/releases/2012/08/120813155715.htm>.
Ludwig Institute for Cancer Research. (2012, August 13). Modification of tumor suppressor affects sensitivity to potential GBM treatment. ScienceDaily. Retrieved September 2, 2014 from www.sciencedaily.com/releases/2012/08/120813155715.htm
Ludwig Institute for Cancer Research. "Modification of tumor suppressor affects sensitivity to potential GBM treatment." ScienceDaily. www.sciencedaily.com/releases/2012/08/120813155715.htm (accessed September 2, 2014).

Share This




More Health & Medicine News

Tuesday, September 2, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Snack Attack: Study Says Action Movies Make You Snack More

Snack Attack: Study Says Action Movies Make You Snack More

Newsy (Sep. 2, 2014) — You're more likely to gain weight while watching action flicks than you are watching other types of programming, says a new study published in JAMA. Video provided by Newsy
Powered by NewsLook.com
U.N. Says Ebola Travel Restrictions Will Cause Food Shortage

U.N. Says Ebola Travel Restrictions Will Cause Food Shortage

Newsy (Sep. 2, 2014) — The U.N. says the problem is two-fold — quarantine zones and travel restrictions are limiting the movement of both people and food. Video provided by Newsy
Powered by NewsLook.com
Get on Your Bike! London Cycling Popularity Soars Despite Danger

Get on Your Bike! London Cycling Popularity Soars Despite Danger

AFP (Sep. 1, 2014) — Wedged between buses, lorries and cars, cycling in London isn't for the faint hearted. Nevertheless the number of people choosing to bike in the British capital has doubled over the past 15 years. Duration: 02:27 Video provided by AFP
Powered by NewsLook.com
Can You Train Your Brain To Eat Healthy?

Can You Train Your Brain To Eat Healthy?

Newsy (Sep. 1, 2014) — New research says if you condition yourself to eat healthy foods, eventually you'll crave them instead of junk food. Video provided by Newsy
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
 
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:  

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:  

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile iPhone Android Web
Follow Facebook Twitter Google+
Subscribe RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins