Featured Research

from universities, journals, and other organizations

Hope builds for drug that might shut down variety of cancers

Date:
November 7, 2013
Source:
Weill Cornell Medical College
Summary:
The most frequently mutated gene across all types of cancers is a gene called p53. Unfortunately it has been difficult to directly target this gene with drugs. Now a multi-institutional research team has identified a family of enzymes they say is crucial for the growth of cancers that have genetic aberrations in p53.

The most frequently mutated gene across all types of cancers is a gene called p53. Unfortunately it has been difficult to directly target this gene with drugs. Now a multi-institutional research team, led by Dr. Lewis Cantley and investigators at Weill Cornell Medical College, has identified a family of enzymes they say is crucial for the growth of cancers that have genetic aberrations in p53. Targeting these enzymes with novel agents might prevent the growth of p53 mutant cancers, thereby benefiting a broad spectrum of cancer patients, including those with breast, ovarian, lung, colorectal and brain tumors.

In the Nov. 7 issue of Cell, investigators pinpoint two cellular enzymes -- Type 2 phosphatidylinositol-5-phosphate 4-kinases α and β (Type 2 PIP kinases) -- as essential for cancer growth when cells have lost p53, the powerful tumor-suppressor gene long dubbed the "guardian of the genome." More than half of all cancers lose this gene, allowing these cancers to grow at will.

The researchers discovered that the Type 2 PIP kinases are not critical for the growth of normal cells but become essential for cell growth when p53 is lost due to mutations or deletions. The scientists showed, in animal and lab studies of human cancer cells, that targeting these molecules effectively shuts down the growth of p53 mutant cancers.

Although the studies were conducted in human breast cancer cells, the researchers believe Type 2 PIP kinase inhibitors could block the growth of cancers with a mutated or missing p53 gene.

"The fact that one can delete the Type 2 PIP kinases in normal human cells or in mice with essentially no effect on cell survival suggests that inhibitors of these enzymes should have little toxicity," says Dr. Cantley, the study's senior author and director of the Cancer Center at Weill Cornell Medical College and NewYork-Presbyterian Hospital.

Dr. Cantley is already leading an effort to develop drugs to shut down these kinases. "Well-designed Type 2 PIP kinase inhibitors may turn the tide on p53 mutant cancer," he says.

A Crucial Link

Dr. Cantley is known for his discovery of the PI 3-kinase oncogene, and pioneering work in teasing apart how the gene contributes to cancer. PI 3-kinases (PI3K) have been linked to a wide variety of cellular functions, including cell growth and proliferation, and most cancers activate PI3K by one or more mechanisms. Dr. Cantley's discovery led to promising avenues for the development of personalized cancer therapies.

Activity of PI3K is in some cases linked to Type 2 PIP kinases, so in this study, Dr. Cantley sought to understand the function of these enzymes. Because the researchers knew that a subset of breast cancers over-express these molecules, investigators looked at their role in HER2-positive breast cancers, which typically are more aggressive tumors.

The researchers, including those from Harvard Medical School, Beth Israel Deaconess Medical Center and other institutions, discovered that the enzymes are silent in cells that have healthy p53. One critical role of p53 is to "rescue" cells that are producing excess reactive oxygen species (ROS), which are byproducts of cells that are growing too rapidly. The oxidative stress produced by ROS can damage cell structures, so p53 attempts to reduce ROS in affected cells. "If, however, ROS levels exceed the capacity of p53s to rescue it, then p53 takes on a second function, which is to kill the cell," Dr. Cantley says.

"That is why cancers often disable p53. If p53 is mutated or gone, then the cell keeps on growing at a very high rate," he says. "And then ROS begins to damage genes, making the cancer even more aggressive."

The Type 2 PIP kinases are the backup rescue system to p53. But they only reduce ROS enough to keep the cells from dying. (Too much ROS will also kill a cell.)

What this means is that cancer cells become "absolutely dependent on these kinases to be able to grow," Dr. Cantley says.

Taking Advantage of "Synthetic Lethality"

But there is a big and important hitch in this scenario, he adds. If the Type 2 PIP kinases are inhibited, and if p53 is deactivated, the cancer cell essentially "goes to sleep," he says. "It just stops dividing and growing. This is called synthetic lethality: You can get by without one gene or another, but if you lose both of them nothing can grow."

Shutting down these enzymes, as the researchers did in their experiments, puts cancer cells to sleep but has no effect on healthy cells. "A normal cell doesn't need Type 2 PIP kinases at all, so inhibitors of these enzymes should not be toxic to humans," Dr. Cantley says.

Because it is not possible to replace p53 proteins or the gene in cells that have lost it (many attempts have been made), deactivating Type 2 PIP kinases is the next-best thing, he adds. "This would likely be a very powerful advance in the treatment of many cancers."


Story Source:

The above story is based on materials provided by Weill Cornell Medical College. Note: Materials may be edited for content and length.


Journal Reference:

  1. BrookeM. Emerling, JonathanB. Hurov, George Poulogiannis, KazumiS. Tsukazawa, Rayman Choo-Wing, GerburgM. Wulf, EricL. Bell, Hye-Seok Shim, KatjaA. Lamia, LuciaE. Rameh, Gary Bellinger, AtsuoT. Sasaki, JohnM. Asara, Xin Yuan, Andrea Bullock, GinaM. DeNicola, Jiaxi Song, Victoria Brown, Sabina Signoretti, LewisC. Cantley. Depletion of a Putatively Druggable Class of Phosphatidylinositol Kinases Inhibits Growth of p53-Null Tumors. Cell, 2013; 155 (4): 844 DOI: 10.1016/j.cell.2013.09.057

Cite This Page:

Weill Cornell Medical College. "Hope builds for drug that might shut down variety of cancers." ScienceDaily. ScienceDaily, 7 November 2013. <www.sciencedaily.com/releases/2013/11/131107132827.htm>.
Weill Cornell Medical College. (2013, November 7). Hope builds for drug that might shut down variety of cancers. ScienceDaily. Retrieved July 22, 2014 from www.sciencedaily.com/releases/2013/11/131107132827.htm
Weill Cornell Medical College. "Hope builds for drug that might shut down variety of cancers." ScienceDaily. www.sciencedaily.com/releases/2013/11/131107132827.htm (accessed July 22, 2014).

Share This




More Health & Medicine News

Tuesday, July 22, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Courts Conflicted Over Healthcare Law

Courts Conflicted Over Healthcare Law

AP (July 22, 2014) Two federal appeals courts issued conflicting rulings Tuesday on the legality of the federally-run healthcare exchange that operates in 36 states. (July 22) Video provided by AP
Powered by NewsLook.com
Why Do People Believe We Only Use 10 Percent Of Our Brains?

Why Do People Believe We Only Use 10 Percent Of Our Brains?

Newsy (July 22, 2014) The new sci-fi thriller "Lucy" is making people question whether we really use all our brainpower. But, as scientists have insisted for years, we do. Video provided by Newsy
Powered by NewsLook.com
Scientists Find New Way To Make Human Platelets

Scientists Find New Way To Make Human Platelets

Newsy (July 22, 2014) Boston scientists have discovered a new way to create fully functioning human platelets using a bioreactor and human stem cells. Video provided by Newsy
Powered by NewsLook.com
Gilead's $1000-a-Pill Drug Could Cure Hep C in HIV-Positive People

Gilead's $1000-a-Pill Drug Could Cure Hep C in HIV-Positive People

TheStreet (July 21, 2014) New research shows Gilead Science's drug Sovaldi helps in curing hepatitis C in those who suffer from HIV. In a medical study, the combination of Gilead's Hep C drug with anti-viral drug Ribavirin cured 76% of HIV-positive patients suffering from the most common hepatitis C strain. Hepatitis C and related complications have been a top cause of death in HIV-positive patients. Typical medication used to treat the disease, including interferon proteins, tended to react badly with HIV drugs. However, Sovaldi's %1,000-a-pill price tag could limit the number of patients able to access the treatment. TheStreet's Keris Lahiff reports from New York. Video provided by TheStreet
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