Featured Research

from universities, journals, and other organizations

Targeted therapy reactivates 'guardian of the genome' in resistant cancer

Date:
November 15, 2010
Source:
Cell Press
Summary:
A study demonstrating pharmacological rescue of a key tumor suppressor may lead to new therapeutic strategies for human cancer and significantly broaden the types of tumors that respond to targeted therapy, including those that have been resistant to current treatments. The research focuses on cancers exhibiting inhibition of p53, a protein that is critical for initiating cell death pathways in abnormal cells.

A study demonstrating pharmacological rescue of a key tumor suppressor may lead to new therapeutic strategies for human cancer and significantly broaden the types of tumors that respond to targeted therapy, including those that have been resistant to current treatments. The research, published in the Nov. 16 issue of the journal Cancer Cell, focuses on cancers exhibiting inhibition of p53, a protein that is critical for initiating cell death pathways in abnormal cells.

It is common for cancer cells to find some way to disarm p53, also known as "guardian of the genome" due to its action in preventing defective cells from dividing. "The critical importance of the protective function of p53 is underscored by the diversity of molecular strategies employed by cancer cells to subvert p53 activity, such as overexpression of antagonistic proteins like HDM2 and HDMX," explains senior study author Dr. Loren D. Walensky from Harvard Medical School. "Restoration of p53 activity remains an important goal in the quest for more effective cancer therapeutics."

Previous work demonstrated that selective inhibition of HDM2 restored p53 function in cancer cells. However, these results were often compromised by expression of HDMX. In an earlier study, Dr. Walensky and colleagues described the generation of "stapled" peptides designed to resemble the section of p53 that interacts with HDM2. When biochemical and structural studies revealed that HDM2 and HDMX engage the same region of p53, the researchers examined whether the most effective engineered HDM2 inhibitor (SAH-p53-8) could also interfere with HDMX and how this interaction might influence the p53 activity.

The SAH-p53-8 compound was even more effective at targeting HDMX and effectively blocked formation of the inhibitory p53-HDMX complex, thereby restoring the p53 pathway and reducing tumor cell viability. Importantly, when SAH-p53-8 was delivered intravenously to mice with HDMX-expressing cancer, p53 activity was increased and tumor growth was suppressed.

"We found that targeting HDMX overcame HDMX-mediated p53 suppression and resistance to selective HDM2 inhibition, while dual targeting of HDM2 and HDMX maximized therapeutic reactivation of the p53 tumor suppressor pathway in cancers that express both protein antagonists and retain functional p53," concludes Dr. Walensky. "Importantly, monitoring cellular levels of p53-HDMX complex may be useful for predicting cancer cell susceptibility to HDMX inhibition and determining the efficacy of HDM2 inhibitor-mediated p53 restoration, which forms the basis for enhancing the therapeutic impact of dual HDM2/HDMX targeting in resistant cancers."


Story Source:

The above story is based on materials provided by Cell Press. Note: Materials may be edited for content and length.


Journal Reference:

  1. Federico Bernal, Mark Wade, Marina Godes, Tina N. Davis, David G. Whitehead, Andrew L. Kung, Geoffrey M. Wahl, Loren D. Walensky. A Stapled p53 Helix Overcomes HDMX-Mediated Suppression of p53. Cancer Cell, Volume 18, Issue 5, 411-422, 16 November 2010 DOI: 10.1016/j.ccr.2010.10.024

Cite This Page:

Cell Press. "Targeted therapy reactivates 'guardian of the genome' in resistant cancer." ScienceDaily. ScienceDaily, 15 November 2010. <www.sciencedaily.com/releases/2010/11/101115122628.htm>.
Cell Press. (2010, November 15). Targeted therapy reactivates 'guardian of the genome' in resistant cancer. ScienceDaily. Retrieved April 21, 2014 from www.sciencedaily.com/releases/2010/11/101115122628.htm
Cell Press. "Targeted therapy reactivates 'guardian of the genome' in resistant cancer." ScienceDaily. www.sciencedaily.com/releases/2010/11/101115122628.htm (accessed April 21, 2014).

Share This



More Health & Medicine News

Monday, April 21, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Breakfast Foods Are Getting Pricier

Breakfast Foods Are Getting Pricier

AP (Apr. 21, 2014) Breakfast is now being served with a side of sticker shock. The cost of morning staples like bacon, coffee and orange juice is on the rise because of global supply problems. (April 21) Video provided by AP
Powered by NewsLook.com
Nine-Month-Old Baby Can't Open His Mouth

Nine-Month-Old Baby Can't Open His Mouth

Newsy (Apr. 19, 2014) Nine-month-old Wyatt Scott was born with a rare disorder called congenital trismus, which prevents him from opening his mouth. Video provided by Newsy
Powered by NewsLook.com
'Holy Grail' Of Weight Loss? New Find Could Be It

'Holy Grail' Of Weight Loss? New Find Could Be It

Newsy (Apr. 18, 2014) In a potential breakthrough for future obesity treatments, scientists have used MRI scans to pinpoint brown fat in a living adult for the first time. Video provided by Newsy
Powered by NewsLook.com
Little Progress Made In Fighting Food Poisoning, CDC Says

Little Progress Made In Fighting Food Poisoning, CDC Says

Newsy (Apr. 18, 2014) A new report shows rates of two foodborne infections increased in the U.S. in recent years, while salmonella actually dropped 9 percent. 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