Featured Research

from universities, journals, and other organizations

New way found to boost common cancer drugs

Date:
January 14, 2013
Source:
Fox Chase Cancer Center
Summary:
Shutting down a specific pathway in cancer cells appears to improve the ability of common drugs to wipe those cells out, according to new research.

Shutting down a specific pathway in cancer cells appears to improve the ability of common drugs to wipe those cells out, according to new research from scientists at Fox Chase Cancer Center, published in the January issue of Cancer Discovery.

"Ideally, this research will eventually enable scientists to find drugs that disrupt this pathway and boost the impact of current therapies," says Igor Astsaturov, MD, PhD, Attending Physician in the Department of Medical Oncology at Fox Chase. "That's the long-term plan."

The new approach appears to enhance the tumor-killing ability of a commonly prescribed class of drugs that includes cetuximab (Erbitux), used to treat colorectal and head and neck cancers. These drugs work by blocking the activity of the epidermal growth factor receptor (EGFR), which sits on the cell surface and senses cues from the environment, telling cancer cells to grow and divide, says Astsaturov. "The whole mantra of modern day oncology is to suppress these inputs."

Although EGFR inhibitors succeed in killing cancer cells, some malignant cells still find ways to evade the drug, and become resistant to treatment. Consequently, many researchers are actively looking for ways to kill these surviving cancer cells, annihilating tumors completely.

In 2010, Astsaturov and his colleagues identified a pathway in the cell that, when blocked, completely suppressed EGFR activity. Interestingly, the pathway consists of a series of enzymes that, when working in concert, synthesize new molecules of cholesterol, an essential component of the cell wall. This pathway is particularly important to cancer cells, which are constantly dividing and therefore need to produce more cholesterol for the new cells.

Working with cancer cells in the lab, the researchers inactivated a key gene in the cholesterol synthesis pathway, and found the cells became more vulnerable to treatment with cetuximab. The same was true in mice that lacked this particular pathway, says Astsaturov. "Most tumors are only moderately sensitive to inhibitors of EGFR, but when these tumors lack an essential gene in the cholesterol pathway, they become exquisitely sensitive to the anti-EGFR drugs," he says. "The cancers literally melt away in mice."

The researchers then removed one of the cholesterol genes from the mouse genome, and saw that mice developed patchy, scaly skin. When they biopsied this affected skin, they saw no activity of the EGFR protein, reaffirming that shutting down cholesterol synthesis interrupts EGFR. They also observed the same pattern in normal cell lines.

When the cholesterol biosynthesis pathway is blocked, explains Astsaturov, the normal chain of events that creates a cholesterol molecule is interrupted, and cells accumulate intermediate products of cholesterol that block the normal movement of substances around the cell. This cellular traffic jam makes it difficult for the cell to transport important components, such as EGFR, which has to move between the inside of the cell and its surface to function properly. "If you disrupt this traffic, the cancer cells don't survive."

Eventually, says Astsaturov, researchers can design drugs or look for existing ones that block this cholesterol synthesis pathway. For now, his lab is trying to uncover more details of how the pathway works, the role of each protein that is involved -- and whether if, by blocking a protein, they can wipe out tumors in humans that evade current therapies. "These proteins represent targets for additional drugs, which could be combined with EGFR inhibitors," he says.

Astsaturov's co-authors include Erica A. Golemis, Anna Sukhanova, Andrey Gorin, Ilya G. Serebriiskii, Linara Gabitova, Hui Zheng, Diana Restifo, Tetyana Bagnyukova, Hanqing Liu, Anna Nikonova, Gregory P. Adams, Yan Zhou, Ranee Mehra, Barbara Burtness, Kathy Q. Cai, Andres Klein-Szanto, and Brian L. Egleston, Fox Chase; David Cunningham and Gail E. Herman, The Research Institute at Nationwide Children's Hospital and the Department of Pediatrics; Lisa E. Kratz, Richard I. Kelley, The Ohio State University; and Louis M. Weiner, Lombardi Comprehensive Cancer Center.

This research was supported in part by NCI grants, the Pennsylvania Tobacco Settlement CURE grant, NIH core grant CA-06927, and the Pew Charitable Fund.


Story Source:

The above story is based on materials provided by Fox Chase Cancer Center. Note: Materials may be edited for content and length.


Journal Reference:

  1. A. Sukhanova, A. Gorin, I. G. Serebriiskii, L. Gabitova, H. Zheng, D. Restifo, B. L. Egleston, D. Cunningham, T. Bagnyukova, H. Liu, A. Nikonova, G. P. Adams, Y. Zhou, D.-H. Yang, R. Mehra, B. Burtness, K. Q. Cai, A. Klein-Szanto, L. E. Kratz, R. I. Kelley, L. M. Weiner, G. E. Herman, E. A. Golemis, I. Astsaturov. Targeting C4-Demethylating Genes in the Cholesterol Pathway Sensitizes Cancer Cells to EGF Receptor Inhibitors via Increased EGF Receptor Degradation. Cancer Discovery, 2012; 3 (1): 96 DOI: 10.1158/2159-8290.CD-12-0031

Cite This Page:

Fox Chase Cancer Center. "New way found to boost common cancer drugs." ScienceDaily. ScienceDaily, 14 January 2013. <www.sciencedaily.com/releases/2013/01/130114133357.htm>.
Fox Chase Cancer Center. (2013, January 14). New way found to boost common cancer drugs. ScienceDaily. Retrieved April 24, 2014 from www.sciencedaily.com/releases/2013/01/130114133357.htm
Fox Chase Cancer Center. "New way found to boost common cancer drugs." ScienceDaily. www.sciencedaily.com/releases/2013/01/130114133357.htm (accessed April 24, 2014).

Share This



More Health & Medicine News

Thursday, April 24, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Big Pharma Braces for M&A Wave

Big Pharma Braces for M&A Wave

Reuters - Business Video Online (Apr. 22, 2014) Big pharma on the move as Novartis boss, Joe Jimenez, tells Reuters about plans to transform his company via an asset exchange with GSK, and Astra Zeneca shares surge on speculation that Pfizer is looking for a takeover. Joanna Partridge reports. Video provided by Reuters
Powered by NewsLook.com
Study Says Most Crime Not Linked To Mental Illness

Study Says Most Crime Not Linked To Mental Illness

Newsy (Apr. 22, 2014) A new study finds most crimes committed by people with mental illness are not caused by symptoms of their illness or disorder. Video provided by Newsy
Powered by NewsLook.com
Hagel Gets Preview of New High-Tech Projects

Hagel Gets Preview of New High-Tech Projects

AP (Apr. 22, 2014) Defense Secretary Chuck Hagel is given hands-on demonstrations Tuesday of some of the newest research from DARPA _ the military's Defense Advanced Research Projects Agency program. (April 22) Video provided by AP
Powered by NewsLook.com
How Smaller Plates And Cutlery Could Make You Feel Fuller

How Smaller Plates And Cutlery Could Make You Feel Fuller

Newsy (Apr. 22, 2014) NBC's "Today" conducted an experiment to see if changing the size of plates and utensils affects the amount individuals eat. 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