Featured Research

from universities, journals, and other organizations

Experimental Therapy Turns On Tumor Suppressor Gene In Cancer Cells

Date:
January 20, 2009
Source:
Mayo Clinic
Summary:
Researchers have found that the experimental drug they are testing to treat a deadly form of thyroid cancer turns on a powerful tumor suppressor capable of halting cell growth. Few other cancer drugs have this property, they say.

Researchers at Mayo Clinic have found that the experimental drug they are testing to treat a deadly form of thyroid cancer turns on a powerful tumor suppressor capable of halting cell growth. Few other cancer drugs have this property, they say.

Related Articles


In the Feb. 15 issue of Cancer Research (available online Jan. 20), they report that RS5444, being tested in a Phase 1/2 clinical trial to treat anaplastic thyroid cancer, might be useful for treating other cancers. The agent is also known as CS-7017.

From previous research, the investigators knew that RS5444 binds to a protein known as PPAR-gamma, a transcriptional factor that increases the expression of many genes. They had found that human anaplastic thyroid tumor cells treated with RS5444 expressed a protein known as p21, which inhibited cell replication and tumor growth. But they did not understand how. They have now discovered that the agent actually forces PPAR-gamma to turn on the RhoB tumor suppressor gene, which in turn induces p21 expression.

"This is very unusual," says the study's lead investigator, John Copland, Ph.D., a cancer biologist at the Mayo Clinic campus at Jacksonville. "Drugs typically target genes and proteins that are over-expressed and turn them off. We found that RS5444 turns on a valuable tumor suppressor gene. We rarely find a drug that can take a suppressed gene and cause it to be re-expressed."

This finding suggests that other cancers in which RhoB is deactivated might respond to RS5444 or to similar drugs, says co-author Robert Smallridge, M.D., who treats thyroid cancer patients at Mayo Clinic in Jacksonville.

"This study provides a hint that this class of drugs could have a significant effect on cancer biology because of its action on this tumor suppressor gene," says Dr. Smallridge.

According to Dr. Copland, "RS5444 and other so-called PPAR-gamma drugs, which were originally created to treat diabetes because they help regulate glucose metabolism, are in development or being tested as cancer therapies. Taken orally, RS5444 requires 1,000-fold less dosage than current Food and Drug Administration-approved drugs in this class of compounds to inhibit tumor growth."

The researchers have been seeking to identify and characterize the molecular mechanisms underlying the cause and progression of human anaplastic thyroid carcinoma. Their goal is to develop effective molecular targeted therapies.

This cancer is extremely rare — fewer than 600 cases are diagnosed in the U.S. annually — but may be better known of late because it may have been the type of thyroid cancer that led to the death of William Rehnquist, chief justice of the United States. "It is also one of the most aggressive and deadliest known cancers, since it doesn't respond to any known treatment," says Dr. Smallridge. "The rate of survival hasn't changed in 25 years. Eighty-five percent of patients die within a year of diagnosis."

In previous work, the investigators identified a combination of drugs that reduced tumor size in animal models, strongly implicating that this regimen might benefit patients with the cancer. RS5444, developed by Daiichi Sankyo, Co., Ltd., in Japan, was one agent tested in combination with chemotherapy. Sankyo researchers discovered RS5444 in a screen for antitumor activity and then sought help from Mayo Clinic Cancer Center to further study its properties. Their encouraging findings in preclinical studies led to the launch of a multicenter Phase 1/2 clinical trial, testing use of RS5444 and paclitaxel chemotherapy in patients with the cancer. The study, led by Dr. Smallridge, is being conducted at Mayo Clinic campuses in Jacksonville and Rochester, Minn. and at eight other sites nationally.

Clinical Trial Information

This study was designed to look at the specific signaling pathways within anaplastic thyroid cancer cells that are disrupted by RS5444. Researchers had thought that because PPAR-gamma was mutated in a subset of thyroid cancers, PPAR-gamma might be acting as a tumor suppressor gene, and that turning it back on restored that function. This hypothesis made sense, because PPAR-gamma is a powerful nuclear receptor that activates genes involved in such cellular processes as differentiation, apoptosis, cell-cycle control, carcinogenesis, and inflammation.

But they found that PPAR-gamma regulates transcription of the RhoB gene. "Within several hours of administering the drug, we can see that it binds to the PPAR-gamma protein in cancer cells and activates RhoB transcription, causing expression of RhoB messenger RNA that is translated into protein. By a yet-to-be-identified mechanism, RhoB then induces the transcription of p21, thereby shutting down the cell cycle and blocking tumor growth," Dr. Copland says.

"That shows us that turning RhoB back on may be a key mechanism for regulating growth of this cancer," he says.

For proof, the researchers then turned off expression of RhoB in cells that were treated with the drug, and demonstrated that p21 could not be activated. "That shows RhoB is required for p21 transcription," Dr. Copland says.

"RhoB acts as a tumor suppressor, and it is turned off in anaplastic thyroid cancers. Turning this gene back on may lead to an effective molecular targeted chemotherapy regimen to fight this cancer," he says.

Dr. Smallridge adds, "Hitting this pathway inhibits tumor growth up to fourfold in laboratory cells and in animal experiments, and we are optimistic that it could be one cancer pathway capable of manipulation in patients. We hope there are other cancers in which RhoB is silenced, such as head and neck, brain, and lung cancers, that could benefit as well where RhoB has been shown to be down-regulated in patient tumor tissues."

Co-authors included researchers from Daiichi Sankyo, Co., Ltd., Eastern Virginia Medical School, and Mayo Clinic.

The study was funded by grants from the National Institutes of Health, Mayo Clinic Research Committee, the Florida Department of Health Bankhead Coley grant, and a grant for Rare Cancers from Dr. Ellis and Dona Brunton. Funding from the company is being used to conduct the clinical trial. Drs. Copland and Smallridge have a patent application pending on the use of molecular markers to confirm response to PPAR-gamma drugs.


Story Source:

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


Cite This Page:

Mayo Clinic. "Experimental Therapy Turns On Tumor Suppressor Gene In Cancer Cells." ScienceDaily. ScienceDaily, 20 January 2009. <www.sciencedaily.com/releases/2009/01/090120074627.htm>.
Mayo Clinic. (2009, January 20). Experimental Therapy Turns On Tumor Suppressor Gene In Cancer Cells. ScienceDaily. Retrieved October 24, 2014 from www.sciencedaily.com/releases/2009/01/090120074627.htm
Mayo Clinic. "Experimental Therapy Turns On Tumor Suppressor Gene In Cancer Cells." ScienceDaily. www.sciencedaily.com/releases/2009/01/090120074627.htm (accessed October 24, 2014).

Share This



More Health & Medicine News

Friday, October 24, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Doctor in NYC Quarantined With Ebola

Doctor in NYC Quarantined With Ebola

AP (Oct. 24, 2014) An emergency room doctor who recently returned to the city after treating Ebola patients in West Africa has tested positive for the virus. He's quarantined in a hospital. (Oct. 24) Video provided by AP
Powered by NewsLook.com
Breakfast Debate: To Eat Or Not To Eat?

Breakfast Debate: To Eat Or Not To Eat?

Newsy (Oct. 23, 2014) Conflicting studies published in the same week re-ignited the debate over whether we should be eating breakfast. Video provided by Newsy
Powered by NewsLook.com
Ebola Fears Keep Guinea Hospitals Empty

Ebola Fears Keep Guinea Hospitals Empty

AP (Oct. 23, 2014) Fears of Ebola are keeping doctors and patients alike away from hospitals in the West African nation of Guinea. (Oct. 23) Video provided by AP
Powered by NewsLook.com
Despite Rising Death Toll, Many Survive Ebola

Despite Rising Death Toll, Many Survive Ebola

AP (Oct. 23, 2014) The family of a Dallas nurse infected with Ebola in the US says doctors can no longer detect the virus in her. Despite the mounting death toll in West Africa, there are survivors there too. (Oct. 23) Video provided by AP
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:

Strange & Offbeat Stories


Health & Medicine

Mind & Brain

Living & Well

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