Experimental Drug Turns on Tumor Suppressor Gene in Cancer Cells

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.

In the study 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.

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 anti-tumor 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 multi-center 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.