ATA News Release 2004

Small Molecule Holds Promise for Treating Deadly Thyroid Cancer

(VANCOUVER, BC, Oct. 1, 2004)—A novel small molecule provides hope for treating a deadly form of thyroid cancer, according to a new study being presented on Friday, Oct. 1, at the 76th Annual Meeting of the American Thyroid Association in Vancouver, British Columbia, Canada. Mayo Clinic researchers in collaboration with Sankyo Company scientists found that this novel small molecule, called RS-5444, works alone and in combination with other cancer therapies.

“Identifying effective combination therapies that block important pathways responsible for tumor growth and invasiveness will lead to effective treatments for patients diagnosed with this deadly and rapidly progressive disease,” said John A. Copland, PhD, Assistant Professor of Biochemistry & Molecular Biology at the Mayo Clinic Comprehensive Cancer Center and Mayo Clinic College of Medicine in Jacksonville, Fla.

Anaplastic thyroid carcinoma (ATC) is an aggressive form of cancer of the thyroid gland. An invasive type of thyroid cancer, it grows very rapidly. The cause is unknown. No effective treatment strategy — not even surgery, chemotherapy, or radiation — exists for most of these patients, who are, often, over age 60. Patients diagnosed with this type of thyroid cancer survive, on average, three to seven months.

Based on this poor prognosis, Dr. Copland, along with Robert C. Smallridge, MD, and other colleagues, wanted to explore the use of peroxisome proliferator-activated receptor gamma (PPAR) agonists to target the protein transcription factor PPAR as a potential treatment. PPAR drugs have low or little toxicity and can be taken orally, providing a big benefit to patients, instead of having to undergo chemotherapy, which has toxic effects on normal cells in the body.

PPAR inhibits cell proliferation when activated by a PPAR agonist. It was discovered in a subtype of thyroid cancer — follicular carcinoma — that a chromosomal rearrangement occurs in more than 40 percent of cases resulting in the fusion protein PAX8/PPAR. This fusion protein is nonfunctional and blocks the activity of normal PPAR? in follicular thyroid cancer, strongly suggesting that PPAR is essential to normal thyroid function and may have tumor suppressor activity. This mutation has not appeared in ATC, providing a way by which RS-5444, a novel drug therapy, can unlock mechanisms leading to reduced tumor mass and control of the cancer, explain the researchers.

They found that targeting the protein transcription factor, PPAR, inhibits tumor growth in human anaplastic tumor cells in culture. More important, however, is that the same results were found in an animal model for ATC. The data also showed that combining RS-5444 with other chemotherapeutic agents, such as retinoic acid and paclitaxel, enhances antitumor activity in cell cultures and an animal model.

“We may have discovered effective drugs that, when used together, will inhibit the rapid growth of ATC,” said Dr. Smallridge, “providing extended life and quality of life to ATC patients. Effective treatment strategies for ATC and other cancers are dependent upon using drugs in combination that block multiple signaling pathways that promote tumor cell growth and survival.”

# # #