A promising new anti-cancer drug will be tested against several forms of thyroid cancer in a newly opened clinical trial at the Siteman Cancer Center of Washington University School of Medicine in St. Louis and Barnes-Jewish Hospital. Previous research showed that the compound, called 17AAG, has the unusual ability to simultaneously affect multiple proteins implicated in human cancers.
Administered by the Phase II Consortium at the Mayo Clinic, which carries out trials of new anti-cancer drugs, and funded through the National Cancer Institute (NCI), the trial will be conducted at several centers around the country.
Study head Jeffrey Moley, M.D., associate director of clinical investigations at the Siteman Center and professor of surgery, initiated the clinical trial of 17AAG (17-allylamino, 17-demethoxygeldanamycin) after tests in his laboratory demonstrated the drug inhibited growth of thyroid tumor cells in culture.
"We contacted the Phase II Consortium and the NCI with our initial results, and they quickly agreed to set up this trial," says Moley, who is well-known for developing pioneering surgical techniques for management of recurrent thyroid cancers and preventing hereditary thyroid cancer. "This is the first and only NCI-funded therapeutic clinical trial for thyroid cancer that I know of."
The clinical trial will have two arms. One will test the ability of 17AAG to reduce metastatic tumors in differentiated thyroid cancers that were not cured by surgery and radiotherapy. The other arm will examine the drug's effect on metastatic medullary thyroid cancer (MTC), a form that is much harder to treat.
Physicians treat MTC surgically through removal of primary and secondary tumors. More than half of MTC patients treated with surgery will experience a recurrence of the cancer.
"MTC currently has no effective chemotherapy," Moley says. "Unlike other forms of thyroid cancer, MTC tumors don't absorb iodine, so standard therapy with radioactive iodine is of no use against the disease. Similarly, there's no effective chemotherapy for other forms of thyroid cancer once they advance to a stage where they don't take up iodine anymore."
Many thyroid tumors arise from mutations in a gene called RET. The mutations cause cancerous cell growth by turning up the RET protein's activity, so the RET protein is potentially a key target for treating thyroid cancer. The activity of the RET protein was decreased by 17AAG in studies in Moley's laboratory.
Interestingly, 17AAG doesn't directly affect the RET protein. Instead, it interferes with an abundant chaperone protein that nurses the RET protein through its formative stages.
The fact that the drug influences this important chaperone protein, called heat shock protein 90, has focused much scientific attention on 17AAG. 17AAG is one of the few compounds known to specifically inhibit heat shock protein 90, which oversees the formation of innumerable proteins that cells need to function.
Cancer cells have higher amounts of heat shock protein 90 and are especially dependent on it for growth and survival. Because cancer cells have alterations in many cell proteins and signaling pathways, it is thought that the chaperone, with its ability to affect multiple cellular pathways, represents a unique point at which to tackle and cripple cancer cells.
17AAG is currently in use in clinical trials against melanoma and ovarian, breast and prostate cancers, in addition to thyroid cancer. It has been shown to have milder side-effects than most other types of chemotherapeutic agents. It's effectiveness as a chemotherapeutic agent in these trials has not yet been established.
Patients interested in participating in the clinical trial of 17AAG against metastatic thyroid cancer should call 314-747-5591. To be eligible, patients must have thyroid tumors one centimeter or larger and be 18 years or older. All participants will receive the drug.
Funding from the National Institutes of Health supports this research.
Washington University School of Medicine's full-time and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked third in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.