BRAF and COX-2 as Targets for Therapy of Thyroid Cancer

Abstract

In the world of cancer, thyroid cancer has a pretty good reputation. Relatively speaking, it's one of the easier malignancies to diagnose and treat successfully. Studies show that the vast majority of patients who develop the most common forms of the disease (papillary or follicular thyroid cancer) and who undergo surgery and treatment with radioactive iodine will be alive 10 years later.

But the successful track record has come at a cost. Until recently, the field of thyroid cancer has attracted only a trickle of federal research funding - support that has flowed readily into cancer research as a whole.

But that's begun to change, says Dr. Manisha Shah, assistant professor of internal medicine at The Ohio State University Comprehensive Cancer Center and a specialist in endocrine tumors at The Ohio State University Arthur G. James Cancer Hospital and Richard J. Solove Research Institute. Shah says scientists have only recently discovered some of the genetic and biological signatures specific to thyroid cancer, and that may be prompting new interest in thyroid cancer research. In addition, thyroid cancer has emerged as one of the fastest-growing cancers in the United States, increasing in incidence at the rate of 3 percent per year. As a result, investigators are finally attracting the dollars they need to create and study a number of emerging treatments.

Shah and her colleagues in The OSU Comprehensive Cancer Center are conducting clinical trials evaluating two of those new options. One of the studies involves the use of a compound known simply as BAY 43-9006, a new, targeted therapy designed to attack advanced thyroid cancer at its molecular roots. Shah is also directing a second trial examining the popular pain reliever Celebrex as a treatment for metastatic thyroid cancer.

Even though standard treatment is curative in a large majority of patients, the risk of recurrent thyroid cancer doesn't wholly disappear with time. Thyroid cancer can be tricky; it can reappear many years later - as long as 20 to 30 years after the initial diagnosis. At that point, treatment options are often limited. In addition, patients who develop one of the lesser-known and often more aggressive forms of the disease, like anaplastic thyroid cancer, find themselves in a similar situation.

"There just isn't that much out there," says Shah. "People may not be aware that chemotherapy really isn't very useful at any point in treating thyroid cancer," she adds.

Generally, most newly diagnosed patients will undergo surgery and then take one course of radioactive iodine. They also almost always take medication to regulate production of TSH, the hormone produced by the pituitary glad that prompts the thyroid gland to make thyroid hormone. Scientists believe that lower levels of TSH can help keep thyroid cancer at bay.

And today, patients may benefit from the new forms of intervention. Celebrex, for example, is designed to inhibit the activity of an enzyme called COX-2, generally found in inflammation and in the development of some solid tumors.

"Metastatic cancer cells overexpress COX-2 like crazy," Shah says. "This is a big problem because overexpression of COX-2 stimulates the creation of new blood vessels to feed the tumor's growth, and it inhibits normal cell death, as well," says Shah. Celecoxib is designed to reverse those processes.

Patients enrolled in a Phase II Celebrex study at the OSU James Cancer Hospital simply take two pills twice daily. Those whose tumors shrink or remain stable will stay on the study for at least a year while physicians watch them closely for any signs of side effects. Shah says it is still too early to make any definitive statements about the efficacy of the approach, although it appears that it may be helpful in only a small minority of patients.

Ohio State Drs. Matthew Ringel, associate professor in the department of internal medicine, and Dr. Richard Kloos, associate professor of clinical internal medicine and radiology, are thyroid cancer experts and co-investigators with Shah on the BAY 43-9006 trial. Both see many patients with thyroid cancer and study the molecular markers of the disease in Ringel's laboratory in the OSU Comprehensive Cancer Center.

Ringel says BAY 43-9006 may be able to block the effects of a gene known as BRAF, which, when "turned on" - as it is in about 40 percent of all papillary thyroid cancer - allows cancer cells to grow out of control. The BRAF gene is part of an important cascade of cell signals called the RAS pathway that often runs amok in many forms of cancer. Kloos adds that multiple mechanisms may be at work in stimulating overexpression of BRAF, and adds that BAY43-9006 may modulate them as well.

BAY 43-9006 is also designed to slow angiogenesis, the process the body uses to build new blood vessels, by blocking a key growth factor (VEGF, or vascular endothelial growth factor) tumors use to encourage the development of new feeder lines. Ringel's laboratory will be evaluating patients' tumors to determine if any changes in particular genes or biomarkers can help predict which patients will respond to the medication.

Like those in the Celebrex study, participants in the BAY 43-9006 trial will take only a small number of pills daily. In addition, however, they will undergo blood tests, CT, functional MRI (magnetic resonance imaging) or PET (positron emission tomography) scans and other studies so researchers can get a precise handle on things like the density of the blood vessels in their tumors, or which genes or proteins have been altered by the treatment.

According to the American Cancer Society, about 23,600 new cases of thyroid cancer will be diagnosed this year in the United States. Statistics reveal that the disease is three times more likely to occur in women than in men, but it is more frequently fatal in men.

"It is too early to know which, if either, of these new methods under study here is effective in treating our patients," says Shah. "We have gone a long time without any new direction in the treatment of thyroid cancer. We hope these initiatives will help some of our patients and give us some insight into what we need to do next."

The Ohio State University Comprehensive Cancer Center is a network of interdisciplinary research programs with over 200 investigators in 13 colleges across the OSU campus, the Arthur G. James Cancer Hospital and Richard J. Solove Research Institute and Children's Hospital, in Columbus. OSUCCC members conduct research on the prevention, detection, diagnosis and treatment of cancer, generating over $95 million annually in external funding.