American Thyroid Association 86th Annual Meeting:
Precision Medicine: Evolving Rapidly
Precision medicine has been developing for quite awhile, but “what's new now is that the revolution in biomedical technologies means that 'unimaginable precision' is ahead,” Thomas Cech, PhD, distinguished professor at the University of Colorado, Boulder, told attendees at a Friday plenary session at the American Thyroid Association’s 86th annual meeting in Denver, Colorado.
In fact, discussing precision medicine began in the domain of thyroid disease, according to Dr. Cech. ''The use of radioisotopes to treat hyperthyroidism and thyroid cancer, I would argue, is one of the first uses of precision medicine." This reflects the essence of this emerging approach to medical care, by accounting for individual variability in genes, environment and lifestyle in developing targeted disease management.
“What is the future of precision medicine? It won't mean 'a billion treatments for a billion patients' based on their genome," said Dr. Cech. Rather, it is likely to involve using a person's gene, or gene product data, to guide preventive medicine, to indicate what is keeping them healthy, or to guide treatment, if disease occurs.
“Already," he said, “precision medicine has made headway in shifting conventional disease-oriented thinking to a more biologically defined, personalized approach for picking the proper drugs." For instance, blood, tissue or imaging markers might be used to identify which patients would be helped by a particular drug, and which would not.
Another good example of precision medicine, according to Dr. Cech, has been the use of antibody therapy for HER2/neu receptor positive breast cancers. The protein is overexpressed in 20 or 30% of breast cancers; using the antibody therapy may prevent proliferation.
Dr. Cech, who won the Nobel Prize in chemistry, in 1989, with Sidney Altman, for the discovery of catalytic properties of RNA, has focused recently on cloning and sequencing the gene for the catalytic subunit of human telomerase, the enzyme that adds nucleotides to telomeres in cancer and other cells. Mutations in the enzyme have been linked with numerous cancers, although not for thyroid.
Dr. Cech called telomerase the immortality enzyme. “Reactivation of telomerase,“ he said, “allows cancer cells to be immortal, obviously not a good thing.” Too little telomerase has been linked with Dyskeratosis congenital, aplastic anemia and pulmonary fibrosis; and, reactivation of it is involved in 90% of human cancers.
TERT (telomerase reverse transcription) described a catalytic subunit of the enzyme. TERT promoter mutations have been linked with many cancers. Tumor-specific point mutations in the TERT promoter are recurrent in numerous cancers, according to Dr. Cech, including gliobastoma, bladder cancer and liver.
“The mutation occurs upstream from the protein coding region, the area recently suspected as the site. These TERT promoter mutations are the most common non-coding mutation, and in many are the most common mutations," he said. It results in more of the protein being made, longer telomeres, and more immortality. The same mutation has been found in 80% of melanoma samples globally, Dr. Cech said.
"It's not found in thyroid cancer, but it's still of interest. Telomerase still gets activated in thyroid cancer. Researchers have yet to find the exact mutation that activates it,” he said. “Higher expression of TERT has been linked with lower survival in several other cancers. We need to think about therapeutics that would down regulate.”
“A bacterial ‘immune system’ known as CRISPR-Cas9 can cleave DNA in human cells and allow introducing precise genetic mutations and deletions in human cells for research purposes,” Dr. Cech said. After the cleavage, the genome is edited by way of internal repair pathways.
''All that the CRISPR-Cas 9 does is cut the DNA," Dr. Cech explained. "The cutting by itself isn't editing. It's the cell's own DNA repair machinery that completes the job. It's a kind of emergency repair.”
Another option is to use another copy of the gene for repair. Clinically, precision medicine is good news for patients, according to Dr. Cech.
One reason: "As cancer becomes more and more controlled, we can have to back off on therapy, so as not to cause long term damage." Precision medicine will help achieve that goal.
Dr. Cech reports being on the board of directors for Merck.
Antonio Bianco, MD, PhD, president of the American Thyroid Association, and dean of clinical affairs at Rush Medical College, Chicago, commented on the Dr. Cech lecture. "This is the way things are moving along," he says of precision medicine.
“Precision medicine, including Dr. Cech's work, is expected to play a major role in thyroid cancer,” Dr. Bianco said. “And, also in hypothyroidism. Theoretically, knowing a person's genetic information before treatment, such as the mutations that Dr. Cech study’s, will produce better [outcome] results.”