AACE 2011: Personalizing Cancer Therapy Based on Molecular Markers and Models

Molecular medicine is the future of cancer treatment, but also has many potential applications in endocrinology.

"I love to talk to large audiences outside of cancer because so much of what we do in cancer is applicable to other conditions,” said David Sidransky, MD, to attendees at the 20th Annual Meeting and Clinical Congress of the American Association of Clinical Endocrinologists. Sidransky is professor of Otolaryngology—Head and Neck Surgery, Oncology, Pathology, Urology, and Cellular and Molecular Medicine, and director at the Head and Neck Cancer Research at Johns Hopkins. He described the future of molecular medicine, which has been the focus of his research for the last two decades.

“Let me just say a few words about cancer. It is really caused by accumulation of genetic and epigenetic changes. There is often very little we can do about genes, but we can look for drivers in cells that direct the cancer process.” Relevant oncogene mutations account for 95% of cancers, he explained. Among these are mutations in the BRAF gene. His and others’ labs found BRAF mutations in 50% of thyroid cancers. Perhaps most important, according to Sidransky, is the mutations were not present in follicular or benign lesions. “This demonstrates beautiful bifurcation and an extremely specific marker.” His lab also found 60% of papillary thyroid cancers have the BRAF mutation. Therefore BRAF can be effective in detecting and diagnosing cancer, and is a target in drug development. Studies have shown a correlation between clinicopathologic characteristics and BRAF mutation status (positive or negative) in patients with papillary thyroid cancer. And BRAF mutations are also associated with patient outcomes; in a study with mice, those with BRAF therapy lived longer.

Moving away from thyroid cancer, Sidransky discussed gene sequencing. The Cancer Genome Atlas (TCGA) has been sequencing genes and filling in holes from the mutation point of view with information that was missing for decades. This is interesting from cataloging point of view, explained Sidransky, but the challenge is interpretation. Gene sequencing is expensive, so what is it really worth to the patient? One answer lies in the number of mutations found. There may be a typical number of mutations necessary before a lesion turns into cancer, and this varies depending on type of cancer. So theoretically that could affect whether or not treatment is initiated or when. To demonstrate a more practical and clinical application of genetic sequencing, he described a particularly exciting study with a patient who had pancreatic cancer, but started with some background. The KRAS mutation is present in 85% of pancreatic cancers, and other mutations such as ERBB4 and SMAD2 have been reported, though less frequently. The ERBB4 gene encodes erbB-4, which is a receptor tyrosine-protein kinase. Lapatinib, which is an inhibitor of 2 tyrosine kinases targeted in breast cancer, was used to treat the patient with pancreatic cancer. Tumor markers in the patient dropped after 2 months, sending the patient into remission. Sidransky emphasized the point that although clinicians didn’t have the exact tool they wanted, something else was available. He strongly suggested reviewing the literature to learn more about which tumors show which mutations.

He concluded his talk by discussing xenografting. Typically, with xenografting, “the tumor is dead, lying on the table,” Sidransky said. However, it doesn’t necessarily reflect what is going on with living tissue. Despite this apparent limitation, studies have shown “miracle” patients responding to treatment based on xenografting data.

“It is important to individualize therapy, but doing sequencing and grafting is not cheap. Right now these will remain in the academic setting only or be available for a select few,” said Sidransky. “Ultimately, we want to identify cell lines and markers that are more resistant or sensitive to specific treatments.”