New Model of Human Papillary Thyroid Carcinoma Provides Clues to Drug Resistance

Findings suggest a possible therapeutic approach to metastatic thyroid cancer

---

BOSTON – A scientific team led by investigators at Beth Israel Deaconess Medical Center (BIDMC) has developed new experimental models to evaluate targeted therapies for the treatment of papillary thyroid carcinoma (PTC). PTC is the most common type of thyroid cancer, and incidence of the disease is increasing worldwide. The team’s findings, published online in the open-access journal Oncotarget, suggest that combination therapy might offer a new therapeutic strategy for metastatic PTC.

“Molecular analysis of this cancer shows that nearly 60 percent of PTC cases contain a mutation called BRAF-V600E,” explained senior author Carmelo Nucera, MD, PhD, an investigator in the Department of Pathology at BIDMC. “This mutation increases the cancer’s ability to metastasize, or spread to other organs.”

Although targeted therapies that inhibit the BRAF mutation have been successful for the short-term treatment of melanoma and other types of cancer, it has been found that the tumors eventually regrow, becoming more aggressive and resistant to drugs.

“The goal of our study was to generate and test experimental models in both PTC cell cultures and in a mouse model to evaluate therapeutic responses of BRAF inhibitors for the treatment of PTC,” said Nucera, who is also Assistant Professor of Pathology at Harvard Medical School and a member of the Cancer Research Institute and the Center for Vascular Biology Research at BIDMC.

Nucera and colleagues developed three models. The first consisted of normal patient-derived thyroid cells; the second was a model of BRAF-V600E mutation in papillary thyroid cells, and was divided into subgroups of PTC with and without metastasis. The third model consisted of PTC cells without BRAF-V600E mutation.

The scientists went on to test selected BRAF-V600E inhibitors in each of the three models and found significant anti-tumor activity in PTC cells with BRAF-V600E mutation with no metastasis. “It seems that metastasis elicits some intrinsic resistance to these inhibitors,” Nucera said.

The scientists next conducted experiments to determine the mechanism underlying the drug resistance. “We screened patient PTC samples, both with and without metastasis,” said Nucera. “We found two mechanisms that were involved in BRAF-V600E-positive PTC with metastasis: the pro-survival factor MCL1 (1q), which is genomically upregulated and the cell cycle inhibitor P16 (9p), which is genomically deregulated.”

Finally, the researchers combined BRAF-V600E inhibitors with pro-survival inhibitors and discovered that combined therapy was more effective than a single agent treatment at overcoming intrinsic resistance in PTC cells. “Our new models suggest that this combination of targeted drugs might be a crucial therapeutic strategy for metastatic and refractory BRAF-V600E positive PTC,” Nucera noted.

This study was supported by grants from the National Cancer Institute (1R21CA165039-01A1, 1R01CA181183-01A1) as well as support from the American Thyroid Association and ThyCa, and the Thyroid Cancer Survivors Association Inc. for Thyroid Research.

Study coauthors include Mark Duquette (first author), Jennifer N. Sims, Zeus A. Antonello, Amjad Husain and Pier Paolo Pandolfi; Peter M. Sadow, Vania Nose and Dora Dias-Santagata of Massachusetts General Hospital; Andrew H. Fischer of the University of Massachusetts; Chen Song, Elena Castellanos-Rizaldos, G. Mike Makrigiorgos and Paul Van Hummelen of the Dana-Farber Cancer Institute; Junichi Kurebayashi of Kawasaki Medical School; Roderick T. Bronson of Harvard Medical School; and Michelle Vinco and Thomas J. Giordano of the University of Michigan