NCI GRANT WILL HELP RESEARCHERS PROBE MECHANICS OF METASTATIC PROGRESSIVE THYROID CANCER

The National Cancer Institute has awarded a $2.25 million, five-year grant to a team of OSUCCC – James researchers who identified a new pathway that inhibits thyroid cancer metastasis so that therapeutic targets and/or biomarkers can be devised.

In previous studies funded by the NCI, the researchers, led by principal investigator Matthew Ringel, MD, co-leader of the Cancer Biology Program at the OSUCCC – James, identified a gene called regulator of calcineurin 1.4 (RCAN1.4) as a metastasis suppressor. They found that the loss of this gene results in cancer progression by inducing a transcription factor known as Nrf3 that promotes thyroid cancer cell growth and invasion, and is associated with poor prognosis.

The researchers state in their new project abstract that thyroid cancer provides an outstanding model to identify regulators of late-stage cancer progression “due to its typical long latency and the often rapid pace of end-stage progression.” They explain that they have focused on defining genomic alterations in distant metastatic lesions of this disease and have identified RCAN1.4 as a new metastasis suppressor, a function that subsequently has been reported in other solid tumors.

By studying human tissues, human cell lines, mouse xenografts and newly developed genetically engineered mouse models, the team also has discovered, among other things, that overexpression of Nrf3 “is associated with a permissive type 1 immune environment in human thyroid cancer” and that it directly binds to the interleukin 8 (IL8) cytokine promoter and regulates its activity, “suggesting a mechanistic role in regulation of the tumor-immune interface” in this disease.

Ringel, a thyroid cancer specialist who also directs the Division of Endocrinology, Diabetes and Metabolism at Ohio State and is co-director of the Center for Cancer Engineering, and his lab colleagues say their new study will enable them to test their central hypothesis that RCAN1.4 loss and Nrf3 overexpression “induce a tumorigenic and pro-metastatic immune environment that facilitates thyroid cancer progression.”

This signaling pathway could then be targeted by future therapies that might improve the prognosis and offer more hope for patients with metastatic progressive differentiated thyroid cancer, a currently incurable disease.