Posted September 9, 2022

Thyroid cancer occurs when malignant cells develop in the thyroid, an organ at the base of the throat. There are multiple types of thyroid cancer. Differentiated thyroid cancers (DTCs) comprising of papillary and follicular, account for 90% of all thyroid cancers. Treatment for DTCs includes surgery to remove the thyroid gland and radioiodine therapy, resulting in favorable long-term prognoses for a majority of patients. Other types of thyroid cancer include medullary and anaplastic thyroid cancer. Medullary thyroid cancer develops from cells in the thyroid that regulate calcium levels in the blood. Approximately 25% of medullary thyroid cancers have an inherited component.¹ Anaplastic thyroid cancer remains the most aggressive and rarest form of thyroid cancer and accounts for 2% of all thyroid cancers. Anaplastic thyroid cancer grows rapidly from undifferentiated cells and is very difficult to treat due to its rapid rate of metastasis; as a result, anaplastic thyroid cancer has a very poor prognosis.²

Thyroid cancer incidence has been increasing in the United States, with an estimated 43,800 new cases diagnosed in 2022.³ Experts debate the reason for this increase, which may be due to more screening and/or exposures to environmental or occupational risk factors such as exposures to radiation or chemicals, such as pesticides.⁴ A clear need exists to understand the link between exposures and thyroid cancer development and to investigate new treatments for patients that do not respond to the standard of care.

Thyroid Cancer Aggressiveness in Agent Orange-Exposed Veterans
Maaike van Gerwen, M.D., Ph.D., Icahn School of Medicine at Mount Sinai

Dr. van Gerwen currently leads the Thyroid Cancer Research Program in the Department of Otolaryngology - Head and Neck Surgery and Institute for Translational Epidemiology at the Icahn School of Medicine at Mount Sinai and focuses on investigating environmental exposures and thyroid cancer risk. U.S. military personnel during the Vietnam War were at risk of exposure to the herbicide Agent Orange; additionally, many of the planes that transported Agent Orange were still in use through the 1980s, extending the risk of exposure past the end of the war. Agent Orange was contaminated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which has since been classified as an endocrine-disrupting chemical and a human carcinogen associated with increased thyroid cancer risk.⁵ The main objective of Dr. van Gerwen’s Fiscal Year 2020 (FY20) Career Development Award is to investigate the association of Agent Orange exposure and thyroid cancer aggressiveness in Vietnam War Veterans, thus seeking to link environmental exposures to cancer. Results of this study will improve current management protocols for thyroid cancer patients by implementing surveillance protocols or more aggressive treatment options in exposed patients. Further, this research will inform future studies investigating the risks of exposure to other endocrine-disrupting chemicals present in the environment, including those characterized as “forever chemicals” (chemicals that do not degrade).

Overcoming Dedifferentiation of Pediatric Thyroid Cancer Through Molecularly Targeted Therapy
Theodore Laetsch, M.D., and Aime Franco, Ph.D., Children’s Hospital of Philadelphia

Pediatric differentiated thyroid cancer (PedDTC) is the most common childhood thyroid malignancy. When metastatic, there is a high risk of persistent disease, even after surgical removal of the thyroid and radioiodine therapy. The majority of PedDTC tumors are caused by activating mutations in kinases. Even though targeted therapies exist for these kinases, it is unknown how to integrate these therapies into the current standard of care for PedDTC. With an FY21 Translational Team Science Award, Dr. Laetsch, an oncologist, and Dr. Franco, an endocrinology researcher, plan to investigate the use of kinase inhibitors in treating PedDTC. One arm of the project consists of preclinical studies to understand how the mutated kinases cause the cellular changes that lead to PedDTC and how inhibiting the mutated kinases impacts sensitivity to radioiodine therapy. The second arm of this project is a multisite clinical trial for PedDTC patients with lung metastases. These patients will be treated with targeted therapy to evaluate changes in response to radioiodine therapy. Outcomes of this project will inform larger clinical trials and impact the standard of care for PedDTC patients.

Mechanisms of Metastasis Suppression and Translational Applications in Thyroid Cancer
Matthew Ringel, M.D., and Aleksander Skardal, Ph.D., The Ohio State University

DTC incidence has risen over the past few decades. Changes in the genomic drivers of DTC have also occurred, suggesting that environmental factors (such as exposure to ionizing radiation and chemicals) are influencing the biology of DTC, leading to increased incidence and more aggressive disease.⁶ For patients who do not respond to standard-of-care therapy, DTC is characterized by periods of dormancy and disease stability followed by rapid disease progression. Dr. Ringel previously demonstrated that this disease progression is due to a loss of expression of genes, called metastasis progression suppressors (MPS), and identified a new MPS gene, RCAN1.4. Suppression of RCAN1.4 drives DTC disease progression and metastasis.⁷ With an FY21 Impact Award, Dr. Ringel hypothesizes that RCAN1.4 loss alters the tumor microenvironment. Dr. Ringel will collaborate with Dr. Skardal, a biomedical engineer, to use an innovative metastasis on a chip system that consists of tumor organoids that maintain immune cells and their genomic signatures. The overall objective is to elucidate how RCAN1.4 regulates immune suppression, which will lead to the development of biomarkers and potential therapeutic targets to improve outcomes for patients with DTC.

References:

¹https://www.cancer.org/cancer/thyroid-cancer/about/what-is-thyroid-cancer.html

²https://www.thyroid.org/anaplastic-thyroid-cancer/

³https://www.cancer.gov/types/thyroid

⁴Fiore M, Oliveri Conti G, Caltabiano R, et al. 2019. Role of emerging environmental risk factors in thyroid cancer: A brief review. International Journal of Environmental Research and Public Health 16(7):1185. Published 2019 Apr 2. doi:10.3390/ijerph16071185

⁵Le KT, Sawicki MP, Wang MB, et al. 2016. High prevalence of agent orange exposure among thyroid cancer patients in the national VA healthcare system. Endocrine Practice 22:699-702.

⁶Jung CK, Little M P, Lubin J H, et al. 2014. The increase in thyroid cancer incidence during the last four decades is accompanied by a high frequency of BRAF mutations and a sharp increase in RAS mutations. The Journal of Clinical Endocrinology and Metabolism 99(2):E276-E285. doi:10.1210/jc.2013-2503

⁷Wang C, Saji M, Justiniano S E, et al. 2017. RCAN1-4 is a thyroid cancer growth and metastasis suppressor. JCI Insight 2:e90651.

Links:
Abstracts for Dr. van Gerwan
Public and Technical Abstracts: Thyroid Cancer Aggressiveness in Agent Orange-Exposed Veterans

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Last updated Thursday, September 8, 2022