Edward Parker Whitfield

Introduction: Anaplastic thyroid carcinoma (ATC) arises in the follicular cells of the thyroid gland⁵. Unlike the 90% of follicular carcinomas that are well differentiated, ATC exhibits a high level of dedifferentiation, local aggression, metastasis, and fatality^5,6. ATC has distant metastases in 50% of patients at the time of diagnosis, and rapid local progression leading to suffocation is the most common cause of death⁵.  ATC accounts for 1-2% of all thyroid cancers with 1-2 cases per million per year in the US, and has a median survival time of 5-6 months with only 10-15% of patients surviving 2 years after presentation⁵.  The ineffectiveness of current treatments including, chemotherapy, radiation, and surgery has led to pursuit of novel therapies including the inhibition of tumor angiogenesis⁵. Some potential avenues for angiogenesis inhibition in ATC are the drugs apatanib and CLM3, and the oncolytic virus dl922-947^1,3,8. Methods: A combination of in vitro human ATC cell line experiments and nude mice ATC tumor model experiments were run to investigate these treatment options. Results: Apatanib decreased angiogenic proteins ANG (angiogenin) and VEGFR2 (vascular endothelial growth factor receptor) in human ATC cells in vitro³. CLM3 was shown to decrease activation of ERK1/2 (extracellular regulated kinase) pathways in vitro, which inhibits endothelial cell proliferation¹ . CLM3 was also shown to decrease VEGF and tumor microvessel density in vivo in mice growing human ATC tumors¹. Adenovirus dl922-947 was shown to decrease Interleukin 8 (a promoter of cellular proliferation and migration) levels, and tumor microvessel density in vivo in mice growing human ATC tumors⁸. Conclusion: The metastatic and local aggressiveness of ATC are dependent on tumor neovascularization to supply nutrients for growth. This makes angiogenesis a good target for new therapies. In light of the evidence that the above treatment methods did significantly inhibit angiogenesis in ATC cell lines and tumors it is possible that these treatments will be able to improve the decidedly poor prognosis that currently comes with ATC.

1. Antonelli A, Bocci G, Fallahi P, et al. CLM3, a Multitarget Tyrosine Kinase Inhibitor With Antiangiogenic Properties, Is Active Against Primary Anaplastic Thyroid Cancer In Vitro and In Vivo. The Journal of Clinical Endocrinology & Metabolism. 2014;99(4). doi:10.1210/jc.2013-2321.
2. Glaser SM, Mandish SF, Gill BS, Balasubramani GK, Clump DA, Beriwal S. Anaplastic thyroid cancer: Prognostic factors, patterns of care, and overall survival. Head & Neck. 2016;38(S1).doi:10.1002/hed.24384.
3. Jin Z, Cheng X, Feng H, et al. Apatinib Inhibits Angiogenesis Via Suppressing Akt/GSK3β/ANG Signaling Pathway in Anaplastic Thyroid Cancer. Cellular Physiology and Biochemistry. 2017;44(4):1471-1484. doi:10.1159/000485583.
4. Liu G, Wu K, Sheng Y. Elucidation of the molecular mechanisms of anaplastic thyroid carcinoma by integrated miRNA and mRNA analysis. Oncology Reports. 2016;36(5):3005-3013. doi:10.3892/or.2016.5064.
5. Molinaro E, Romei C, Biagini A, et al. Anaplastic thyroid carcinoma: from clinicopathology to genetics and advanced therapies. Nature Reviews Endocrinology. 2017;13(11):644-660. doi:10.1038/nrendo.2017.76.
6. Papp S, Asa SL. When Thyroid Carcinoma Goes Bad: A Morphological and Molecular Analysis. Head and Neck Pathology. 2015;9(1):16-23. doi:10.1007/s12105-015-0619-z.
7. Penna GC, Vaisman F, Vaisman M, Sobrinho-Simões M, Soares P. Molecular Markers Involved in Tumorigenesis of Thyroid Carcinoma: Focus on Aggressive Histotypes. Cytogenetic and Genome Research. 2017;150(3-4):194-207. doi:10.1159/000456576.
8. Passaro C, Borriello F, Vastolo V, et al. The oncolytic virus dl922-947 reduces IL-8/CXCL8 and MCP-1/CCL2 expression and impairs angiogenesis and macrophage infiltration in anaplastic thyroid carcinoma. Oncotarget. 2015;7(2). doi:10.18632/oncotarget.6430.
9. Vosgha H, Ariana A, Smith RA, Lam AK-Y. miR-205 targets angiogenesis and EMT concurrently in anaplastic thyroid carcinoma. Endocrine-Related Cancer. 2018;25(3):323-337. doi:10.1530/erc-17-0497