Moving toward a better understanding of radioiodine action

Abstract

The selective tropism for thyroid tissue makes radioiodine (RAI or I) a unique targeted therapy for both benign and malignant thyroid disorders. The efficacy of I is reliant upon uptake and retention of the isotope in thyrocytes to achieve doses of ionizing radiation sufficient to elicit clinically meaningful cytotoxicity. The processes that govern this can be impaired, eliminating I effectiveness or requiring the administration of higher activity that can lead to greater toxicity. Gaining insight into biologic mechanisms of I action is critical for rationally devising therapeutic strategies to circumvent the limitations to I therapy that are commonly encountered clinically. In this issue of endocrine, Russo et al. [1] evaluate the mechanism of I-mediated cytotoxicity. The investigators approached this question by developing a method for culturing small thyroid tissues for up to 3 weeks in vitro. The advantage of this approach is the preservation of some of the three-dimensional follicular architecture that better represents the spatial considerations relevant in vivo. Using this model, the investigators observed that I induced apoptosis 3 days after isotope addition. Presumably, apoptosis in this scenario is a cellular response to DNA damage incurred by ionizing radiation. Greater insight into how known DNA damage pathways may modulate this response in thyrocytes could potentially generate new hypotheses for how to increase I efficacy and/or diminish the activity required to generate therapeutic response. Understanding how I elicits cytotoxicity is also relevant for informing the therapeutic use of I for recurrent and/or metastatic differentiated thyroid cancers. RAIrefractory (RAIR) thyroid cancer continues to be a challenging clinical problem. Without I, the continuous administration of palliative chemotherapy remains the only systemic option for these patients, which can be associated with cumulative toxicity and acquired drug resistance. It is conceivable that alterations in the DNA damage response presumably necessary for theI induced apoptosis observed by Russo and colleagues could serve as a mechanism of resistance in RAIR disease. Much of the research regarding RAIR thyroid cancer, however, has been focused upon the mechanisms by which thyroid tumors lose the ability to concentrate I. Indeed, the loss of RAI avidity has been correlated to significantly worse prognosis for patients with thyroid cancer [2], and efforts to address I resistance have largely focused upon developing strategies to restore RAI incorporation in tumors. The loss of RAI avidity has been associated with diminished expression of a subset of thyroid specific genes, including the sodium iodide symporter (NIS) which mediates iodide uptake into thyroid cells. Strategies to ‘‘redifferentiate’’ tumors and restore expression of these key genes to enhance RAI incorporation have been attempted, but unfortunately yielded at best only modest benefit [3–6]. More recently, significant progress has been made with the recognition from several groups that the aberrant activation of the mitogen-activated protein kinase (MAPK) signaling pathway that occurs in about 70 % of papillary thyroid cancers (PTC) via mutually exclusive genetic alterations (i.e., RET, NTRK, RAS, and BRAF) leads to the diminished expression of genes that govern RAI incorporation in tumors. Pharmacologic inhibition of the pathway in a murine model of PTC driven by oncogenic BRAF successfully restored NIS expression and RAI avidity [7]. Based on this, a pilot study was performed to test if A. L. Ho (&) Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA e-mail: hoa@mskcc.org