Redifferentiation of Radioiodine Refractory Differentiated Thyroid Cancer for Reapplication of I-131 Therapy

Abstract

Although most differentiated thyroid cancers show excellent prognosis, treating radioiodine refractory differentiated thyroid cancer (RR-DTC) is challenging. Various therapies, including chemotherapy, radiotherapy, and targeted therapy, have been applied for RR-DTC but show limited effectiveness. Redifferentiation followed by radioiodine therapy is a promising alternative therapy for RR-DTC. Retinoic acids, histone deacetylase inhibitors, and peroxisome proliferator-activated receptor-gamma agonists are classically used as redifferentiation agents, and recent targeted molecules are also used for this purpose. Appropriate selection of redifferentiation agents for each patient, using current knowledge about genetic and biological characteristics of thyroid cancer, might increase the efficacy of redifferentiation treatment. In this review, we will discuss the mechanisms of these redifferentiation agents, results of recent clinical trials, and promising preclinical results.

Keywords: I-131; NIS; differentiated thyroid cancer; radioiodine refractory; redifferentiation.

Figure 1

Redifferentiation of thyroid cancer schematic. MAPK (RAS/RAF/MEK) and PI3K/AKT/mTOR pathways are main signaling pathways in thyroid carcinogenesis. Extracellular signals activate RTK and RAS, which in turn activates RAF (mainly BRAF in differentiated thyroid cancer). Activated BRAF phosphorylates and activates the MEK, which in turn phosphorylates and activates ERK. Phosphorylated ERK translocate into the nucleus, where it regulates transcription of the genes involved in cell differentiation, proliferation, survival, and thyroid-specific genes transcriptions. PI3K/AKT activates mTOR which is a key regulator of cell proliferation, inhibitor of apoptosis, and thyroid-specific genes transcriptions. Signaling cascade can be blocked by new targeted therapies. RA binds to nuclear receptors designated as RA receptors (RAR) or retinoid X receptors (RXR). PPARγ agonists bind to RXR and form heterodimers and regulate the transcription of various genes. RAR or RXR complexes bind to the responsive elements in gene promoter sites and activate the transcription of their target genes. HDAC is an enzyme that acetylates histone and silences gene expression; HDAC inhibitors increase gene expression at an epigenetic level. RTK, receptor tyrosine kinase; VEGFR, vascular endothelial growth factor receptor; RET, rearranged during transfection; PDGFR, platelet-derived growth factor receptors; HER, human epidermal growth factor receptor; PI3K, phosphoinositide 3-kinase; PIP2, phosphatidylinositol 4,5-bisphosphate; PIP3, phosphatidylinositol (3,4,5)-trisphosphate; PTEN, phosphatase and tensin homolog; PDK-1, pyruvate dehydrogenase lipoamide kinase isozyme 1; AKT, protein kinase B; mTOR, mechanistic target of rapamycin; RAS, rat sarcoma; RAF, rapidly accelerated fibrosarcoma; MAPK, mitogen-activated protein kinase kinase; ERK, extracellular signal-regulated kinase; HDAC, histone deacetylase; PPARγ, peroxisome proliferator-activated receptor γ.