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Modulation of the JAK/STAT pathway in advanced thyroid cancer as a potential therapeutic target: effect on iodine uptake, tumor stem cell characteristics

Abstract

Differentiated thyroid cancer (TC) is the most frequent type, with a good prognosis. However, around 10% of the cases progress with metastases, lose the ability to capture radioiodine and no longer respond to conventional radioiodine therapy. Anaplastic (ATC) carcinomas are the rarest (1-2%) and the most aggressive TC, are highly undifferentiated, do not capture radioiodine, and do not respond to chemotherapy. Patients have a survival rate of 3-12 months after diagnosis. Targeted therapies (e. g. MAKP inhibitors) are the therapeutic option for these cases. However, some patients do not respond to these therapies, become resistant or abandon due to the serious side effects, increasing mortality. Several studies showed that the JAK/STAT pathway would be a pathway activated during the TC progression and metastases. Recent transcriptome, genomic and proteomic studies have associated this pathway with drug resistance, cell dedifferentiation radioiodine resistance, and it was identified as a druggable pathway for ATC treatment. Thus, this study aims to investigate the JAK/STAT pathway as a therapeutic target for ATC, exploring the ability to modulate cancer stem cells (CSC) characteristics, increase radioiodine uptake, and attenuate drug resistance using repositioned drugs, nifuroxazide (NFZ) and metformin, and 3 NFZ derivatives. Furthermore, we propose to advance in the preclinical study of the most promising drug using 3-dimensional (3D) cultures of spheroids and patients-derivates thyroid tumors organoids. One of the biggest challenges of drug discovery is to translate the good results obtained in two dimensions cell cultures into clinical use (from bench to bed). The 3D cultures can better represent the patient's tumor characteristics such as nutrient gradients, cellular interactions, and drug penetration. Our hypothesis is that nifuroxazide and metformin, cheap and safe drugs used for decades, and the NFZ derivates are inhibitors of the JAK/STAT pathway in ATC. It was shown that NFZ modulates STAT3 in other cancers but has never been investigated in TC, as well as the new derivatives. Few studies have investigated the metformin action on JAK/STAT, being suggested the blockade of IL-6 through AMPK activation and STAT3 inhibition. ATC strains with different genotypes will be employed to determine the association between mutational background and drug response. STAT3 will be deleted with CRISPR/CAS9 to confirm the involvement of the JAK/STAT pathway in the action of the compounds. The expression of SOX2, NANOG, and the sphere formation will be quantified to determine the effect of the compounds on CSC characteristics. We will also quantify the expression and activity of ALDH1, capable to activate NFZ, which selectively eradicates CSCs. We will investigate the effect of the drugs on iodine uptake modulation and the ability to reverse drug resistance. The 3-D studies will be conducted in spheroids and organoids developed using the hanging drop or magnetic levitation technics. The organoids will be characterized through mutation detection and gene expression analysis. Thus, at the end of the project, we will have original results of the potential benefits of JAK/STAT pathway modulation JAK/STAT in ATC and a complete in vitro preclinical analysis of a potential antineoplastic drug for ATC. In addition, it will allow the setting up of a drug testing platform, aiming at personalized and precision medicine. (AU)

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