Background and rationale: Radioiodine-refractory (RAI-R) differentiated thyroid cancer (DTC) is a challenging tumor. Several mechanisms have been claimed for RAI-R.
Hypothesis: RAI-R DTC have peculiar assets that underline resistance and differentiate these tumors from RAI-sensitive (RAI-S) ones.
Aims:
- Evaluate the genetic, trascriptomic profiles and the role of cancer stem cells (CSC), epithelial-mesenchymal transition (EMT) and immunity in RAI-R DTC;
- Identify RAI-R DTC biomarkers;
- Develop RAI-R DTC organoids.
Methods: High risk DTC patients (pts) will be enrolled. Pts will be followed as in use in clinical practice. RAI-R pts will be evaluated. An equal number of RAI-S pts, matched for histology, age, sex and tumor stage will be analyzed. Genes, CSC, EMT and immunity profiles as well as biomarkers will be compared in RAI-R and RAI-S. The project will consist of:
- Task 1: Genetic and molecular profiling of RAI-R and RAI-S DTC. Exome sequencing will be performed. Gene expression profile will be investigated. Focus on genes involved in EMT or in CSC biology will be posed to explore their role in RAI-R. CD133+ cells will be isolated and implanted in mice for further analysis. Annexin V and CD133-PE staining will be performed.
- Task 2: Biomarkers profiling of RAI-R and RAI-S DTC. miRNA and proteins will be tested as serum biomarkers. Images will be analyzed (radiomics and/or machine/deep learning approaches) to test their prognostic role.
- Task 3: RAI-R organoids. Tissue samples will be used to develop RAI-R DTC organoids that will be used to evaluate the mechanisms involved in RAI-R and to test drugs that may restore RAI sensitivity.
Expected results and potential impact: Diverse molecular and genetic profiles as well as different biomarkers between RAI-R and RAI-S are expected. The identification of reliable biomarkers will impact on high risk DTC pts management and treatment potentially improving quality of life of pts and healthcare costs.