Targeting non-canonical pathways as a strategy to modulate the sodium iodide symporter

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• The sodium iodide symporter (NIS) is crucial for radioiodide therapy efficacy in cancer treatment.
• Oncogenic pathways and complex regulation of NIS impede effective radioiodide ablation and increase recurrence.
• Targeting NIS function is essential to improve outcomes for patients undergoing radioiodide therapy.

Purpose of the Study:

• To identify key cellular processes regulating NIS function through high-throughput drug screening.
• To discover novel combinatorial drug strategies to enhance radioiodide uptake.
• To investigate the role of proteostasis in NIS regulation and its clinical relevance in predicting patient recurrence.

Main Methods:

• High-throughput drug screening to identify compounds affecting NIS function.
• Evaluation of proteasomal degradation and autophagy pathways in NIS cellular processing.
• Utilizing specific inhibitors to develop combinatorial drug strategies.
• Analysis of core proteostasis gene expression in human tumors.
• Development and validation of a 13-gene risk score classifier for patient recurrence prediction.

Main Results:

• Multiple proteostasis pathways, including proteasomal degradation and autophagy, are central to NIS cellular processing.
• Combinatorial drug strategies targeting distinct molecular processes achieved over a 5-fold increase in radioiodide uptake.
• Significant dysregulation of core proteostasis genes was observed in human tumors.
• A 13-gene risk score classifier independently predicted recurrence in radioiodide-treated patients.

Conclusions:

• Proteostasis pathways are critical, targetable regulators of NIS function.
• Combinatorial drug strategies show promise for enhancing radioiodide therapy.
• Proteostasis gene dysregulation and the developed risk score offer potential biomarkers for predicting patient outcomes.