Evaluation of the activity of Nifuroxazide and derivatives in JAK/STAT3 pathway in anaplastic thyroid cancer

• Grant number: 24/05597-0
• Support Opportunities: Scholarships in Brazil - Master
• Start date: December 01, 2024
• End date: November 30, 2026
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Ileana Gabriela Sánchez de Rubió
• Grantee: Gustavo Maresi Rodrigues
• Host Institution: Instituto de Ciências Ambientais, Químicas e Farmacêuticas (ICAQF). Universidade Federal de São Paulo (UNIFESP). Campus Diadema. Diadema , SP, Brazil

Abstract

Anaplastic thyroid cancer (ATC) is the most aggressive type of thyroid cancer (TC) and has the lowest survival rate, 6 to 18 months. Treatment options are limited due to iodine non-uptake and acquisition of resistance, mainly to the tyrosine kinase inhibitors, such as MAPK and PI3K/AKT/mTOR pathways inhibitors. The JAK/STAT signaling pathway in ATC has been associated with the development, resistance, and progression of cancer, and its inhibition has shown promising results in other tumor models. Nifuroxazide (NFZ), a drug with antimicrobial and antiparasitic effects, used since 1966, has been able to reduce cell viability in different cancer models through STAT3 inhibition. However, there is currently no data regarding NFZ activity on ATC. Therefore, the aim of this project is to evaluate the action of NFZ and three NFZ derivatives on the JAK/STAT3 signaling pathway, to determine the involvement of the MAPK and PI3K/AKT/mTOR signaling pathways in the drugs action, and to verify the effect of combined treatment of NFZ or a derivative with a MAPK inhibitor in an ATC cell line model. The ATC cell lines KTC-2, HTH83, and HTH83 with deletion in STAT3 through CRISPR/Cas9, produced by our group and available in the laboratory, will be used. Proliferation and cell viability, migration, invasion, and colony formation assays will be performed to evaluate drug action. Real-time PCR and western blot assays will be used to assess signaling pathway modulation. At the end of the project, we hope to obtain promising, original, and relevant results regarding NFZ repositioning as a potential inhibitor of the JAK/STAT3 pathway in ATC, as well as to present data on new potentially antineoplastic compounds and on the synergistic or non-synergistic effects of inhibiting different signaling pathways associated with TC, which may assist in the development of new treatment options with lower chances of recurrence and resistance.