New therapeutic proposal for cancer: combination of mitogen with a cell stress pathway inhibitor.

• Grant number: 24/09407-0
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: August 01, 2024
• End date: June 30, 2027
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Hugo Aguirre Armelin
• Grantee: Thompson Eusébio Pavan Torres
• Host Institution: Instituto Butantan. São Paulo , SP, Brazil
• Associated research grant: 13/07467-1 - CeTICS - Center of Toxins, Immune-Response and Cell Signaling, AP.CEPID

Abstract

This research project aims to explore a novel therapeutic approach to cancer proposed by Dias and colleagues in 2019 and 2024, Torres and colleagues (in preparation) and the patent number BR 10 2024 006319-8. The central proposal states that malignant cells, unlike normal cells, undergo cell death when exposed to a specific combination of a mitogen and a defined stress pathway inhibitor. This pathophysiological difference between normal and malignant cells provides a unique therapeutic opportunity. Our results have demonstrated that in vitro combinations of FGF-2 (mitogen) + Bortezomib (a clinically used proteasome inhibitor) and LB-100 (a mitogen-like, inhibitor of phosphatase PP2A/PP5) + Bortezomib synergistically induce tumor cell death without harming normal cells. Furthermore, in vivo, these combinations inhibit tumor growth and metastasis without toxicity in xenograft models (human triple-negative breast cancer cell line, MDA-MB-231) and in orthotopic models (murine triple-negative breast cancer cell line, 4T1). The continuation of these studies will explore the applicability of this approach across different types of malignant cell lines (prostate triple-negative, glioblastoma, liver cancer, etc.) in xenograft models, identifying their specific vulnerabilities to mitogenic activation. By exploring stress response pathways after mitogenic activation, we seek to innovate in cancer therapy.