Exploring the Balance Between Mitogenic Activation and Inhibition of Stress Pathways in Cancerous and Normal Cells

• Grant number: 24/09408-7
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: August 01, 2024
• End date: June 30, 2026
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Hugo Aguirre Armelin
• Grantee: Kátia Andrea de Menezes Torres
• Host Institution: Instituto Butantan. Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
• Associated research grant: 13/07467-1 - CeTICS - Center of Toxins, Immune-Response and Cell Signaling, AP.CEPID

Abstract

Current therapeutic approaches for cancer rely on the inhibition of mitogenic stimuli. Research conducted in our laboratory has demonstrated that the classic growth factor FGF-2 inhibits the proliferation of malignant cells from the Y1 adrenocortical lineage (Dias et al., 2019). Furthermore, it has been observed that the combination of mitogens with stress pathway inhibitors results in the death of these tumor cell lines both in vitro and in vivo (Torres, Wailemann & Armelin, manuscript in preparation). Our results, which culminated in a patent application under number BR 10 2024 006319-8, indicate that in vitro combinations of FGF-2 (mitogen) + Bortezomib (a clinically used proteasome inhibitor) and LB-100 (a phosphatase PP2A/PP5 inhibitor) + Bortezomib synergistically induce tumor cell death without harming normal cells. Additionally, in vivo, these combinations inhibit tumor growth and metastasis without affecting xenograft models (human triple-negative breast cancer cell line, MDA-MB-231, and Balb-3T3 transformed cell line with HRASG12V, B61) and orthotopic models (murine triple-negative breast cancer cell line, 4T1). To further our results, we plan to test the combination of FGF-2 + Bortezomibe and LB-100 + Bortezomibe in the cell lines Balb3T3-B61 (tumor cells) and Balb3T3 (parental normal cells) of murine origin, in order to find the mechanisms of action underlying the death of tumor cells and in the resistance of normal cells, because our hypothesis is that these combinations lead to the death of cancer cells without compromising the survival of normal cells, allowing development of new and unconventional therapeutic protocols for the treatment of cancer.