Study of ingenol-3-angelate as a new class of resistance sensitizer to TRAIL-based therapy in human cancer cells

• Grant number: 19/23245-5
• Support type: Scholarships in Brazil - Scientific Initiation
• Effective date (Start): April 01, 2020
• Effective date (End): December 31, 2020
• Field of knowledge: Biological Sciences - Pharmacology - Ethnopharmacology
• Principal researcher: Viviane Aline Oliveira Silva
• Grantee: Camila Aparecida Faleiros
• Home Institution: Hospital do Câncer de Barretos. Fundação Pio XII (FP). Barretos , SP, Brazil

Abstract

Cancer is responsible for a significant and growing number of patients in the world, representing the second leading cause of death worldwide. Among the advances in the development of new anti-tumor therapeutic alternatives, selective induction of cell death stands out as a fundamental tool. In particular, the tumor necrosis factor-related apoptosis-inducing ligand, TRAIL, induces selective pro-apoptotic activity in tumor cells involving their cognate death receptors DRs (DR4 and / or DR5) in vitro and in vivo. Phase I / II clinical trials have demonstrated their benefit in patients by promoting partial responses with tolerability and safety. However, clinical application of TRAIL is still limited due to inherent or acquired resistance following repeated administration of TRAIL. In this context, the combination of TRAIL with agents that reverse tumor resistance represents a promising future. Preliminary studies from the Barretos Cancer Hospital Research Center on Molecular Oncology have revealed increased expression of the DR5 receptor in tumor lines treated with the synthetic compound PEP005, an ingenol-3-angelate diterpene ester derived from the Euphorbia peplus plant and approved by the Foodand Drug Administration for topical use in the treatment of actinic keratosis. From ligand-sensitive and resistant tumor line models, a sensitizing effect of these ligands was demonstrated when the synthetic compound was combined with recombinant TRAIL ligand molecule (rhTRAIL) suggesting DR5 receptor overexpression as a possible mechanism of reversal of the resistance to TRAIL therapy. Inserted in this context, we propose in this project the study of the mechanisms of action involved in the reversal of resistance to TRAIL therapy based on the combined treatment of synthetic compound PEP005 and rhTRAIL ligand in tumor lineages. These approaches will be fundamental to characterize the combinatorial treatment of compound PEP005 and rhTRAIL ligand as antineoplastic therapeutic modality and potential candidates for future clinical trials.