Abstract 6129: The proapoptotic peptide PEP-010 is efficient on several models of different tumor origins and it can be monitored by pharmacodynamic biomarker candidates in clinical practice

Abstract

Abstract In cancer cells, the proapoptotic proteins caspase-9 and PP2A interaction prevents them to play their role in apoptosis. PEP-010, a drug candidate developed by PEP-Therapy, a French Biotech company, is a proapoptotic peptide targeting and disrupting this interaction leading to restoration of the apoptotic cascade. PEP-010 is an innovative bifunctional peptide. It penetrates into cells thanks to its cell penetrating part and specifically disrupts the caspase-9/PP2A interaction thanks to its interfering part. PEP-010 is currently in Phase I a/b multicenter clinical trial for the treatment of advanced solid tumors.To the aim of screening different potential therapeutic targets, to investigate the molecular mechanism-of-action of PEP-010 and to identify potential pharmacodynamic biomarkers, we have tested PEP-010 efficacy on several cell models of different tumor origins. By the Annexin V/Propidium Iodide staining and flow cytometry analysis, we found that PEP-010 induces apoptosis in most of the tested models. One possible mechanism-of-action is an involvement of the PP2A which, once released by PEP-010, could regulate expression and/or activity of different intracellular factors leading to caspases activation and cell death.The identification of the major molecular features involved in PEP-010 mechanism-of-action, were instrumental to identify different pharmacodynamic biomarker candidates (e.g. active caspase-3). Hence, such biomarkers could be useful in clinical practice to monitor the effect of PEP-010 at molecular level. We have compared specific features related to the mechanism-of-action of PEP-010 in sensitive (MDA-MB-231, IGROV1) and not sensitive cell models of different tumor origins and in tissue sections derived from Patient-Derived Xenografts models of breast cancer treated or not with PEP-010. Widely used techniques as immunofluorescent staining and immunohistochemistry were employed, making these results easily transferable in clinical routine.Taken together, our pre-clinical data showed the potential of PEP-010 as an anti-cancer peptide on a wide variety of malignancies and enabled the identification of pharmacodynamic biomarker candidates, important to ease the clinical development. Citation Format: Rayan Farhat, Laura Dadon, F Nemati, A Rebollo, D Decaudin, Joelle Wiels, Catherine Brenner, Diego Germini. The proapoptotic peptide PEP-010 is efficient on several models of different tumor origins and it can be monitored by pharmacodynamic biomarker candidates in clinical practice. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6129.