Abstract Esophageal adenocarcinoma belong to the cancer entities with a sharply increasing incidence. Though multimodal therapies have improved outcomes, prognoses remain poor in advanced stages and the 5-year survival rate is only between 20 to 25%. For this purpose, new therapeutic options are urgently necessary. In this context, this project investigated a SIX1-specific PROTAC (ELX19) in EAC - including potential adverse effects on the immune system. SIX1 is an embryonic transcription factor, which is required during embryogenesis for the development of various organs and tissues. In contrast, it is no longer or only weakly expressed in adult tissue. However, many cancers show a reactivation of cancer, which leads to different pro-tumorigenic features, making SIX1 a potentially therapeutic target. We first tested the efficiency of ELX19 in degrading SIX1 via WB and ELISA. Thereby, a higher SIX1 expression correlated with a better degradation efficiency, leading to a DC50 of below 1 µM in FLO-1 cells. ELX19 also reduced proliferation and increased apoptosis in FLO-1 cells. Importantly, ELX19 did not affect proliferation and apoptosis in a cell line with low SIX1 expression (OE19) suggesting that the effects caused by ELX19 are SIX1-specific. As adverse effects on the immune system can be a major impediment for further clinical development, we tested the effect of ELX19 on primary T helper and cytotoxic T cells. Thereby, unspecific effects only started 3 µM which is common for VHL-based PROTACs. In conclusion, these preliminary results show the potential of a SIX1-targeting PROTAC for the treatment of esophageal adenocarcinoma. Citation Format: Asad Faili, Vic Scharfenberger, Ellen Weber, Samaneh Heydarzadeh, Reinhard Buettner, Tristan Lerbs. Development of a SIX1-specific PROTAC for the treatment of esophageal adenocarcinoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3076.
Faili et al. (2026) studied this question.