Abstract 4036: Selective inhibition of the transcription factor Brachyury in chordoma and non-small cell lung cancer

Abstract Chordoma is a rare and slow-growing cancer arising from remnants of the notochord, a structure present during embryonic development. It most commonly affects the sacrum and cervical spine, accounting for about 20% of primary spinal tumors and 3% of all bone tumors. While surgery and radiation are the primary treatments, the tumor's location often makes complete removal challenging, and recurrence is common. There are no approved therapies at this time. A hallmark of chordoma is the aberrant expression of the transcription factor (TF) Brachyury (TBXT) which plays a key role in notochord development but is normally silenced in adult tissues. In chordoma, Brachyury is reactivated and contributes to tumor initiation and progression, making it both a diagnostic marker, and a potential therapeutic target. Talus Bio has developed a groundbreaking technology, TF-Scan, the first cell-based global screening platform specifically designed to target TF. TF-Scan integrates functional proteomics, automated cell processing, and machine learning to evaluate a drug’s ability to modulate the activity of DNA-bound proteins in live human cells. Using our platform, we identified compounds that target TBXT. Hit validation and hit-to-lead optimization led to the development of a covalent small molecule, TAL61, that effectively modulates TBXT activity. In preclinical studies using a patient-derived xenograft (PDX) model for chordoma, TAL61 demonstrated significant efficacy in reducing tumor burden. TBXT has also been shown to be overexpressed in different cancers particularly lung cancer and breast cancer. We tested our lead compound in a model of NSCLC and were able to significantly decrease tumor burden by more than 50% and visualize additive effects while doing combination with a chemotherapy agent. We are conducting other studies to further characterize TAL61 and uncover new cancer indications where TBXT plays a key role. The development of TF-Scan represents a paradigm shift in drug discovery, enabling the identification of compounds capable of disrupting targets that were previously inaccessible to conventional approaches. Citation Format: Gaelle Mercenne, Yang Gao, Brian McEllin, Andrea Gutierrez, Julia Robbins, Bodhi Hueffmeier, Erin Broderick, Daniele Canzani, William Fondrie, Lindsay Pino, Alex Federation. Selective inhibition of the transcription factor Brachyury in chordoma and non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4036.