Abstract 5647: Targeting HAUS7/gamma-tubulin interaction with HTIP1 suppresses tumorigenesis in esophageal squamous cell carcinoma

Abstract Background: Unlimited cell division resulting from cell cycle deregulation is a cancer hallmark. We hypothesized targeting deregulated cell cycle molecule with prognostic significance could be viable to counteract tumorigenesis. Our on-going effort showed HAUS7 was such a molecule highly relevant to esophageal squamous cell carcinoma (ESCC). This research targeted HAUS7/gamma-tubulin interaction using a novel peptide HTIP1, which was strategically designed based on our new understanding on the therapeutic mechanism associated with HAUS7 suppression. Methods: Clinical relevance of HAUS7 upregulation was studied in local and public ESCC cohorts. Physiological microtubule-regulating and tumorigenic functions of HAUS7 relative to other HAUS members were examined in vitro and/or in vivo. A multidisciplinary approach, which included using RNA-seq, mass spectrometry, electron microscopy, in silico predictions, bioinformatics analysis, biochemical methods, cellular assays, immunoassays and animal models, was employed to decode the mechanism underlying HAUS7 suppression. HTIP1 was designed by structure modelling and docking simulation. Its properties, cancer selectivity, anti-tumor efficacy, off-target effect and mechanism of action were comprehensively evaluated. Patient-derived tumor xenograft models were used to provide preclinical evidence. Results: Among HAUSs, HAUS7 was most essential for regulating microtubule dynamics in ESCC. Its overexpression was correlated with aggressive tumor phenotypes and poor prognosis. Mechanistically, HAUS7 suppression released its binding partner g-tubulin. The free g-tubulin upon phosphorylation seized LMAN1 and together both of them relocalized to the nucleus. Given the protein-transporting function of LMAN1 at endoplasmic reticulum (ER), its removal from the innate location triggered ER stress and apoptosis. Capable to perturb HAUS7/gamma-tubulin interaction, HTIP1 treatment manifested similar anti-tumor effects like HAUS7 suppression, while demonstrating high tumor specificity, negligible off-target effects and more potent than relevant compounds. Conclusions: We first discovered a unique physiological function and pathological relevance of HAUS7 among other HAUSs in ESCC. A new therapeutic mechanism was dissected under HAUS7 suppression. To target cancer with HAUS7 dependency, a novel peptide HTIP1 was designed to interrupt HAUS7/gamma-tubulin interaction. This invention paved a new strategy to counter tumorigenesis. By translating the scientific evidence to support further R&D of HTIP1, our ultimate goal is to produce a brand new drug. Citation Format: Ziqing CAI, Yu Hong Ian WONG, Ying Kit Simon LAW. Targeting HAUS7/gamma-tubulin interaction with HTIP1 suppresses tumorigenesis in esophageal squamous cell carcinoma [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 5647.