分子靶向药物是食管癌治疗的研究重点，热休克蛋白Hsp90已成为国际公认的抗癌新靶点。申请者长期研究的四氢吲唑酮类化合物SNX-2112是新型Hsp90抑制剂。前期研究发现：①SNX-2112抑制食管癌细胞生长，且效果比5-FU高出近100倍；②GRP78、PERK、IRE1等内质网应激（ERS）相关蛋白表达下调；③细胞死亡（凋亡及自噬）通路被激活。基于此，本题拟以SNX-2112阻断ERS、诱导细胞死亡为切入点，①应用细胞生物学、肿瘤药理学手段，证实SNX-2112通过影响GRP78相互作用而使ERS阻断；②工具药增强或阻滞ERS后，研究SNX-2112对凋亡及自噬等死亡通路的影响；③在裸鼠体内评价SNX-2112抗食管癌药效，联合用药探讨ERS在SNX-2112治疗食管癌中的作用。本课题将为阐明SNX-2112诱导食管癌细胞死亡机制提供科学依据，同时也为食管癌提供一种全新的化疗策略。

Molecular-targeting drug has been the focus in cancer therapy. Heat shock protein 90 is a well-known anti-cancer target. Previously we found synthetic tetrahydroindazolone compound SNX-2112, as a novel Hsp90 inhibitor, could remarkably inhibit the growth of esophageal cells, down-regulate expression of endoplasmic reticulum stress (ERS) proteins such as GRP78, and activate apoptosis and autophagy pathway. Basing on this, to study the mechanisms of esophageal therapy, SNX-2112 could be used as the breakthrough point through its ability to block ERS and induce cell death. The contents of this project include the following: investigate whether SNX-2112 affects on proteins by interact with GRP78 and consequently blocks functions of ERS protein; evaluate whether SNX-2112-blocked ERS could induce apoptosis, autophagy and other cell death pathways; establish esophageal cancer nude mouse xenograft model, and evaluate the anti-cancer activity of SNX-2112 in the model; determine the contribution of SNX-2112-blocked ERS in the treatment of patients with esophageal. This project not will not help to elucidate the esophageal cell death mechanisms induced by SNX-2112, but also provide a new strategy of esophageal chemotherapy.