Abstract A002: Targeting nuclear IL-17RA transcriptional regulation with a novel aptamer to treat hypoxia-induced pancreatic ductal adenocarcinoma

Abstract Pancreatic ductal adenocarcinoma (PDAC) is characterized by high aggressiveness and extremely poor prognosis. Current therapies, including chemotherapy and targeted therapy, show limited clinical effectiveness. A key contributor to these clinical challenges is the severely hypoxic tumor microenvironment, which profoundly influences both tumor progression and response to therapy. However, the molecular mechanisms underlying hypoxia-induced PDAC progression remain unclear. This study investigates the role of IL-17RA as a potential therapeutic target in hypoxic PDAC. We identified nuclear IL-17RA as a critical hypoxia-responsive regulator of PDAC progression, demonstrating its significant upregulation under hypoxic conditions and its functional role in driving tumor growth through binding to nuclear transcriptional factor STAT3. To target this pathway, we developed and comprehensively validated hypo-PDAC-Aptamer, a novel aptamer-based therapeutic agent specifically designed to inhibit nuclear IL-17RA function. Using a combination of hypoxic PDAC cell models and preclinical mouse models, we employed chromatin immunoprecipitation (ChIP) and promoter binding assays to delineate the mechanistic basis of IL-17RA's oncogenic activity, while systematically evaluating the therapeutic potential of hypo-PDAC-Aptamer through both in vitro proliferation assays and in vivo efficacy studies. Our results demonstrate that hypo-PDAC-Aptamer effectively blocks nuclear IL-17RA function, leading to significant tumor growth inhibition at a low dose (5 mg/kg) that outperforms conventional gemcitabine therapy (100 mg/kg). Our study establishes nuclear IL-17RA as a novel molecular driver in hypoxia-induced PDAC progression and identifies hypo-PDAC-Aptamer as a promising precision therapeutic candidate. The novel targeted therapy has strong potential to overcome hypoxia-mediated therapeutic resistance in PDAC and potentially other hypoxic solid tumors. Citation Format: Zheng Chen, Minchuan Lyu, Feng Ding, Zonghua Su, Jinfang Zhang, Yun He, Shuangying Qiao, Liu Yang, Xinxing Cui, Aiping Lyu, Yuanyuan Yu, Fangfei Li. Targeting nuclear IL-17RA transcriptional regulation with a novel aptamer to treat hypoxia-induced pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr A002.