Abstract 546: A novel approach to treat relapsed/refractory acute myeloid leukemia by targeting nucleolin as an innovative and promising biomarker

Abstract Acute myeloid leukemia (AML) is a rapidly growing cancer of abnormal white blood cells accompanied by various genetic alteranation. Cytarabine (Ara-C) and daunorubicin are treated as the standard first-line chemotherapy for AML but approximately 30% of the patients are refractory and more than 50% of them face a relapse because of resistance. Moreover, FLT3 inhibitors, the only targeted therapy for AML, can treat only 20% of patients and resistance develops within a few months. Therefore, there is a strong unmet to develop a next-generation targeted therapy to overcome resistance. Nucleolin (NCL) is a protein highly expressed and localized on the cell surface of cancer cells. In this study, we confirmed that NCL was highly expressed in various human AML cell lines and patient-derived bone marrow cells compared to normal cells. Furthermore, it was particularly overexpressed in drug-resistant AML cells and refractory/relapsed (R/R) AML patient-derived bone marrow cells. NCL is a promising target for cancer treatment as mentioned above, but to date, no therapy has been developed to specifically target NCL. APTA-16 is a first-in-class AML treatment that specifically targets NCL developed by aptamer-drug conjugation (APTA-DC) technology. APTA-16 showed an outstanding anti-leukemic activity in drug-resistant AML cells through NCL inhibition whereas standard chemotherapies showed no efficacy in vitro and in vivo. We also identified the resistance-overcoming mechanism of APTA-16 in terms of intracellular drug metabolism and biological signaling pathway. The alternative activies of equilibrative nucleoside transporter (ENT) and deoxycytidine kinase (dCK) are main mechanisms by which cancer cells acquire Ara-C resistance. APTA-16 can avoid this process by entering cells via NCL on the surface of AML cells. We also figured out that NCL-DNMT1-axis signaling pathway plays an important role in drug-resistant AML cells and APTA-16 treatment significantly regulated the pathway. Collectively, our findings show that NCL can be an innovative biomarker targeting entire population of R/R AML patients regardless of their genetic defects and APTA-16 has can be developed as the first innovative NCL-targeted therapy. Based on the excellent ex vivo results using patient-derived AML cells, successful clinical results are expected. GLP safety/toxicity studies of APTA-16 have been completed and orphan drug designation (ODD) was grantd by FDA in 2021. Citation Format: Jihyun Um, Kyung Jin Kim, Eun-Hye Huh, Eun Jung Shin, Yumi Ji, Sung Hwan Moon, Je-Hwan Lee, Soo Jin Lee. A novel approach to treat relapsed/refractory acute myeloid leukemia by targeting nucleolin as an innovative and promising biomarker [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 546.