Abstract 5152: SJP1604, a nucleolin-targeted therapeutic agent for relapsed/refractory acute myeloid leukemia
| Autor: | Jihyun Um, Soo Jin Lee, Sung Hwan Moon, Min-Hyo Ki, Yongbin Park, Dohyeong Lee |
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| Rok vydání: | 2020 |
| Předmět: |
Cancer Research
business.industry Venetoclax Myelodysplastic syndromes medicine.medical_treatment Myeloid leukemia Cancer medicine.disease Targeted therapy chemistry.chemical_compound medicine.anatomical_structure Oncology chemistry Cancer cell medicine Cancer research Bone marrow business Nucleolin |
| Zdroj: | Cancer Research. 80:5152-5152 |
| ISSN: | 1538-7445 0008-5472 |
| Popis: | Acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) are cancers characterized by the rapid growth of abnormal white blood cells. Although the standard first-line therapy leads to high rates of remission, approximately 30% of the treated patients are refractory and more than 50% of them face a relapse because of the occurrence of drug resistance and high toxicity. Therefore, there is a strong unmet medical need for the next-generation targeted therapy to overcome drug resistance and reduce toxicity in AML/MDS. Here, we designed an aptamer-drug conjugate (SJP1604) specific for nucleolin, which is highly expressed only on the cell membrane of cancer cells including AML cells. We identified that SJP1604 (APTA-16) inhibited the growth of AML cells and drug-resistant AML cells in vitro. SJP1604 presented outstanding anti-leukemic efficacy in vivo via syngeneic mouse model and xenograft mouse model. In addition, the synergistic effects were observed upon combination treatmeant with venetoclax in vitro. We also figured out that nucleolin as a clinical biomarker was significantly highly expressed on relapsed/refractory (R/R) AML patient-derived bone marrow cells ex vivo. SJP1604 selectively targeted cancer cells by nucleolin-binding on cell membrane with its high targeting ability and plasma stability owing to its unique conformational property, therefore, it demonstrated less cytotoxicity in vitro/in vivo and a superior therapeutic index based on AUC comparison in pharmacokinetic studies. The mechanism of the anti-leukemic efficacy of SJP1604 was also studied. First of all, SJP1604 decreased the expression of nucleolin and inactivated NFκB signaling pathway via dephosphorylation of NFκB, which resulted in diminished expression of DNMT1 followed by restored p15 expression. In addition, SJP1604 increased p53 expression and decreased bcl-2 expression in the protein and mRNA level. These could be one of potential mechanism of anti-leukemogenesis of SJP1604. In conclusion, these findings suggest that SJP1604 targeting nucleolin could be developed as a first-in-class drug for relapsed/refractory AML and MDS. GLP safety/toxicology studies of SJP1604 have been completed and clinical trials will be initiated in 2020. Citation Format: Jihyun Um, Dohyeong Lee, Yongbin Park, Sung Hwan Moon, Soo Jin Lee, Min-Hyo Ki. SJP1604, a nucleolin-targeted therapeutic agent for relapsed/refractory acute myeloid leukemia [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5152. |
| Databáze: | OpenAIRE |
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