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SJP1604 (APTA-16) is an aptamer-drug conjugate (APTA-DC) specifically targeting nucleolin, which is highly expressed only on the cell membrane of acute myeloid leukemia (AML) cells including relapsed/refractory aute myeloid leukemia (R/R AML). We previously presented the outstanding anti-leukemic activity of SJP1604 on AML cells including drug-resistant AML cells while standard chemotherapies showed no efficacy in vitro and in vivo. Therefore, we were able to conclude that only SJP1604 exhibits excellent resistance overcoming efficacy regardless of genetic defects of AML cells. Additionally, we recently identified that SJP1604 markedly eradicated AML cell engraftment with decreasing expression level of nucleolin protein in the bone marrow cells of MOLM-13 xenograft mouse model. These findings demonstrate that SJP1604 contributes to anti-leukemic effects through the regulation of nucleolin protein. We also figured out that nucleolin as a clinical biomarker was significantly highly expressed on AML and R/R AML patient-derived bone marrow cells. In particular, nucleolin expression is highly overexpressed in the bone marrow cells of entire population of R/R AML patients. Upto recent, considered as one of the major targeted therapeutics for AML, FLT3 inhibitors can target 25-30% of AML patients only. Therefore, our results mentioned above are very noteworthy finding showing the high potential of SJP1604 to be further developed as the first innovative targeted therapy to treat entire population of R/R AML patients. Herein, we show a phase I clinical trial design of SJP1604 to perform an open-label, first-in-human, dose escalation study to evaluate the safety, tolerability, pharmacokinetics and anti-tumor activity in patients with R/R AML. Citation Format: Jihyun Um, Dohyeong Lee, So Hee Kim, Eun-Hye Huh, Yongbin Park, Sung Hwan Moon, Soo Jin Lee, Je-Hwan Lee, Min-Hyo Ki. In vivo PoC study and design for Phase I clinical study of SJP1604, a nucleolin-targeted therapeutic agent to treat entire population of relapsed/refractory acute myeloid leukemia patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1430.

Dermal fibroblasts play essential roles in wound healing. However, they lose their normal regenerative functions under certain pathologic conditions such as in chronic diabetic wounds. Here, we show that substance P (SP) rescues the malfunctions of dermal fibroblasts in diabetes. SP increased the proliferation of diabetic dermal fibroblasts dose-dependently, although the effect was lower compared to the SP-stimulated proliferation of normal dermal fibroblasts. In contrast to normal dermal fibroblasts, SP increased the expression level of vascular endothelial growth factor (VEGF) and stromal cell-derived factor-1 (SDF-1) in diabetic dermal fibroblast hence, rescuing their angiogenic potential. The cellular characteristics of diabetic dermal fibroblasts modulated by SP would be able to accelerate the wound healing process through faster wound contraction and improved angiogenesis in diabetic chronic wounds. Moreover, SP pretreatment into dermal fibroblasts isolated from diabetic patients would be a promising strategy to develop autologous cell therapy for treating diabetic chronic wounds.

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.

Acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) are cancers characterized by the rapid growth of abnormal white blood cells. Generally, cytarabine (Ara-C), azacitidine, and decitabine are treated as the standard first-line chemotherapy for AML/MDS. Although the 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 need for the next-generation targeted therapy to overcome drug resistance and reduce toxicity in AML/MDS. Here, we designed an aptamer-nucleoside drug conjugate (SJP1604) via utilizing easy and continuous synthesis specific for nucleolin, which is highly expressed only on the cell membrane of cancer cells. In particular, AML, CLL (chronic lymphoblastic leukemia) and ALL (acute lymphoblastic leukemia) cells are known to express the highest mRNA level of nucleolin among various cancer cells, relatively. SJP1604 can be delivered into cancer cells with its high targeting ability and plasma stability via its unique conformational property. In this study, we verified that SJP1604 selectively targeted cancer cells by nucleolin-binding on the cancer cell membrane in the drug uptake assay. Owing to the selectivity, SJP1604 demonstrated less cytotoxicity on murine bone marrow cells in vitro and mouse white blood cells in vivo. SJP1604 also exhibited a long-lasting plasma stability in 50% human plasma up to 48 hours in contrast to unstability of general aptamers. Furthermore, SJP1604 inhibited the growth of various human AML/MDS cancer cells. Interestingly, SJP1604 showed the significantly reduced IC50 values with the decreased expression level of nucleolin in cytarabine-, azacitidine- and decitabine-resistant MOLM-13 while cytarabine caused no effect on the cell growth and the expression of nucleolin of the same resistant cell lines. Injection of SJP1604 led to tumor regression and improved survival rate in MOLM-13 xenograft mouse model and C1498 syngeneic mouse model. In ex vivo study, we figured out that the expression level of nucleolin is highly up-regulated in AML patient-derived bone marrow cells and the level is much higher in relapsed/refractory (R/R) AML patient-derived bone marrow cells. Moreover, SJP1604 also significantly reduced the colony forming unit (CFU) of R/R AML patient-derived bone marrow cells compared to that of AS1411 treatment. In conclusion, these findings suggest that SJP1604 could be developed as a first-in-class drug for novel targeted therapy of AML/MDS with less drug toxicity as well as as a remarkable orphan drug for overcoming drug resistance of AML/MDS in which distinctive solutions do not exist up until recently. Citation Format: Jihyun Um, Dohyeong Lee, Jisun Oh, Yongbin Park, Sung Hwan Moon, Su Jin Lee, Min-Hyo Ki, Eui Hwan Cho. SJP1604, a novel targeted therapeutic agent for AML (acute myeloid leukemia) including standard therapy-resistant AML [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 344.

Dermal fibroblasts play essential roles in wound healing and their dysfunction has been shown to be associated with impaired wound healing in diabetes. In the present study, we aimed at investigating whether Yes-associated protein (YAP), a mediator of mechanotransduction in dermal fibroblasts, is associated with impaired wound healing in diabetic mice. Compared with that in the control, the rate of wound contraction was decreased twofold in db/db type 2 diabetic mice (db/db mice). To mimic diabetic pathological condition, dermal fibroblasts were cultured under high glucose conditions (25.5 mM glucose). Further, dermal fibroblast-mediated contraction of wound was evaluated by in vitro collagen gel contraction assay. Dermal fibroblasts cultured under hyperglycemic condition showed impaired gel contraction and mitochondrial dysfunction, compared to the cells cultured under normoglycemic conditions (5.5 mM glucose). Importantly, compared with the normal dermal fibroblasts, diabetic db/db dermal fibroblasts expressed lower levels of growth factors and cytokines that enhance wound healing, such as insulin-like growth factor-1, stromal cell-derived factor-1, connective tissue growth factor, and transforming growth factor-β (TGF-β). The quantity of YAP mRNA was also lower in diabetic db/db dermal fibroblasts, compared with that in the control fibroblasts. These results indicate that impaired wound healing in diabetics is associated with the dysfunction of dermal fibroblasts, including downregulation of YAP, which plays essential roles in extracellular matrix remodeling and TGF-β-mediated wound healing.

Acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) are cancers characterized by the rapid growth of abnormal white blood cells. Generally, cytarabine (Ara-C), azacitidine, and decitabine are treated as the standard first-line chemotherapy for AML/MDS. Although the 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 need for the next-generation targeted therapy to overcome drug resistance and reduce toxicity in AML/MDS. Aptamers mostly consist of oligonucleotides, which can specifically bind to their target molecules with high affinity. Here, we designed a synthetic DNA aptamer-nucleoside drug conjugate (SJP1604) specific for nucleolin, which is highly expressed only on the cell membrane of cancer cells. In particular, AML and ALL (acute lymphoblastic leukemia) cells are known to express the highest mRNA level of nucleolin among various cancer cells, relatively. Owing to the unique conformational property of SJP1604, it can be delivered into cancer cells with its high targeting ability and plasma stability. In this study, we verified that SJP1604 selectively targeted cancer cells by nucleolin-binding on the cancer cell membrane in the drug uptake assay. SJP1604 also exhibited a long-lasting plasma stability in 50% human plasma up to 48 hours in sharp contrast to unstability of general aptamers. Furthermore, SJP1604 inhibited not only the growth of human AML/MDS cell lines (MV-4-11, HL-60, MOLM-13, THP-1 and KG-1) but also drug-resistant cell lines (cytarabine-, azacitidine- and decitabine-resistant MOLM-13, cytarabine-resistant HL60 and cytarabine-resistant MV-4-11). Interestingly, SJP1604 showed the significantly reduced IC50 values with the decreased expression level of nucleolin in cytarabine-, azacitidine- and decitabine-resistant MOLM-13 while cytarabine caused no effect on the cell growth and the expression of nucleolin of the same resistant cell lines. Intravenous administration of SJP1604 (150 mg/kg) led to tumor regression and improved survival rate in MOLM-13 xenograft mouse model. In conclusion, these findings suggest that SJP1604 could be developed as a first-in-class drug for novel targeted therapy of AML/MDS with less drug toxicity as well as an orphan drug for overcoming drug resistance of AML/MDS, using aptamer-drug conjugation technology. Citation Format: Jihyun Um, Dohyeong Lee, Yongbin Park, Sung Hwan Moon, Su Jin Lee, Min-Hyo Ki, Hee Jong Shin, Eui Hwan Jo. SJP1604, a novel nucleolin-targeted anti-cancer drug for acute myeloid leukemia using aptamer-drug conjugation technology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1946.

Steroids are treated for most inflammatory diseases but cause serious side effects such as diabetes and osteoporosis after their long-term usage. Recently, we identified novel roles of Substance-P (SP) in the suppression of the injury-mediated inflammation and also in stem cell mobilization. In this study, for clinical application of SP as an anti-inflammatory agent, its safety in long-term usage was evaluated with regard to diabetes and osteoporosis. Dexamethasone (DEX) and methylprednisolone (MP) were used as comparative drugs. While DEX-injection for 24 weeks developed severe weight loss, unstable blood glucose, and bone loss, SP-injection did not affect blood glucose and bone mass. MP-injection for 24 weeks also influenced blood glucose and body weight much milder than DEX-injection. After 66 weeks, MP-injection caused unstable blood glucose, alleviation in the age-related increase of body weight, and bone weakness, which was featured by reduction in collagen deposition and trabecular bone volume based on histological and micro CT analysis. However, SP-injection for 66 weeks rather increased collagen deposition, bone volume, and bone density. Therefore, this comparative study suggests that SP, even after long-term usage of effective dose, may not cause side effects such as osteoporosis in comparison to that of DEX and MP and can be developed as an anti-inflammatory agent and/or stem cell mobilizer for long-term treatment.