Search

ROR1, a member of the ROR (Receptor Tyrosine Kinase-Like Orphan Receptor)-family, is overexpressed in the process of embryo and fetal development, and controls cell polarity, cell migration and neurite growth. The expression is gradually reduced as development progresses, and it is hardly expressed in adults, but the overexpression of ROR1 is observed in various blood and solid cancer cells, so it is classified as an oncofetal gene. ABL102, a First-in-Class bispecific antibody targeting ROR1 and 4-1BB, elicits superior T cell activation by tumor specific T cell engagement through ROR1 dependent 4-1BB clustering. Our data showed that tumor target dependents binding of ROR1 and costimulatory 4-1BB by ABL102 induced 4-1BB activation in cell-based 4-1BB bioassay. ABL102 lead to IFN-γ secretion and tumor cell killing with a ROR1 dependent manner in co-culture assay with tumor cells and human PBMC. In h4-1BB knock-in mouse model bearing hROR1-expressing tumors, ABL102 potently inhibited tumor progression with a high rate of complete remission (CR). Mice with CR were further protected from the rechallenge of previously exposed tumors after 3 months of cessation of ABL102 treatment, implicating that immunological memory might be generated. In 4-week pilot toxicity study using cynomolgus monkeys, no ABL102-related toxicity was observed up to 100mg/kg, including mortality, body weight, hematology, liver toxicity, clinical chemistry and pathology, indicating a favorable safety profile. In conclusion, ABL102 exhibited potent in vitro and vivo anti-tumor activity and it was well tolerated and safe in the NHP toxicity study. These results strongly suggest that ABL102 is promising therapeutics for ROR1 positive cancer patients. Citation Format: Yangsoon Lee, Kyeong-Su Park, Wonjun Son, Sora Kim, Hyunseong Youn, Jiseon Yoo, Hanbyul Lee, Jonghwa Won. ROR1 targeted 4-1BB costimulatory bispecific antibody, ABL102, exhibits potent in vitro and vivo antitumor activity and superior safety profile [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2941.

G-protein-coupled receptor 81 (GPR81) functions as a receptor for lactate and plays an important role in the regulation of anti-lipolytic effects in adipocytes. However, to data, a role for GPR81 in the tumor microenvironment has not been clearly defined. Here, GPR81 expression in breast cancer patients and several breast cancer cell lines was significantly increased compared with normal mammary tissues and cells. GPR81 knockdown resulted in impaired breast cancer growth and led to apoptosis both in vitro and in vivo. Furthermore, the inhibition of GPR81 signaling suppressed angiogenesis through a phosphoinositide 3-OH kinase (PI3K)/Akt-cAMP response element binding protein (CREB) pathway, which led to decreased production of the pro-angiogenic mediator amphiregulin (AREG). Overall, these findings identify GPR81 as a tumor-promoting receptor in breast cancer progression and suggest a novel mechanism that regulates GPR81-dependent activation of the PI3K/Akt signaling axis in tumor microenvironment.

The purpose of this study is to investigate the effects of astronomical animation module on students` conceptual change regarding the concepts of diurnal motion of stars. Four students participated in this study, who never learned about the diurnal motion of stars. An animation module was developed by using Flash MX to readily understand the concept of space. In addition, we inserted a teacher`s voice with supplementary materials into the animation module to help students learn individually. The animation module was comprised of the movement of the Earth, the Moon and the planet. The earth science gifted students` preconception on diurnal motion of stars was analyzed with pre-test using questionnaires and interviews. After the instruction with animation module, the effect of conceptual change was examined by comparing pre and post-test. The results indicated that three students correctly presented about the motion of the star by all directions in middle latitude. Four students showed their understanding that stars travelled straight in all directions. Finally, all of four students whose preconceptions were that the star rotated perpendicularly showed the conceptual change of diurnal motion that the star traveled diagonally.

The concept of discrete curvature is a discretization of the curvature. Many literatures introduce discrete curvatures derived from arc length of circular arcs. We propose a new concept of discrete curvature of a polygon at each vertex, which is derived from area of fan shapes. We estimate the error of the discrete curvature and compare the discrete curvature with old one.

E2-EPF ubiquitin carrier protein (UCP) stabilizes hypoxia-inducible factor-1α (HIF-1α) inducing ischemic vascular responses. Here, we investigated the effect of UCP gene transfer on therapeutic angiogenesis. Adenovirus-encoded UCP (Ad-F-UCP) increased the expression of vascular endothelial growth factor (VEGF) and fibroblast growth factor-2 (FGF-2) in cells and mice. Conditioned media from UCP-overexpressing cells promoted proliferation, tubule formation, and invasion of human umbilical-vascular-endothelial cells (HUVECs), and vascularization in chorioallantoic membrane (CAM) assay. Ad-F-UCP increased the vessel density in the Martigel plug assay, and generated copious vessel-like structures in the explanted muscle. The UCP effect on angiogenesis was dependent on VEGF and FGF-2. In mouse hindlimb ischemia model (N = 30/group), autoamputation (limb loss) occurred in 87% and 68% of the mice with saline and Ad encoding β-galactosidase (Ad-LacZ), respectively, whereas only 23% of the mice injected with Ad-F-UCP showed autoamputation after 21 days of treatment. Ad-F-UCP increased protein levels of HIF-1α, platelet-endothelial cell adhesion molecule-1 (PECAM-1), smooth muscle cell actin (SMA) in the ischemic muscle, and augmented blood vessels doubly positive for PECAM-1 and SMA. Consequently, UCP gene transfer prevented muscle degeneration and autoamputation of ischemic limb. The results suggest that E2-EPF UCP may be a target for therapeutic angiogenesis.

Background Missense mutation of VHL gene is frequently detected in type 2 VHL diseases and linked to a wide range of pVHL functions and stability. Certain mutant pVHLs retain ability to regulate HIFs but lose their function by instability. In this case, regulating of degradation of mutant pVHLs, can be postulated as therapeutic method. Method The stability and cellular function of missense mutant pVHLs were determine in HEK293T transient expressing cell and 786-O stable cell line. Ubiquitination assay of mutant VHL proteins was performed in vitro system. Anticacner effect of adenovirus mediated shUCP expressing was evaluated using ex vivo mouse xenograft assay. Results Three VHL missense mutants (V155A, L158Q, and Q164R) are directly ubiquitinated by E2-EPF UCP (UCP) in vitro. Mutant pVHLs are more unstable than wild type in cell. Missense mutant pVHLs interact with UCP directly in both in vitro and cellular systems. Lacking all of lysine residues of pVHL result in resistance to ubiquitination thereby increase its stability. Missense mutant pVHLs maintained the function of E3 ligase to ubiquitinate HIF-1α in vitro. In cells expressing mutant pVHLs, Glut-1 and VEGF were relatively upregulated compared to their levels in cells expressing wild-type. Depletion of UCP restored missense mutant pVHLs levels and inhibited cell growth. Adenovirus-mediated shUCP RNA delivery inhibited tumor growth in ex vivo mouse xenograft model. Conclusion These data suggest that targeting of UCP can be one of therapeutic method in type 2 VHL disease caused by unstable but functional missense mutant pVHL. Electronic supplementary material The online version of this article (doi:10.1186/s12885-015-1786-8) contains supplementary material, which is available to authorized users.