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Anti-SEMA3A Antibody: A Novel Therapeutic Agent to Suppress Glioblastoma Tumor Growth
Lee, Jaehyun,Shin, Yong Jae,Lee, Kyoungmin,Cho, Hee Jin,Sa, Jason K.,Lee, Sang-Yun,Kim, Seok-Hyung,Lee, Jeongwu,Yoon, Yeup,Nam, Do-Hyun 대한암학회 2018 Cancer Research and Treatment Vol.50 No.3
<P><B>Purpose</B></P><P>Glioblastoma (GBM) is classified as one of the most aggressive and lethal brain tumor. Great strides have been made in understanding the genomic and molecular underpinnings of GBM, which translated into development of new therapeutic approaches to combat such deadly disease. However, there are only few therapeutic agents that can effectively inhibit GBM invasion in a clinical framework. In an effort to address such challenges, we have generated anti-SEMA3A monoclonal antibody as a potential therapeutic antibody against GBM progression.</P><P><B>Materials and Methods</B></P><P>We employed public glioma datasets, Repository of Molecular Brain Neoplasia Data and The Cancer Genome Atlas, to analyze <I>SEMA3A</I> mRNA expression in human GBM specimens. We also evaluated for protein expression level of SEMA3A via tissue microarray (TMA) analysis. Cell migration and proliferation kinetics were assessed in various GBM patient-derived cells (PDCs) and U87-MG cell-line for SEMA3A antibody efficacy. GBM patient-derived xenograft (PDX) models were generated to evaluate tumor inhibitory effect of anti-SEMA3A antibody <I>in vivo</I>.</P><P><B>Results</B></P><P>By combining bioinformatics and TMA analysis, we discovered that SEMA3A is highly expressed in human GBM specimens compared to non-neoplastic tissues. We developed three different anti-SEMA3A antibodies, in fully human IgG form, through screening phage-displayed synthetic antibody library using a classical panning method. Neutralization of SEMA3A significantly reduced migration and proliferation capabilities of PDCs and U87-MG cell line <I>in vitro</I>. In PDX models, treatment with anti-SEMA3A antibody exhibited notable tumor inhibitory effect through down-regulation of cellular proliferative kinetics and tumor-associated macrophages recruitment.</P><P><B>Conclusion</B></P><P>In present study, we demonstrated tumor inhibitory effect of SEMA3A antibody in GBM progression and present its potential relevance as a therapeutic agent in a clinical framework.</P>
WNT signaling in glioblastoma and therapeutic opportunities
Lee, Yeri,Lee, Jin-Ku,Ahn, Sun Hee,Lee, Jeongwu,Nam, Do-Hyun Springer Science and Business Media LLC 2016 Laboratory investigation Vol.96 No.2
<P>WNTs and their downstream effectors regulate proliferation, death, and migration and cell fate decision. Deregulation of WNT signaling is associated with various cancers including GBM, which is the most malignant primary brain cancer. In this review, we will summarize the experimental evidence supporting oncogenic roles of WNT signaling in GBM and discuss current progress in the targeting of WNT signaling as an anti-cancer approach. In particular, we will focus on (1) genetic and epigenetic alterations that lead to aberrant WNT pathway activation in GBM, (2) WNT-mediated control of GBM stem cell maintenance and invasion, and (3) cross-talk between WNT and other signaling pathways in GBM. We will then review the discovery of agents that can inhibit WNT signaling in preclinical models and the current status of human clinical trials.</P>
USP1 targeting impedes GBM growth by inhibiting stem cell maintenance and radioresistance
Lee, Jin-Ku,Chang, Nakho,Yoon, Yeup,Yang, Heekyoung,Cho, Heejin,Kim, Eunhee,Shin, Yongjae,Kang, Wonyoung,Oh, Young Taek,Mun, Gyeong In,Joo, Kyeung Min,Nam, Do-Hyun,Lee, Jeongwu Oxford University Press 2016 Neuro-oncology Vol.18 No.1
<P>USP1-mediated protein stabilization promotes GSC maintenance and treatment resistance, thereby providing a rationale for USP1 inhibition as a potential therapeutic approach against GBM.</P>
Radiosensitization of brain metastasis by targeting c-MET.
Yang, Heekyoung,Lee, Hye Won,Kim, Yonghyun,Lee, Yeri,Choi, Yeon-Sook,Kim, Kang Ho,Jin, Juyoun,Lee, Jeongwu,Joo, Kyeung Min,Nam, Do-Hyun United States and Canadian Academy of Pathology [e 2013 Laboratory investigation Vol.93 No.3
<P>Radiotherapy is the most widely used therapeutic modality in brain metastasis; however, it only provides palliation due to inevitable tumor recurrence. Resistance of tumor cells to ionizing radiation is a major cause of treatment failure. A critical unmet need in oncology is to develop rationale driven approaches that can enhance the efficacy of radiotherapy against metastatic tumor. Utilizing in vivo orthotopic primary tumor and brain metastasis models that recapitulate clinical situation of the patients with metastatic breast cancer, we investigated a molecular mechanism through which metastatic tumor cells acquire resistance to radiation. Recent studies have demonstrated that the hepatocyte growth factor (HGF)-c-Met pathway is essential for the pathologic development and progression of many human cancers such as proliferation, invasion and resistance to anticancer therapies. In this study, c-Met signaling activity as well as total c-Met expression was significantly upregulated in both breast cancer cell lines irradiated in vitro and ex vivo radio-resistant cells derived from breast cancer brain metastatic xenografts. To interrogate the role of c-Met signaling in radioresistance of brain metastasis, we evaluated the effects on tumor cell viability, clonogenicity, sensitivity to radiation, and in vitro/in vivo tumor growth after targeting c-Met by small-hairpin RNA (shRNA) or small-molecule kinase inhibitor (PF-2341066). Although c-Met silencing or radiation alone demonstrated a modest decrease in clonogenic growth of parental breast cancers and brain metastatic derivatives, combination of two modalities showed synergistic antitumor effects resulting in significant prolongation of overall survival in tumor-bearing mice. Taken together, optimizing c-Met targeting in combination with radiation is critical to enhance the effectiveness of radiotherapy in the treatments of brain metastasis.</P>
Han Suji,Shin Hyemi,Lee Jin-Ku,Liu Zhaoqi,Rabadan Raul,Lee Jeongwu,Shin Jihye,Lee Cheolju,Yang Heekyoung,Kim Donggeon,Kim Sung Heon,Kim Jooyeon,Oh Jeong-Woo,Kong Doo-Sik,Lee Jung-Il,Seol Ho Jun,Choi J 생화학분자생물학회 2020 Experimental and molecular medicine Vol.52 No.-
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Suji Han,Hyemi Shin,Jin-Ku Lee,Zhaoqi Liu,Raul Rabadan,Jeongwu Lee,Jihye Shin,Cheolju Lee,Heekyoung Yang,Donggeon Kim,Sung Heon Kim,Jooyeon Kim,Jeong-Woo Oh,Doo-Sik Kong,Jung-Il Le,Ho Jun Seol,Jung Wo 생화학분자생물학회 2019 Experimental and molecular medicine Vol.51 No.-
Glioblastoma (GBM) is the most lethal primary brain tumor with few treatment options. The survival of gliomainitiating cells (GICs) is one of the major factors contributing to treatment failure. GICs frequently produce and respond to their own growth factors that support cell proliferation and survival. In this study, we aimed to identify critical autocrine factors mediating GIC survival and to evaluate the anti-GBM effect of antagonizing these factors. Proteomic analysis was performed using conditioned media from two different patient-derived GBM tumor spheres under a growth factor-depleted status. Then, the antitumor effects of inhibiting an identified autocrine factor were evaluated by bioinformatic analysis and molecular validation. Proteins secreted by sphere-forming GICs promote cell proliferation/survival and detoxify reactive oxygen species (ROS). Among these proteins, we focused on midkine (MDK) as a clinically significant and pathologically relevant autocrine factor. Antagonizing MDK reduced the survival of GBM tumor spheres through the promotion of cell cycle arrest and the consequent apoptotic cell death caused by oxidative stress-induced DNA damage. We also identified PCBP4, a novel molecular predictor of resistance to anti-MDK treatment. Collectively, our results indicate that MDK inhibition is an important therapeutic option by suppressing GIC survival through the induction of ROS-mediated cell cycle arrest and apoptosis.
Wnt activation is implicated in glioblastoma radioresistance.
Kim, Yonghyun,Kim, Kang Ho,Lee, Jeena,Lee, Young-Ae,Kim, Misuk,Lee, Se Jeong,Park, Kernyu,Yang, Heekyoung,Jin, Juyoun,Joo, Kyeung Min,Lee, Jeongwu,Nam, Do-Hyun United States and Canadian Academy of Pathology [e 2012 Laboratory investigation Vol.92 No.3
<P>Glioblastoma (GBM) patients have dismal median survival even with the most rigorous treatments currently available. Radiotherapy is the most effective non-surgical therapy for GBM patients; however, patients succumb due to tumor recurrence within a year. To develop a curative therapeutic approach, we need to better understand the underlying molecular mechanism of radiation resistance in GBM. Towards this goal, we developed an in vivo orthotopic GBM model system that mimics the radiation response of human GBM, using both established-GBM cell line and patient-derived freshly dissociated GBM specimen. In-vivo ionizing radiation (IR) treatment prolonged the survival of mice with intracranical tumor derived from U373MG, but failed to prevent tumor recurrence. U373MG and GBM578 cells isolated after in-vivo IR (U373-IR and 578-IR) were more clonogenic and enriched with stem cell-like characteristics, compared with mock-treated control tumor cells. Transcriptomic analyses and quantitative real-time reverse-transcription PCR analyses using these matched GBM cells before and after radiation treatment revealed that Wnt pathways were preferentially activated in post-IR GBM cells. U373-IR cells and 578-IR were enriched with cells positive for both active β-catenin (ABC) and Sox2 population, and this subpopulation was further increased after additional in-vitro radiation treatment, suggesting that radiation resistance of GBM is mediated due, in part, to the activation of stem cell-associated pathways including Wnt. Finally, pharmacological and siRNA inhibition of Wnt pathway significantly decreased the survival and clonogenicity of GBM cells and reduced their ABC(+)/Sox2(+) population. Together, these data suggest that Wnt activation is a molecular mechanism to confer GBM radioresistance and an important therapeutic target.</P>