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| 1 | Sphingomyelin synthase 2 facilitates M2-like macrophage polarization and tumor progression in a mouse model of triple-negative breast cancer显示文摘High infiltration of M2-polarized macrophages in the primary tumor indicates unfavorable prognosis and poor overall survival in the patients with triple-negative breast cancer(TNBC).Thus,reversing M2-polarized tumor-associated macrophages in the tumors has been considered as a potential therapeutic strategy for TNBC.Sphingomyelin synthase 2(SMS2)is the key enzyme for sphingomyelin production,which plays an important role in plasma membrane integrity and function.In this study we investigated whether SMS2 inhibitor or SMS2 gene knockout could reduce macrophages M2 polarization and tumor progression in a mouse model of TNBC.We showed that SMS2 mRNA expression was linked to immunosuppressive tumor microenvironment and poor prognosis in TNBC patients.The knockout of SMS2 or application of 15w(a specific SMS2 inhibitor)markedly decreased the generation of M2-type macrophages in vitro,and reduced the tumor weight and lung metastatic niche formation in a 4T1-TNBC mouse model.We further demonstrated that the in vivo antitumor efficacy of 15w was accompanied by a multifaceted remodeling of tumor immune environment reflecting not only the suppression of M2-type macrophages but also diminished levels of regulatory T cells and myeloid-derived suppressor cells leading to a dramatically improved infiltration of antitumor CD8+T lymphocytes.Collectively,our results reveal a novel and important role of SMS2 in the protumorigenic function and may offer a new strategy for macrophage-targeted anticancer therapy. | Yan Deng Jia-chun Hu Shu-hua He Bin Lou Ting-bo Ding Jin-tong Yang Ming-guang Mo De-yong Ye Lu Zhou Xian-cheng Jiang Ker Yu Ji-bin Dong | 2021 | Acta Pharmacologica Sinica2021，42，1： | 2 |
| 2 | The microstrueture and phase equilibrium of new high performance high - entropy alloys 显示文摘 | Ker - Chang Hsieh Cheng - Fu Yu Wen - Tai Hsieh Wei - Ren Chiang Jin Son Ku Jiun -Hui Lai Chin -Pan T Chih Chao Yang | 2008 | Journal of Alloys and Compounds2008，，8： | 1 |
| 3 | Robust H∞ control for uncerrain T-S fuzzy systems with state and input delays显示文摘 | Ker Wei Yu Chang Hua Lien | 2008 | Chaos Solitons and Fractals 372008，，： | 1 |
| 4 | Novel-smoothened inhibitors for therapeutic targeting of naive and drug-resistant hedgehog pathway-driven cancers显示文摘The G protein-coupled receptor (GPCR) smoothened (SMO) is a key signaling component of the sonic hedgehog (Hh) pathway and a clinically validated target for cancer treatment. The FDA-approved SMO inhibitors GDC-0449/Vismodegib and LDE225/Sonidegib demonstrated clinical antitumor efficacy. Nevertheless, relatively high percentage of treated patients would eventually develop acquired cross resistance to both drugs. Here, based on published structure and activity of GDC-0449 inhibitor class, we replaced its amide core with benzimidazole which retained bulk of the SMO-targeting activity as measured in our Hh/SMO/Gli1-reporter system. Synthesis and screening of multiple series of benzimidazole derivatives identified HH-1, HH-13, and HH-20 with potent target suppression (IC50: <0.1μmol/L) in the reporter assays. In NIH3T3 cells stimulated with a secreted Hh (SHH), these inhibitors dose dependently reduced mRNA and protein expression of the endogenous pathway components PTCH-1, Gli1, and cyclin D1 resulting in growth inhibition via G0/G1 arrest. Mechanistically, the SMO-targeted growth inhibition involved downregulation of mTOR signaling inputs and readouts consistent with diminished mTORC1/mTORC2 functions and apoptosis. In mice, as with GDC-0449, orally administered HH inhibitors blocked paracrine activation of stromal Hh pathway in Calu-6 tumor microenvironment and attenuated growth of PTCH^+/-/P53^-/- medulloblastoma allograft tumors. Furthermore, HH-13 and HH-20 potently targeted the drug-resistant smoothened SMO-D473H (IC50: <0.2μmol/L) compared to the poor inhibition by GDC-0449 (IC50: >60μmol/L). These results identify HH-13 and HH-20 as potent inhibitors capable of targeting nave and drug-resistant Hh/SMO-driven cancers. The current leads may be optimized to improve pharmaceutical property for potential development of new therapy for treatment of Hh pathway-driven cancers. | Qing-rou Li Hui Zhao Xue-sai Zhang Henk Lang Ker Yu | 2019 | Acta Pharmacologica Sinica2019，40，2： | 0 |
| 5 | BCL9 regulates CD226 and CD96 checkpoints in CD8^(+)T cells to improve PD-1 response in cancer显示文摘To date,the overall response rate of PD-1 blockade remains unsatisfactory,partially due to limited understanding of tumor immune microenvironment(TIME).B-cell lymphoma 9(BCL9),a key transcription co-activator of the Wnt pathway,is highly expressed in cancers.By genetic depletion and pharmacological inhibition of BCL9 in tumors,we found that BCL9 suppression reduced tumor growth. | Mei Feng Zhongen Wu Yan Zhou Zhuang Wei Enming Tian Shenglin Mei Yuanyuan Zhu Chenglong Liu Fenglian He Huiyu Li Cao Xie Joy Jin Jibin Dong Dehua Yang Ker Yu Junbin Qian Diether Lambrechts Ming-Wei Wang Di Zhu | 2021 | Signal Transduction and Targeted Therapy2021，6，9： | 0 |
| 6 | AXL antibody and AXL-ADC mediate antitumor efficacy via targeting AXL in tumor-intrinsic epithelial-mesenchymal transition and tumor-associated M2-like macrophage显示文摘The receptor tyrosine kinase AXL is an emerging driver of cancer recurrence,while its molecular mechanism remains unclear.In this study we investigated how AXL regulated the disease progression and poor prognosis in non-small cell lung cancer(NSCLC)and triple negative breast cancer(TNBC).We performed AXL transcriptome analysis from TCGA datasets,and found that AXL expression was significantly elevated in NSCLC and TNBC correlating with poor prognosis,epithelial-mesenchymal transition(EMT)and immune-tolerant tumor microenvironment(TME).Knockdown of AXL or treatment with two independent AXL antibodies(named anti-AXL and AXL02)all diminished cell migration and EMT in AXL-high expressing NSCLC and TNBC cell lines.In a mouse model of 4T1 TNBC,administration of anti-AXL antibody substantially inhibited lung metastases formation and growth,accompanied by reduced downstream signaling activation,EMT and proliferation index,as well as an increased apoptosis and activated anti-tumor immunity.We found that AXL was abundantly activated in tumor nodule-infiltrated M2-macrophages.A specific anti-AXL antibody blocked bone marrow-derived macrophage(BMDM)M2-polarization in vitro.Targeting of AXL in M2-macrophage in addition to tumor cell substantially suppressed CSF-1 production and eliminated M2-macrophage in TME,leading to a coordinated enhancement in both the innate and adaptive immunity reflecting M1-like macrophages,mature dendritic cells,cytotoxic T cells and B cells.We generated a novel and humanized AXL-ADC(AXL02-MMAE)employing a site-specific conjugation platform.AXL02-MMAE exerted potent cytotoxicity against a panel of AXL-high expressing tumor cell lines(IC_(50)<0.1 nmol/L)and suppressed in vivo growth of multiple NSCLC and glioma tumors(a minimum efficacy dose<1 mg/kg).Compared to chemotherapy,AXL02-MMAE achieved a superior efficacy in regressing large sized tumors,eliminated AXL-H tumor cell-dependent M2-macrophage infiltration with a robust accumulation of inflammatory macrophages and mature dendritic cells.Our results support AXL-targeted therapy for treatment of advanced NSCLC and TNBC. | Jin-peng Pei Yue Wang Lan-ping Ma Xin Wang Liang Liu Yu Zhang Rui Jin Zhi-qiang Ren Yan Deng Jing-kang Shen Tao Meng Ker Yu | 2023 | Acta Pharmacologica Sinica2023，44，6： | 0 |
| 7 | Therapeutic efficacy and mechanism of CD73-TGFβ dual-blockade in a mouse model of triple-negative breast cancer显示文摘Although chemotherapy and recently approved immunotherapies have improved treatment of triple-negative breast cancer (TNBC), the clinical outcome for this deadly disease remains unsatisfactory. We found that both cluster of differentiation 73 (CD73) and transforming growth factor (TGF)β were elevated in TNBC and correlated with the epithelial–mesenchymal transition (EMT), fibrotic stroma, an immune-tolerant tumor environment, and poor prognosis. To explore the efficacy of CD73-TGFβ dual-blockade, we generated a bifunctional anti-CD73-TGFβ construct consisting of the CD73 antibody MEDI9447 fused with the TGFβRII extracellular-domain (termed MEDI-TGFβR). MEDI-TGFβR retained full and simultaneous blocking efficiency for CD73 and TGFβ. Compared with MEDI9447 activity alone, MEDI-TGFβR demonstrated superior inhibitory activity against CD73-dependent cell migration and the EMT in CD73-high TNBC cells and effectively reduced lung metastasis in a syngeneic mouse model of TNBC. Mechanistically, the CD73-TGFβ dual-blockade reverted the EMT and stromal fibrosis and induced tumor cell death, which was accompanied by the accumulation of M1-macrophages and production of tumor necrosis factor α (TNFα). The CD73-TGFβ dual- blockade promoted a multifaceted inflammatory tumor microenvironment, as shown by the diminished levels of myeloid-derived suppressor cells (MDSCs) and M2-macrophages, and substantially increased levels of activated dendritic cells, cytotoxic T cells, and B cells. Collectively, our results have highlighted a novel strategy for TNBC treatment. | Yun Xing Zhi-qiang Ren Rui Jin Liang Liu Jin-peng Pei Ker Yu | 2022 | Acta Pharmacologica Sinica2022，43，9： | 0 |
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