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Small-molecule agents for cancer immunotherapy

Acta Pharmaceutica Sinica B 2024年第3期14卷 905-952页

作者： Fang Wang Kai Fu Yujue Wang Can Pan Xueping Wang Zeyu Liu Chuan Yang Ying Zheng Xiaopeng Li Yu Lu kenneth kin wah to Chenglai Xia Jianye Zhang Zhi Shi Zeping Hu Min Huang Liwu Fu State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer MedicineGuangdong Esophageal Cancer InstituteGuangdong Provincial Clinical Research Center for CancerSun Yat-sen University Cancer CenterGuangzhou 510060China School of Pharmaceutical Sciences Tsinghua-Peking Center for Life SciencesBeijing Frontier Research Center for Biological StructureTsinghua UniversityBeijing 100084China State Key Laboratory of Drug Research Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China Department of Cell Biology&Institute of Biomedicine National Engineering Research Center of Genetic MedicineMOE Key Laboratory of Tumor Molecular BiologyGuangdong Provincial Key Laboratory of Bioengineering MedicineCollege of Life Science and TechnologyJinan UniversityGuangzhou 510632China Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target&Clinical Pharmacology NMPA and State Key Laboratory of Respiratory DiseaseSchool of Pharmaceutical Sciences and the Fifth Affiliated HospitalGuangzhou Medical UniversityGuangzhou 511436China School of Pharmacy The Chinese University of Hong KongHong Kong 999077China Affiliated Foshan Maternity and Child Healthcare Hospital Southern Medical UniversityFoshan 528000China

Cancer immunotherapy,exemplified by the remarkable clinical benefits of the immune checkpoint blockade and chimeric antigen receptor T-cell therapy,is revolutionizing cancer *** induce long-term tumor regression and overall survival benefit in many types of *** the advances in our knowledge about the tumor immune microenvironment,remarkable progress has been made in the development of small-molecule drugs for *** molecules targeting PRR-associated pathways,immune checkpoints,oncogenic signaling,metabolic pathways,cytokine/chemokine signaling,and immune-related kinases have been extensively *** of smallmolecule immunotherapeutic drugs and their combinations with other antitumor modalities are under active clinical investigations to overcome immune tolerance and circumvent immune checkpoint inhibitor ***,we review the latest development of small-molecule agents for cancer immunotherapy by targeting defined pathways and highlighting their progress in recent clinical investigations.

关键词： Cancer immunotherapy Small-molecule agents Immune checkpoints Oncogenic signaling Metabolic pathways Cytokine/chemokine signaling Antitumor immunity Tumor immune microenvironment

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A20 promotes colorectal cancer immune evasion by upregulating STC1 expression to block “eat-me” signal

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Signal Transduction and Targeted Therapy 2023年第9期8卷 4403-4415页

作者： Min Luo Xueping Wang Shaocong Wu Chuan Yang Qiao Su Lamei Huang Kai Fu Sainan An Fachao Xie kenneth kin wah to Fang Wang Liwu Fu State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer MedicineGuangdong Esophageal Cancer InstituteSun Yat-sen University Cancer CenterGuangzhou 510060P.R.China Laboratory Animal Centre The First Affiliated Hospital of Sun Yat-sen UniversityGuangzhou 510080P.R.China School of Pharmacy The Chinese University of Hong KongHong KongChina

Immune checkpoint inhibitors(ICIs)have induced durable clinical responses in a subset of patients with colorectal cancer(CRC).However,the dis-satisfactory response rate and the lack of appropriate biomarkers for selecting suitable patients to be treated with ICIs pose a major challenge to current ***-related molecule A20 is closely related to cancer immune response,but the effect of A20 on“eat-me”signal and immunotherapy efficacy remains *** found that A20 downregulation prominently improved the antitumor immune response and the efficacy of PD-1 inhibitor in CRC in vitro and in *** A20 expression was associated with less infiltration of immune cells including CD3(+),CD8(+)T cells and macrophages in CRC tissues and also poorer ***-and loss-A20 functional studies proved that A20 could decrease the“eat-me”signal calreticulin(CRT)protein on cell membrane translocation via upregulating stanniocalcin 1(STC1),binding to CRT and detaining in ***,A20 inhibited GSK3βphosphorylating STC1 at Thr86 to slow down the degradation of STC1 *** findings reveal a new crosstalk between inflammatory molecule A20 and“eat-me”signal in CRC,which may represent a novel predictive biomarker for selecting CRC patients most likely to benefit from ICI therapy.

关键词： STC1 GSK3β A20

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Rociletinib(CO-1686) enhanced the efficacy of chemotherapeutic agents in ABCG2-overexpressing cancer cells in vitro and in vivo

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Acta Pharmaceutica Sinica B 2020年第5期10卷 799-811页

作者： Fanpu Zeng Fang Wang Zongheng Zheng Zhen Chen kenneth kin wah to Hong Zhang Qian Han Liwu Fu The Third Affiliated Hospital of Sun Yat-sen University Guangzhou 510000China State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer MedicineGuangdong Esophageal Cancer InstituteSun Yat-sen University Cancer CenterGuangzhou 510060China School of Pharmacy Faculty of Medicinethe Chinese University of Hong KongHong KongSARChina Guangzhou Handy Biotechnological Co. Ltd.Guangzhou 511400China

Overexpression of adenosine triphosphate(ATP)-binding cassette subfamily G member 2(ABCG2)in cancer cells is known to cause multidrug resistance(MDR),which severely limits the clinical efficacy of ***,there is no FDA-approved MDR modulator for clinical *** this study,rociletinib(CO-1686),a mutant-selective epidermal growth factor receptor(EGFR)tyrosine kinase inhibitor(TKI),was found to significantly improve the efficacy of ABCG2 substrate chemotherapeutic agents in the transporter-overexpressing cancer cells in vitro and in MDR tumor xenografts in nude mice,without incurring additional *** studies revealed that in ABCG2-overexpressing cancer cells,rociletinib inhibited ABCG2-mediated drug efflux and increased intracellular accumulation of ABCG2 probe ***,rociletinib,inhibited the ATPase activity,and competed with[125I]iodoarylazidoprazosin(IAAP)photolabeling of ***,ABCG2 expression at mRNA and protein levels was not altered in the ABCG2-overexpressing cells after treatment with *** addition,rociletinib did not inhibit EGFR downstream signaling and phosphorylation of protein kinase B(AKT)and extracellular signal-regulated kinase(ERK).Our results collectively showed that rociletinib reversed ABCG2-mediated MDR by inhibiting ABCG2 efflux function,thus increasing the cellular accumulation of the transporter substrate anticancer *** findings advocated the combination use of rociletinib and other chemotherapeutic drugs in cancer patients with ABCG2-overexpressing MDR tumors.

关键词： Rociletinib Tyrosine kinase inhibitor Multidrug resistance ABCG2 ATPase

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Surgical cystogastrostomy: Is it still worthwhile?

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World Journal of Gastroenterology 2024年第17期30卷 2298-2301页

作者： kin Pan Au kenneth Siu Ho Chok Department of Surgery Queen Mary HospitalThe University of Hong KongHong Kong 999077China Department of Surgery The Chinese University of Hong KongHong Kong 999077China

The article by Ker et al explores the treatment of peripancreatic fluid collection(PFC).The use of percutaneous drainage,endoscopy,and surgery for managing PFC are *** drainage is noted for its low risk profile,while endoscopic cystogastrostomy is more effective due to the wider orifice of the metallic *** cystogastrostomy is a definitive treatment with a reduced need for reintervention,especially for cases with extensive collections and significant *** choice of treatment modality should be tailored to individual patient characteristics and disease factors,considering the expertise available.

关键词： Endoscopic cystgastrostomy Surgical cystgastrostomy Pancreatitis Pancreatic necrosis Peripancreatic collection

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Polyoxypregnanes as safe, potent, and specific ABCB1-inhibitory pro-drugs to overcome multidrug resistance in cancer chemotherapy in vitro and in vivo

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Acta Pharmaceutica Sinica B 2021年第7期11卷 1885-1902页

作者： Xu Wu Chun Yin Jiang Ma Stella Chai Chunyuan Zhang Sheng Yao Onat Kadioglu Thomas Efferth Yang Ye kenneth kin-wah To Ge Lin School of Biomedical Sciences Faculty of Medicinethe Chinese University of Hong KongHong Kong 999077China Joint Research Laboratory of Promoting Globalization of Traditional Chinese Medicines between the Chinese University of Hong Kong and Shanghai Institute of Materia Medica Chinese Academy of SciencesHong Kong 999077China State Key Laboratory of Drug Research and Natural Products Chemistry Department Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China Department of Pharmaceutical Biology Johannes Gutenberg UniversityMainz 55099Germany School of Pharmacy Faculty of Medicinethe Chinese University of Hong KongHong Kong 999077China Laboratory of Molecular Pharmacology Department of PharmacologySchool of PharmacySouthwest Medical UniversityLuzhou 646000China

Multidrug resistance(MDR)mediated by ATP binding cassette subfamily B member 1(ABCB1)is significantly hindering effective cancer ***,currently,no ABCB1-inhibitory drugs have been approved to treat MDR cancer clinically,mainly due to the inhibitor specificity,toxicity,and drug ***,we reported that three polyoxypregnanes(POPs)as the most abundant constituents of Marsdenia tenacissima(***)were novel ABCB1-modulatory pro-drugs,which underwent intestinal microbiota-mediated biotransformation in vivo to generate active *** metabolites at non-toxic concentrations restored chemosensitivity in ABCB1-overexpressing cancer cells via inhibiting ABCB1 efflux activity without changing ABCB1 protein expression,which were further identified as specific non-competitive inhibitors of ABCB1 showing multiple binding sites within ABCB1 drug *** POPs did not exhibit ABCB1/drug metabolizing enzymes interplay,and their repeated administration generated predictable pharmacokinetic interaction with paclitaxel without obvious toxicity in *** further showed that these POPs enhanced the accumulation of paclitaxel in tumors and overcame ABCB1-mediated *** results suggested that these POPs had the potential to be developed as safe,potent,and specific pro-drugs to reverse ABCB1-mediated *** work also provided scientific evidence for the use of *** in combinational chemotherapy.

关键词： Multidrug resistance ABCB1 Polyoxypregnane Combination chemotherapy Marsdenia tenacissima

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Rociletinib(CO-1686) enhanced efficacy of chemotherapeutic agents in ABCG2-overexpressing cancer cells in vitro and in vivo

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中国药理学与毒理学杂志 2019年第10期 891-892页

作者： ZENG Fan-pu WANG Fang ZHENG Zong-heng CHEN Zhen kenneth kin wah to ZHANG Hong HAN Qian FU Li-wu State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine Guangdong Esophageal Cancer Institute Sun Yat-Sen University Cancer Center

The abnormal expression and function of ATP-binding cassette subfamily G member 2(ABCG2) is correlated with development of multidrug resistance(MDR), and lead to lower response to ***, there is no FDA-approved commercial MDR modulator for clinical use. Here, We found rociletinib(CO-1686), a mutant-selective epidermal growth factor receptor(EGFR) tyrosine kinase inhibitor(TKI), significantly improved the efficacy of substrate chemotherapeutic agents in ABCG2-overexpressing cancer cells and also in ABCG2-overexpressing S1-MI-80 cell xenografts in nude mice, without incurring additional toxicity. Mechanistic studies revealed that in ABCG2-overexpressing cancer cells, rociletinib inhibited ABCG2-mediated drug efflux, and increased intracellular accumulation of ABCG2 probe substrates. Moreover, rociletinib, inhibited the ATPase activity, and competed with [125 I] iodoarylazidoprazosin(IAAP) photolabeling of ABCG2. The expression of ABCG2 at protein and m RNA levels was not altered when ABCG2-overexpressing cells were treated with rociletinib. In addition, rociletinib did not inhibit Erb B downstream signaling of AKT and ERK and their phosphorylations. The all results showed that rociletinib increased the accumulation of substrates in cells by inhibiting the efflux function of ABCG2, and reversed ABCG2-related MDR. Therefore, rociletinib might be useful in developing combination chemotherapy in the patients with ABCG2-overexpressing MDR tumors.

关键词： rociletinib combination chemotherapy chemotherapeutic agents

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Phytochemical Guttiferone K Triggers Apoptosis Through Inducing Endoplasmic Reticulum Stress Aggravation in Colorectal Cancer Cells

Phytochemical Guttiferone K Triggers Apoptosis Through Induc...

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第十四届全国中药和天然药物学术研讨会

作者： Kai-Kei Miu kenneth kin-wah To Hong-Xi Xu Ge Lin School of Biomedical Sciences The Chinese University of Hong Kong School of Pharmacy The Chinese University of Hong Kong Shanghai University of Traditional Chinese Medicine

＜正＞Guttiferone K（GutK）is a polycyclic polyprenylated acylphloroglucinol（PPAP）isolated from Garcinia *** group had previously confirmed that GutK can trigger apoptosis in colorectal cancer cells,however,the mechanism underlying GutK-induced apoptosis is *** present study demonstrated that GutK elicited endoplasmic reticulum（ER）stress in a variety

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Apatinib（YN968D 1） enhances the efficiency of conventional chemotherapeutical drugs by inhibiting P-glycoprotein function in leukemia cells

Apatinib（YN968D 1） enhances the efficiency of conventional...

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2011医学科学前沿论坛第十二届全国肿瘤药理与化疗学术...

作者： Shu Liang,Xu Zhang,Jie-hua He,Xing-Gui Chen,Yong-ju Liang,Fang Wang, Yan-jun Mi,kenneth kin wah to,Xiu-zhen Tong,Li-wu Fu

＜正＞Background:P-glycoprotein（P-gp,ABCB1） overexpression and enrichment of stem-like cells have been shown to correlate with poor prognosis in leukemia patients. Methodology/Principal Findings:We investigate the effect of apatinib,an oral small-molecule multi-targeted tyrosine kinase inhibitor（TKI）,on the efficiency of conventional anticancer drugs in leukemia side population（SP） cells and ABCB1-,ABCC1/MRP1-,ABCC4/MRP4-,ABCC10/MRP7- and lung resistance protein（LRP）-overexpression cancer *** results show that apatinib significantly enhanced the cytotoxicity of conventional chemotherapeutic drugs in SP

关键词： multidrug resistance ATP-binding cassette transporters P-glycoprotein apatinib leukemia stem-like cells ABCB1 ABCG2 Doxorubicin side population leukemia cells

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CircTUBD1: A Novel Circular RNA Molecule as a Therapeutic Target in Radiation-induced Liver Fibrosis

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Journal of Clinical and Translational Hepatology 2022年第4期10卷 571-573页

作者： Catherine Yujia Gu Terence kin wah Lee Department of Applied Biology and Chemical Technology The Hong Kong Polytechnic UniversityHong KongChina State Key Laboratory of Chemical Biology and Drug Discovery The Hong Kong Polytechnic UniversityHong KongChina

Citation of this article:Gu CY,Lee ***1:A Nov-el Circular RNA Molecule as a Therapeutic Target in Radiation-induced Liver Fibrosis.J Clin Transl Hepatol 2022;10(4):***:10.14218/*** liver cancer is the sixth most commonly diagnosed cancer and the fourth leading cause of cancer mortality worldwide.1 Liver transplantation and surgical resection are two curative therapeutic options for liver cancer patients at the early ***,most patients are diagnosed at advanced stages.

关键词： Liver Therapeutic cancer

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Investigation of the genetic etiology in male infertility with apparently balanced chromosomal structural rearrangements by genome sequencing

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Asian Journal of Andrology 2022年第3期24卷 248-254页

作者： Matthew Hoi kin Chau Ying Li Peng Dai Mengmeng Shi Xiaofan Zhu Jacqueline Pui wah Chung Yvonne K Kwok Kwong Wai Choy Xiangdong Kong Zirui Dong Department of Obstetrics and Gynaecology The Chinese University of Hong KongHong KongChina Shenzhen Research Institute The Chinese University of Hong KongShenzhen 518057China Hong Kong Hub of Paediatric Excellence The Chinese University of Hong KongHong KongChina Genetics and Prenatal Diagnosis Center The First Affiliated Hospital of Zhengzhou UniversityZhengzhou 450052China The Chinese University of Hong Kong-Baylor College of Medicine Joint Center for Medical Genetics Hong KongChina

Apparently balanced chromosomal structural rearrangements are known to cause male infertility and account for approximately 1%of azoospermia or severe ***,the underlying mechanisms of pathogenesis and etiologies are still largely ***,we investigated apparently balanced interchromosomal structural rearrangements in six cases with azoospermia/severe oligospermia to comprehensively identify and delineate cryptic structural rearrangements and the related copy number *** addition,high read-depth genome sequencing(GS)(30-fold)was performed to investigate point mutations causative of male ***-pair GS(4-fold)revealed additional structural rearrangements and/or copy number changes in 5 of 6 cases and detected a total of 48 ***,the breakpoints caused truncations of 30 RefSeq genes,five of which were associated with ***,the breakpoints disrupted 43 topological-associated *** disruptions or potential dysregulations of genes,which play potential roles in male germ cell development,apoptosis,and spermatogenesis,were found in all cases(n=6).In addition,high read-depth GS detected dual molecular findings in case MI6,involving a complex rearrangement and two point mutations in the gene ***,our study provided the molecular characteristics of apparently balanced interchromosomal structural rearrangements in patients with male *** demonstrated the complexity of chromosomal structural rearrangements,potential gene disruptions/dysregulation and single-gene mutations could be the contributing mechanisms underlie male infertility.

关键词： azoospermia balanced structural rearrangements genome sequencing male infertility severe oligospermia

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