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Boosting synergism of chemo- and immunotherapies via switching paclitaxel-induced apoptosis to mevalonate metabolism-triggered ferroptosis by bisphosphonate coordination lipid nanogranules

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Acta Pharmaceutica Sinica B 2024年第2期14卷 836-853页

作者： Ge Song Minghui Li Shumin Fan Mengmeng Qin Bin Shao Wenbing Dai Hua Zhang Xueqing Wang Bing He Qiang Zhang Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems School of Pharmaceutical SciencesPeking UniversityBeijing 100191China State Key Laboratory of Natural and Biomimetic Drugs School of Pharmaceutical SciencesPeking UniversityBeijing 100191China department of Medical Oncology Key Laboratory of Carcinogenesis and Translational Research(Ministry of Education)Peking University Cancer HospitalBeijing 100142China

Conventional chemotherapy based on cytotoxic drugs is facing tough challenges recently following the advances of monoclonal antibodies and molecularly targeted *** is critical to inspire new potential to remodel the value of this classical therapeutic ***,we fabricate bisphosphonate coordination lipid nanogranules(BC-LNPs)and load paclitaxel(PTX)to boost the chemo-and immuno-therapeutic synergism of cytotoxic *** in BC-LNPs@PTX,a bisphosphonate to block mevalonate metabolism,works as both the structure and drug constituent in nanogranules,where alendronate coordinated with calcium ions to form the particle *** synergy of alendronate enhances the efficacy of paclitaxel,suppresses tumor metastasis,and alters the cytotoxic *** from the paclitaxel-induced apoptosis,the involvement of alendronate inhibits the mevalonate metabolism,changes the mitochondrial morphology,disturbs the redox homeostasis,and causes theaccumulation of mitochondrial ROS and lethal lipid peroxides(LPO).These factors finally trigger the ferroptosis of tumor cells,an immunogenic cell death mode,which remodels the suppressive tumor immune microenvironment and synergizes with ***,by switching paclitaxel-induced apoptosis to mevalonate metabolism-triggered ferroptosis,BC-LNPs@PTX provides new insight into the development of cytotoxic drugs and highlights the potential of metabolism regulation in cancer therapy.

关键词： Bisphosphonate coordinationlipid nanogranules Ferroptosis Mevalonatemetabolism Mitochondrial metabolism Nano-systematic biology

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Genomic profiling of colorectal cancer in large-scale Chinese patients:amplification and somatic mutations in ERBB2

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Oncology Research 2024年第9期32卷 1429-1438页

作者： YUZHI LIU EVELYNE BISCHOF ZHIQIN CHEN JIAHUAN ZHOU BEI ZHANG DING ZHANG YONG GAO MING QUAN department of Oncology Shanghai East HospitalTongji University School of MedicineShanghaiChina State Key Laboratory of Oncogenes and Related Genes Shanghai Cancer InstituteDepartment of OncologyRenji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghaiChina Jiangsu Hengrui Pharmaceuticals Co. Ltd.ShanghaiChina D Medicines Inc. ShanghaiChina

Objectives:Human epidermal growth factor receptor 2(HER2)-targeted therapies have demonstrated potential benefits for metastatic colorectal cancer(mCRC)patients with HER2 amplification,but are not satisfactory in cases of HER2 mutant ***:Consequently,further elucidation of amplifications and somatic mutations in erythroblastic oncogene B-2(ERBB2)is *** genomic profiling was conducted on 2454 Chinese CRC cases to evaluate genomic alterations in 733 cancer-related genes,tumor mutational burden,microsatellite instability,and programmed death ligand 1(PD-L1)***:Among 2454 CRC patients,85 cases(3.46%)exhibited ERBB2 amplification,and 55 cases(2.24%)carried ERBB2 mutation.p.R678Q(28%),p.V8421(24%),and p.S310F/Y(12%)were the most prevalent of the 16 detected mutation *** comparison to the ERBB2 altered(alt)group,KRAS/BRAF mutations were more prevalent in ERBB2 wild-type(wt)samples(ERBB2wt ***2alt,KRAS:50.9%vs.25.6%,p<0.05;BRAF:8.5%vs.2.3%,p<0.05).32.7%(18/55)of CRCs with ERBB2 mutation exhibited microsatellite instability high(MSI-H),while no cases with HER2 amplification displayed *** genes varied between ERBB2 copy number variation(CNV)and ERBB2 single nucleotide variant(SNV);TP53 alterations tended to co-occur with ERBB2 amplification(92.3%)as opposed to ERBB2 mutation(58.3%).KRAS and PIK3CA alterations were more prevalent in ERBB2 SNV cases(KRAS/PIK3CA:45.8%/31.2%)compared to ERBB2 amplification cases(KRAS/PIK3CA:14.1%/7.7%).Conclusion:Our study delineates the landscape of HER2 alterations in a large-scale cohort of CRC patients from *** findings enhance our understanding of the molecular features of Chinese CRC patients and offer valuable implications for further investigation.

关键词： Colorectal cancer ERBB2 HER2 Human epidermal growth factor receptor 2 Genetic profiling Precision oncology

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Tumor biomarkers for diagnosis,prognosis and targeted therapy

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Signal Transduction and Targeted Therapy 2024年第6期9卷 2391-2476页

作者： Yue Zhou Lei Tao Jiahao Qiu Jing Xu Xinyu Yang Yu Zhang Xinyu Tian Xinqi Guan Xiaobo Cen Yinglan Zhao department of Biotherapy Cancer Center and State Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu 610041China West China School of Pharmacy Sichuan UniversityChengdu 610041China School of Medicine Tibet UniversityLhasa 850000China National Chengdu Center for Safety Evaluation of Drugs State Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu 610041China

Tumor biomarkers,the substances which are produced by tumors or the body’s responses to tumors during tumorigenesis and progression,have been demonstrated to possess critical and encouraging value in screening and early diagnosis,prognosis prediction,recurrence detection,and therapeutic efficacy monitoring of *** the past decades,continuous progress has been made in exploring and discovering novel,sensitive,specific,and accurate tumor biomarkers,which has significantly promoted personalized medicine and improved the outcomes of cancer patients,especially advances in molecular biology technologies developed for the detection of tumor ***,we summarize the discovery and development of tumor biomarkers,including the history of tumor biomarkers,the conventional and innovative technologies used for biomarker discovery and detection,the classification of tumor biomarkers based on tissue origins,and the application of tumor biomarkers in clinical cancer *** particular,we highlight the recent advancements in biomarker-based anticancer-targeted therapies which are emerging as breakthroughs and promising cancer therapeutic *** also discuss limitations and challenges that need to be addressed and provide insights and perspectives to turn challenges into opportunities in this ***,the discovery and application of multiple tumor biomarkers emphasized in this review may provide guidance on improved precision medicine,broaden horizons in future research directions,and expedite the clinical classification of cancer patients according to their molecular biomarkers rather than organs of origin.

关键词： diagnosis breakthrough biomarkers

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Apple polyphenol phloretin inhibits type II glucose transporter and enhances anti-HER2 antibody drug binding as an adjuvant treatment for HER2-positive breast cancer

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Food Science and Human Wellness 2024年

作者： Han-Sheng Chang Tzu-Chun Cheng Shih-Hsin Tu Pei-Han Liao Yu-Ching Lee Chi-Tang Ho Min-Hsiung Pan Li-Ching Chen Yuan-Soon Ho department of Biological Science & Technology College of Life Sciences China Medical University Institute of Biochemistry and Molecular Biology College of Life Sciences China Medical University department of Surgery School of Medicine College of Medicine Taipei Medical University Research Center of cancer Translational Medicine Taipei Medical University department of Food Science Rutgers University New Jersey USA Institute of Food Sciences and Technology Taiwan University

This study presents novel findings on the potential of phloretin， an apple polyphenol， to enhance the effectiveness of anti-HER2 antibody therapy in HER2-positive breast cancer patients. Our research reveals that phloretin inhibits type II glucose transporter (GLUT2) activity， significantly reducing cancer cell glucose uptake. We confirmed the overexpression of GLUT1 and GLUT2 mRNA in paired human breast tumor tissues， with GLUT2 overexpression associated explicitly with poorer survival rates in breast cancer patients. Treatment with phloretin was observed to increase the interaction between GLUT2 and HER2 proteins， attenuate glycolysis， and enhance the binding affinity of anti-HER2 antibody drugs to target human breast cancer cells. Furthermore， the efficacy of the combination therapy involving phloretin and antibody drugs was reaffirmed in a cell-derived xenograft (CDX) tumor animal model， particularly in suppressing the growth of Trastuzumab-resistant HER2+ breast cancer. These significant findings suggest that targeting GLUT2 activity with phloretin in combination with anti-HER2 antibody drugs may help mitigate the development of drug-resistant breast cancer， offering valuable insights for enhancing tumor treatment strategies and contributing to developing more effective therapies.

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Making incurable pancreatic cancer curable

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Malignancy Spectrum 2024年第1期1卷 46-52页

作者： Jianhong An Dacheng Xie Keping Xie Center for Pancreatic cancer Research The South China University of Technology School of MedicineGuangzhouGuangdongChina department of Oncology Shanghai Pulmonary HospitalTongji UniversityShanghaiChina

Pancreatic cancer is one of the deadliest malignancies,with limited effectiveness of standard therapies,resulting in little improvement in the 5-year survival rate over the past few ***,advanced radiotherapy techniques and emerging treatment modalities,such as immunotherapy and targeted therapy,are showing tremendous potential as effective treatment options for pancreatic cancer patients who were previously considered *** review summarizes the current advances and challenges in pancreatic cancer treatment strategies and proposes further optimization directions,aiming to provide insights into the cure of incurable pancreatic cancer.

关键词： pancreatic cancer early screening radiotherapy immunotherapy targeted therapy tumor microenvironment

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Multi-omics analysis of human tendon adhesion reveals that ACKR1-regulated macrophage migration is involved in regeneration

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Bone Research 2024年第2期12卷 390-406页

作者： Xinshu Zhang Yao Xiao Bo Hu Yanhao Li Shaoyang Zhang Jian Tian Shuo Wang Zaijin Tao Xinqi Zeng Ning-Ning Liu Baojie Li Shen Liu department of Orthopaedics Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine600 Yishan RdShanghai 200233PR China Section of Spine Surgery Department of OrthopaedicsChangzheng HospitalNaval Medical UniversityShanghai 200003PR China Bio-X Institutes Key Laboratory for the Genetics of Developmental and Neuropsychiatric DisordersMinistry of EducationShanghai Jiao Tong UniversityShanghai 200241PR China department of Orthopaedics Wuxi Ninth People’s Hospital Affiliated to Soochow UniversityWuxi 214062PR China State Key Laboratory of Systems Medicine for cancer Center for Single-Cell OmicsSchool of Public HealthShanghai Jiao Tong University School of MedicineShanghai 200025China

Tendon adhesion is a common complication after tendon injury with the development of accumulated fibrotic tissues without effective anti-fibrotic therapies,resulting in severe *** are widely recognized as a fibrotic trigger during peritendinous adhesion ***,different clusters of macrophages have various functions and receive multiple regulation,which are both still *** our current study,multi-omics analysis including single-cell RNA sequencing and proteomics was performed on both human and mouse tendon adhesion tissue at different stages after tendon *** transcriptomes of over 74000 human single cells were *** results,we found that SPP1^(+)macrophages,RGCC^(+)endothelial cells,ACKR1^(+)endothelial cells and ADAM12^(+)fibroblasts participated in tendon adhesion ***,despite specific fibrotic clusters in tendon adhesion,FOLR2^(+)macrophages were identified as an antifibrotic cluster by in vitro experiments using human ***,ACKR1 was verified to regulate FOLR2^(+)macrophages migration at the injured peritendinous site by transplantation of bone marrow from Lysm-Cre;R26R^(tdTomato) mice to lethally irradiated Ackr1^(-/-)mice(Ackr1^(-/-)chimeras;deficient in ACKR1)and control mice(WT chimeras).Compared with WT chimeras,the decline of FOLR2^(+)macrophages was also observed,indicating that ACKR1 was specifically involved in FOLR2^(+)macrophages *** together,our study not only characterized the fibrosis microenvironment landscape of tendon adhesion by multi-omics analysis,but also uncovered a novel antifibrotic cluster of macrophages and their *** results provide potential therapeutic targets against human tendon adhesion.

关键词： tendon analysis landscape

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Development of pharmacological immunoregulatory anticancer therapeutics:current mechanistic studies and clinical opportunities

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Signal Transduction and Targeted Therapy 2024年第6期9卷 2477-2526页

作者： Nanhao Yin Xintong Li Xuanwei Zhang Shaolong Xue Yu Cao Gabriele Niedermann You Lu Jianxin Xue Division of Thoracic Tumor Multimodality Treatment Cancer Center&State Key Laboratory of Biotherapyand The National Clinical Research Center for GeriatricsWest China HospitalSichuan UniversityNo.37Guoxue LaneChengdu 610041 SichuanPR China department of Gynecology and Obstetrics West China Second University HospitalSichuan UniversityNo.20Section 3South Renmin RoadChengdu 610041 SichuanPR China department of Emergency Medicine Laboratory of Emergency MedicineWest China HospitalSichuan UniversityNo.37Guoxue LaneChengdu 610041 SichuanPR China Institute of Disaster Medicine&Institute of Emergency Medicine Sichuan UniversityNo.17Gaopeng AvenueChengdu 610041 SichuanPR China department of Radiation Oncology Medical Center—University of FreiburgFaculty of MedicineUniversity of FreiburgGerman Cancer Consortium(DKTK)Partner Site DKTK-FreiburgRobert-Koch-Strasse 379106 FreiburgGermany Laboratory of Clinical Cell Therapy West China HospitalSichuan UniversityNo.2222Xinchuan RoadChengdu 610041 SichuanPR China

Immunotherapy represented by anti-PD-(L)1 and anti-CTLA-4 inhibitors has revolutionized cancer treatment,but challenges related to resistance and toxicity still *** to the advancement of immuno-oncology,an increasing number of novel immunoregulatory targets and mechanisms are being revealed,with relevant therapies promising to improve clinical immunotherapy in the foreseeable ***,comprehending the larger picture is *** this review,we analyze and summarize the current landscape of preclinical and translational mechanistic research,drug development,and clinical trials that brought about next-generation pharmacological immunoregulatory anti-cancer agents and drug candidates beyond classical immune checkpoint *** with further clarification of cancer immunobiology and advances in antibody engineering,agents targeting additional inhibitory immune checkpoints,including LAG-3,TIM-3,TIGIT,CD47,and B7 family members are becoming an important part of cancer immunotherapy research and discovery,as are structurally and functionally optimized novel anti-PD-(L)1 and anti-CTLA-4 agents and agonists of co-stimulatory molecules of T *** by bispecific T cell engagers,newly emerging bi-specific and multi-specific antibodies targeting immunoregulatory molecules can provide considerable clinical ***-generation agents also include immune epigenetic drugs and cytokine-based *** therapies,cancer vaccines,and oncolytic viruses are not covered in this *** comprehensive review might aid in further development and the fastest possible clinical adoption of effective immuno-oncology modalities for the benefit of patients.

关键词： clinical immuno landscape

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Anti-vascular endothelial growth factor drugs combined with laser photocoagulation maintain retinal ganglion cell integrity in patients with diabetic macular edema: study protocol for a prospective, non-randomized, controlled clinical trial

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Neural Regeneration Research 2024年第4期19卷 923-928页

作者： Xiangjun Li Chunyan Li Hai Huang Dan Bai Jingyi Wang Anqi Chen Yu Gong Ying Leng department of Ophthalmology Affiliated Hospital of Beihua University department of Endocrinology Affiliated Hospital of Beihua University

The integrity of retinal ganglion cells is tightly associated with diabetic macular degeneration that leads to damage and death of retinal ganglion cells,affecting *** major clinical treatments for diabetic macular edema are anti-vascular endothelial growth factor drugs and laser ***,although the macular thickness can be normalized with each of these two therapies used alone,the vision does not improve in many *** might result from the incomplete recovery of retinal ganglion cell ***,a prospective,non-randomized,controlled clinical trial was designed to investigate the effect of anti-vascular endothelial growth factor drugs combined with laser photocoagulation on the integrity of retinal ganglion cells in patients with diabetic macular edema and its relationship with vision *** this trial,150 patients with diabetic macular edema will be equally divided into three groups according to therapeutic methods,followed by treatment with anti-vascular endothelial growth factor drugs,laser photocoagulation therapy,and their *** patients will be followed up for 12 *** primary outcome measure is retinal ganglion cell-inner plexiform layer thickness at 12 months after *** secondary outcome measures include retinal ganglion cell-inner plexiform layer thickness before and 1,3,6,and 9 months after treatment,retinal nerve fiber layer thickness,best-corrected visual acuity,macular area thickness,and choroidal thickness before and 1,3,6,9,and 12 months after *** measure is the incidence of adverse events at 1,3,6,9,and 12 months after *** study protocol hopes to validate the better efficacy and safety of the combined treatment in patients with diabetic macula compared with the other two monotherapies alone during the 12-month follow-up *** trial is designed to focus on clarifying the time-effect relationship between imaging measures related to the integrity of retinal

关键词： choroidal thickness diabetic macular edema laser photocoagulation retinal ganglion cell-inner plexiform layer thickness retinal ganglion cells retinal nerve fiber layer thickness thickness of the macular area vascular endothelial growth factor visual acuity

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Flux Balance Analysis Reveals Potential Anti-HIV-1 Metabolic Targets

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Infectious Diseases & Immunity 2024年第2期4卷 61-68页

作者： Runpeng Han Fei Luo Haisheng Yu Yajun Yan Yan Gong Conghua Xie Liang Cheng department of Radiation and Medical Oncology Medical Research InstituteZhongnan Hospital of Wuhan UniversityWuhan UniversityWuhan 430071China Frontier Science Center for Immunology and Metabolism Zhongnan Hospital of Wuhan UniversityState Key Laboratory of VirologyWuhan UniversityWuhan 430071China Guangzhou Eighth People's Hospital Guangzhou Medical UniversityGuangzhou 510440China department of Infectious Diseases Zhongnan Hospital of Wuhan UniversityWuhan 430071China department of Biological Repositories Zhongnan Hospital of Wuhan UniversityWuhan 430071China Wuhan Research Center for Infectious Diseases and cancer Chinese Academy of Medical SciencesWuhan 430071China

Background:Human immunodeficiency virus type 1(HIV-1)remains a persistent global health ***,a continuous exploration of novel therapeutic strategies is essential.A comprehensive understanding of how HIV-1 utilizes the cellular metabolism machinery for replication can provide insights into new therapeutic ***:In this study,we performed a flux balance analysis using a genome-scale metabolic model(GEM)integrated with an HIV-1 viral biomass objective function to identify potential targets for anti–HIV-1 *** generated a GEM by integrating an HIV-1 production reaction into CD4+T cells and optimized for both host and virus optimal states as objective functions to depict metabolic profiles of cells in the status for optimal host biomass maintenance or for optimal HIV-1 virion *** analysis was used to predict biochemical reactions altered optimal for HIV-1 *** addition,we conducted in silico simulations involving gene and reaction knock-outs to identify potential anti–HIV-1 targets,which were subsequently validated by human phytohemagglutinin(PHA)blasts infected with ***:Differential analysis identified several altered biochemical reactions,including increased lysine uptake and oxidative phosphorylation(OXPHOS)activities in the virus optima compared with the host *** silico gene and reaction knock-out simulations revealed de novo pyrimidine synthesis,and OXPHOS could serve as potential anti–HIV-1 metabolic *** vitro assay confirmed that targeting OXPHOS using metformin could suppress the replication of HIV-1 by 56.6%(385.4±67.5 pg/mL in the metformintreated group vs.888.4±32.3 pg/mL in the control group,Ptherapies.

关键词： HIV-1 Flux balance analysis Genome-scale metabolic models Viral biomass objective function Therapeutic target

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Overview of perspectives on cancer,newer therapies,and future directions

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Oncology and Translational Medicine 2024年第3期10卷 105-109页

作者： Rajeev M.Joshi Bhushan Telang Gagan Soni Asma Khalife department of General Surgery T.N.Medical College&B.Y.L.Nair Charitable HospitalMumbaiIndia department of Surgical Oncology Government Cancer Hospital AurangabadMaharashtraIndia department of Surgical Disciplines All India Institute of Medical ScienceNew DelhiIndia

Theword“cancer”is associated with terrifying situations,and there is often an aggressive intent to *** about survival and fear of disfigurement cause major turmoil in the minds of patients and *** with multimodal care is the key to achieving satisfactory *** imaging modalities have aided in early detection and derivation of optimal treatment *** radical excision of tumors with neoadjuvant or concurrent chemotherapy/radiotherapy has long been the best management option,we have moved froma radical to a conservative *** advanced disease,the plan should be to provide supportive care and improve quality of *** and counseling play important *** support for correcting cancer cachexia is equally important during tumor *** therapies such as targeted therapy,stem cell therapy,and chemodynamic therapy are all focused on ensuring safe and efficient outcomes;however,the war against cancer continues to oscillate between hope and despair.

关键词： cancer Modern medicine Preventive oncology Psychology Nutrition

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