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Targeting proprotein convertase subtilisin/kexin type 9(PCSK9):from bench to bedside

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Signal Transduction and Targeted Therapy 2024年第2期9卷 509-557页

作者： Xuhui Bao Yongjun Liang Hanman Chang Tianji Cai Baijie Feng Konstantin Gordon Yuekun Zhu Hailian Shi Yundong He Liyi Xie Institute of Therapeutic cancer Vaccines Fudan University Pudong Medical CenterShanghaiChina Shanghai Key Laboratory of Regulatory Biology School of Life SciencesEast China Normal UniversityShanghaiChina department of Oncology Fudan University Pudong Medical CenterShanghaiChina Center for Clinical Research Fudan University Pudong Medical CenterShanghaiChina Clinical Research Center for Cell-based Immunotherapy Fudan UniversityShanghaiChina department of Pathology Duke University Medical CenterDurhamNCUSA Center for Medical Research and Innovation Fudan University Pudong Medical CenterShanghaiChina Institute for Food Safety and Health Illinois Institute of TechnologyChicagoILUSA department of Sociology University of MacaoTaipaMacaoChina Medical Institute Peoples’Friendship University of RussiaMoscowRussia A.Tsyb Medical Radiological Research Center ObninskRussia department of Colorectal Surgery The First Affiliated Hospital of Harbin Medical UniversityHarbinHeilongjiangChina Shanghai Key Laboratory of Compound Chinese Medicines Institute of Chinese Materia MedicaShanghai University of Traditional Chinese MedicineZhangjiang Hi-tech ParkShanghaiChina department of Radiation Oncology Fudan University Shanghai Cancer CenterShanghaiChina department of Oncology Shanghai Medical CollegeFudan UniversityShanghaiChina

Proprotein convertase subtilisin/kexin type 9(PCSK9)has evolved as a pivotal enzyme in lipid metabolism and a revolutionary therapeutic target for hypercholesterolemia and its related cardiovascular diseases(CVD).This comprehensive review delineates the intricate roles and wide-ranging implications of PCSK9,extending beyond CVD to emphasize its significance in diverse physiological and pathological states,including liver diseases,infectious diseases,autoimmune disorders,and notably,*** exploration offers insights into the interaction between PCSK9 and low-density lipoprotein receptors(LDLRs),elucidating its substantial impact on cholesterol homeostasis and cardiovascular *** also details the evolution of PCSK9-targeted therapies,translating foundational bench discoveries into bedside applications for optimized patient *** advent and clinical approval of innovative PCSK9 inhibitory therapies(PCSK9-iTs),including three monoclonal antibodies(Evolocumab,Alirocumab,and Tafolecimab)and one small interfering RNA(siRNA,Inclisiran),have marked a significant breakthrough in cardiovascular *** therapies have demonstrated unparalleled efficacy in mitigating hypercholesterolemia,reducing cardiovascular risks,and have showcased profound value in clinical applications,offering novel therapeutic avenues and a promising future in personalized medicine for cardiovascular ***,emerging research,inclusive of our findings,unveils PCSK9’s potential role as a pivotal indicator for cancer prognosis and its prospective application as a transformative target for cancer *** review also highlights PCSK9’s aberrant expression in various cancer forms,its association with cancer prognosis,and its crucial roles in carcinogenesis and cancer *** conclusion,this synthesized review integrates existing knowledge and novel insights on PCSK9,providing a holistic perspective on its transformative impact in reshaping therapeutic paradigms acr

关键词： PCSK9 metabolism convert

CRISPR beyond: harnessing compact RNA-guided endonucleases for enhanced genome editing

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Science China Life Sciences 2024年

作者： Feizuo Wang Shengsheng Ma Senfeng Zhang Quanquan Ji Chunyi Hu department of Biological Sciences Faculty of Science National University of Singapore cancer Science Institute of Singapore National University of Singapore department of Biochemistry Yong Loo Lin School of Medicine National University of Singapore Precision Medicine Translational Research Programme (TRP) Yong Loo Lin School of Medicine National University of Singapore

The CRISPR-Cas system, an adaptive immunity system in prokaryotes designed to combat phages and foreign nucleic acids, has evolved into a groundbreaking technology enabling gene knockout, large-scale gene insertion, base editing, and nucleic acid detection. Despite its transformative impact, the conventional CRISPR-Cas effectors face a significant hurdle—their size poses challenges in effective delivery into organisms and cells. Recognizing this limitation, the imperative arises for the development of compact and miniature gene editors to propel advancements in gene-editing-related therapies. Two strategies were accepted to develop compact genome editors: harnessing OMEGA(Obligate Mobile Element-guided Activity) systems, or engineering the existing CRISPR-Cas system. In this review, we focus on the advances in miniature genome editors based on both of these strategies. The objective is to unveil unprecedented opportunities in genome editing by embracing smaller, yet highly efficient genome editors, promising a future characterized by enhanced precision and adaptability in the genetic interventions.

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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

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

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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Recent advances and remaining challenges in lung cancer therapy

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Chinese Medical Journal 2024年第5期137卷 533-546页

作者： Tasha Barr Shoubao Ma Zhixin Li Jianhua Yu department of Hematology and Hematopoietic Cell Transplantation City of Hope National Medical CenterLos AngelesCalifornia 91010USA Comprehensive cancer Center City of HopeLos AngelesCalifornia 91010USA department of Immuno-Oncology Beckman Research InstituteLos AngelesCalifornia 91010USA

Lung cancer remains the most common cause of cancer *** the continued research into new drugs and combination therapies,outcomes in lung cancer have been improved,and clinical benefits have been expanded to a broader patient ***,the overall cure and survival rates for lung cancer patients remain low,especially in metastatic *** the available lung cancer treatment options,such as surgery,radiation therapy,chemotherapy,targeted therapies,and alternative therapies,immunotherapy has shown to be the most *** exponential progress in immuno-oncology research and recent advancements made in the field of immunotherapy will further increase the survival and quality of life for lung cancer *** progress has been made in targeted therapies using tyrosine kinase inhibitors and monoclonal antibody immune checkpoint inhibitors with many US Food And Drug Administration(FDA)-approved drugs targeting the programmed cell death ligand-1 protein(e.g.,durvalumab,atezolizumab),the programmed cell death-1 receptor(e.g.,nivolumab,pembrolizumab),and cytotoxic T-lymphocyte-associated antigen 4(e.g.,tremelimumab,ipilimumab).Cytokines,cancer vaccines,adoptive T cell therapies,and Natural killer cell mono-and combinational therapies are rapidly being studied,yet to date,there are currently none that are FDA-approved for the treatment of lung *** this review,we discuss the current lung cancer therapies with an emphasis on immunotherapy,including the challenges for future research and clinical applications.

关键词： Lung cancer Therapy Immunotherapy Combination therapy Adoptive T cell therapies

Pharmacological methods for ovarian function and fertility preservation in women with cancer:A literature review

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Oncology Research 2024年第8期32卷 1309-1322页

作者： ANA S.CVETANOVIC MATTEO LAMBERTINI KEVIN PUNIE GORANA G.MATOVINA BRKO NIKOLA D.ZIVKOVIC MAJA J.POPOVIC MARIJANA M.MILOVIC KOVACEVIC LAZAR S.POPOVIC department for Oncology Medical Faculty NisUniversity of NisNis18000Serbia Clinic of Oncology University Clinical Centre NisNis18000Serbia department of Internal Medicine and Medical Sciences(DiMI) School of MedicineUniversity of GenovaGenova16100Italy department of Medical Oncology U.O.C Clinica di Oncologia MedicaIRCCS Ospedale Policlinico San MartinoGenova16100Italy department of General Medical Oncology and Multidisciplinary Breast Centre Leuven Cancer InstituteUniversity Hospitals LeuvenLeuven3001Belgium department of Medical Oncology Oncology Institute of VojvodinaSremska Kamenica21208Serbia department for Pathology Medical Faculty NisUniversity of NisNis18000Serbia Center for Pathology University Clinical Centre NisNis18000Serbia Faculty of Medicine University of Novi SadNovi Sad21000Serbia department of Medical Oncology Institute of Oncology and Radiology SerbiaBelgrade11000Serbia

Oncofertility is an extremely signiﬁcant topic that is increasingly being discussed owing to increased evidence indicating that fertility preservation does not affect the treatment outcomes of patients with cancer but signiﬁcantly contributes to preserving life *** effect of chemotherapy can range from minimal effects to complete ovarian *** data are available on the effects of monoclonal antibodies and targeted therapies on the ovaries and *** ovarian suppression by administering a gonadotropin-releasing hormone agonist(GnRHa)during chemotherapy decreases the gonadotoxic effect of chemotherapy,thereby diminishing the chance of developing premature ovarian insufﬁciency(POI).At present,the concomitant administration of GnRH analogs during chemotherapy is the only accepted pharmacological method for preserving ovarian ***,most randomized studies on the effectiveness of luteinizing hormone-releasing hormone agonists during chemotherapy in preventing POI have been conducted in women with breast cancer,with a considerably small number of studies on patients with hematological ***,most randomized controlled trials on breast cancer have revealed a decrease in treatment-induced POI risk,regardless of the hormone receptor *** addition,studies on hematological malignancies have yielded negative results;nevertheless,theﬁndings must be interpreted with caution owing to numerous *** guidelines from the American Society of Clinical Oncology and ESMO Clinical Practice Guidelines recommend sperm,oocyte,and embryo cryopreservation as a standard practice and only offering GnRHa to patients when proven fertility preservation methods are not *** this manuscript,we present a comprehensive literature overview on the application of ovarian suppression with GnRHa during chemotherapy in patients with cancer by addressing preclinical and clinical data,as well as future perspectives in thisﬁeld

关键词： Gonadotropin-releasing hormone agonists(GnRHa) Fertility preservation Premature ovarian insufficiency(POI) Premenopausal patients

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

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