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Dostarlimab in the treatment of mismatch repair deficient recurrent or advanced endometrial cancer

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Cancer Pathogenesis and Therapy 2024年第3期2卷 135-141页

作者： Siddhant Shukla Harsh Patel Shuzhen chen Rainie Sun Liuya Wei zhe-sheng chen Institute for Biotechnology St.John's UniversityNew YorkNew York 11439United States Department of Pharmaceutical Sciences College of Pharmacy and Health SciencesSt.John's UniversityNew YorkNew York 11439United States School of Pharmacy Weifang Medical UniversityWeifangShandong 261053China Stuyvesant High School New YorkNew York 10282United States

Dostarlimab,a programmed death receptor-1(PD-1)-blocking IgG4 humanized monoclonal antibody,gained accelerated approval from the US Food and Drug Administration(FDA)in April 2021,and received a full approval in February *** was approved for treating adult patients with mismatch repair deficient(dMMR)recurrent or advanced endometrial cancer(EC)that progressed during or after prior treatment who have no other suitable treatment ***,we review the structure-based mechanism of action of dostarlimab and the results of a clinical study(GARNET;NCT02715284)to comprehensively clarify the efficacy and toxicity of the *** efficacy and safety of dostarlimab as monotherapy was assessed in a non-randomized,multicenter,open-label,multi-cohort trial that included 209 patients with dMMR recurrent or advanced solid tumors after receiving systemic *** received 500 mg of dostarlimab intravenously every three weeks until they were given four ***,patients received 1000 mg dostarlimab intravenously every six weeks until disease progression or unacceptable *** overall response rate,as determined by shrinkage in tumor size,was 41.6%(95%confidence interval[CI];34.9,48.6),with 34.7 months as the median response *** conclusion,dostarlimab is an immunotherapy-based drug that has shown promising results in adult patients with recurrent or advanced dMMR ***,its efficacy in other cancer subtypes,the development of resistance to monotherapy,and efficacy and safety in combination with other immunotherapeutic drugs have not yet been studied.

关键词： Dostarlimab PD-1 Immunotherapy Endometrial cancer Check-point inhibitor

Redox signaling-governed drug-tolerant persister cancer cell:a key spark of treatment failure

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Signal Transduction and Targeted Therapy 2022年第4期7卷 955-957页

作者： Liwu Fu zhe-sheng chen State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer MedicineGuangdong Esophageal Cancer InstituteCancer CenterSun Yat-Sen UniversityGuangzhou 510060China Department of Pharmaceutical Sciences College of Pharmacy and Health SciencesSt.John’s UniversityQueensNY 11439USA Institute for Biotechnology St.John’s UniversityQueensNY 11439USA

In a recent study published in EMBO Molecular medicine,Zhang et *** a novel insight regarding better knowledge of the drug resistant contribution of drug-tolerant persister(DTP)state in tumor evolution,especially in terms of mechanistic insights into redox regulation involved,unambiguously establishing a novel therapeutic strategy of treating multi-drug-resistant(MDR)cancer cells and preventing tumor recurrence by disequilibrating Niemann–Pick C1-like 1(NPC1L1)-mediated redox homeostasis.

关键词： cancer homeostasis insight

Progress in the studies on the molecular mechanisms associated with multidrug resistance in cancers

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Acta Pharmaceutica Sinica B 2023年第3期13卷 982-997页

作者： Lei Zhang Biwei Ye Zhuo chen zhe-sheng chen State Key Laboratory of Structural Chemistry Fujian Institute of Research on the Structure of MatterChinese Academy of SciencesFuzhou 350002China University of Chinese Academy of Sciences Beijing 100049China Fujian Agriculture and Forestry University Fuzhou 350002China Department of Pharmaceutical Sciences College of Pharmacy and Health SciencesSt.John's UniversityNew YorkNY 11439USA

Chemotherapy is one of the important methods to treat cancer,and the emergence of multidrug resistance(MDR)is one major cause for the failure of cancer *** all anti-tumor drugs develop drug resistance over a period of time of application in cancer patients,reducing their effects on killing cancer *** can lead to a rapid recurrence of cancers and ultimately patient *** may be induced by multiple mechanisms,which are associated with a complex process of multiple genes,factors,pathways,and multiple steps,and today the MDR-associated mechanisms are largely *** this paper,from the aspects of protein–protein interactions,alternative splicing(AS)in pre-mRNA,non-coding RNA(ncRNA)mediation,genome mutations,variance in cell functions,and influence from the tumor microenvironment,we summarize the molecular mechanisms associated with MDR in *** the end,prospects for the exploration of antitumor drugs that can reverse MDR are briefly discussed from the angle of drug systems with improved targeting properties,biocompatibility,availability,and other advantages.

关键词： Multidrug resistance(MDR) ABC transporter family Signaling pathway Alternative splicing(AS) Gene mutation None-coding RNA(ncRNA) Tumor microenvironment

Gut microbes regulate the feeding center:a newdiscovery of Gut Brain Axis

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Signal Transduction and Targeted Therapy 2022年第9期7卷 3168-3169页

作者： Fengwu chen Kajian Hou zhe-sheng chen Department of Endocrinology and metbolic diseases The First Afliated Hospital of Shantou University Medical Collge515000 ShantouGuangdongPR China Department of Pharmaceutical Sciences College of Pharmacy and Health SciencesSt.John's UniversityNew YorkNY 11439USA

Recently,llana Gabanyi and colleagues published an article in Science,1identifying a microbial sensing mechanism that regulates feeding behavior and host *** their study,a sex-and age-dependent gut-brain cross-talk is *** study confrmed that hypothalamic neurons can directly sense the structural components of the gut bacterial microbiota and regulate feeding and nesting behavior,affecting food intake and body temperature.

关键词： temperature. intake feeding

Signaling pathways and therapeutic interventions in gastric cancer

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Signal Transduction and Targeted Therapy 2022年第11期7卷 4118-4155页

作者： Zi-Ning Lei Qiu-Xu Teng Qin Tian Wei chen Yuhao Xie Kaiming Wu Qianlin Zeng Leli Zeng Yihang Pan zhe-sheng chen Yulong He Guangdong Provincial Key Laboratory of Digestive Cancer Research Digestive Diseases CenterScientific Research CenterThe Seventh Affiliated Hospital of Sun Yat-Sen University518107ShenzhenGuangdongChina Department of Pharmaceutical Sciences College of Pharmacy and Health SciencesSt.John’s UniversityQueensNY11439USA Institute for Biotechnology St.John’s UniversityQueensNY11439USA

Gastric cancer(GC)ranks fifth in global cancer diagnosis and fourth in cancer-related *** tremendous progress in diagnosis and therapeutic strategies and significant improvements in patient survival,the low malignancy stage is relatively asymptomatic and many GC cases are diagnosed at advanced stages,which leads to unsatisfactory prognosis and high recurrence *** the recent advances in genome analysis,biomarkers have been identified that have clinical importance for GC diagnosis,treatment,and *** molecular classifications have uncovered the vital roles that signaling pathways,including EGFR/HER2,p53,PI3K,immune checkpoint pathways,and cell adhesion signaling molecules,play in GC tumorigenesis,progression,metastasis,and therapeutic *** biomarkers and molecular classifications open the way for more precise diagnoses and treatments for GC ***,the relative significance,temporal activation,interaction with GC risk factors,and crosstalk between these signaling pathways in GC are not well ***,we review the regulatory roles of signaling pathways in GC potential biomarkers,and therapeutic targets with an emphasis on recent *** therapies,including signaling-based and immunotherapies exploited in the past decade,and the development of treatment for GC,particularly the challenges in developing precision medications,are *** advances provide a direction for the integration of clinical,molecular,and genomic profiles to improve GC diagnosis and treatments.

关键词： diagnosis therapeutic precise

Tumor cell plasticity in targeted therapy-induced resistance:mechanisms and new strategies

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Signal Transduction and Targeted Therapy 2023年第4期8卷 1503-1523页

作者： zhen-Duo Shi Kun Pang Zhuo-Xun Wu Yang Dong Lin Hao Jia-Xin Qin Wei Wang zhe-sheng chen Cong-Hui Han Department of Urology Xuzhou Clinical School of Xuzhou Medical UniversityJiangsuChina Department of Urology Xuzhou Central HospitalXuzhouJiangsuChina School of Life Sciences Jiangsu Normal UniversityJiangsuChina Department of Urology Heilongjiang Provincial HospitalHeilongjiangChina Department of Pharmaceutical Sciences College of Pharmacy and Health SciencesSt.John’s UniversityQueensNY 11439USA Department of Medical College Southeast UniversityNanjingChina

Despite the success of targeted therapies in cancer treatment,therapy-induced resistance remains a major obstacle to a *** cells evade treatments and relapse via phenotypic switching driven by intrinsic or induced cell *** mechanisms have been proposed to circumvent tumor cell plasticity,including epigenetic modifications,regulation oftranscription factors,activation or suppression of key signaling pathways,as well as modification of the tumor ***-to-mesenchymal transition,tumor cell and cancer stem cell formation also serve as roads towards tumor cell *** treatment strategies have recently been developed that either target plasticity-related mechanisms or employcombination *** this review,we delineate the formation of tumor cell plasticity and its manipulation of tumor evasionfrom targeted *** discuss the non-genetic mechanisms of targeted drug-induced tumor cell plasticity in various types oftumors and provide insights into the contribution of tumor cell plasticity to acquired drug *** therapeutic strategiessuch as inhibition or reversal of tumor cell plasticity are also *** also discuss the multitude of clinical trials that areongoing worldwide with the intention of improving clinical *** advances provide a direction for developing noveltherapeutic strategies and combination therapy regimens that target tumor cell plasticity.

关键词： targeted plasticity resistance

Microbiota in health and diseases

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Signal Transduction and Targeted Therapy 2022年第5期7卷 1491-1518页

作者： Kaijian Hou Zhuo-Xun Wu Xuan-Yu chen Jing-Quan Wang Dongya Zhang Chuanxing Xiao Dan Zhu Jagadish B.Koya Liuya Wei Jilin Li zhe-sheng chen Department of Endocrine and Metabolic Diseases Longhu HospitalThe First Affiliated Hospital of Medical College of Shantou UniversityShantouGuangdong 515000China Department of Pharmaceutical Sciences Institute for BiotechnologyCollege of Pharmacy and Health SciencesSt.John’s UniversityQueensNY 11439USA Microbiome Research Center Moon(Guangzhou)Biotech LtdGuangzhou 510535China School of Pharmacy Weifang Medical UniversityWeifangShandong 261053China Department of Cardiovascular The Second Affiliated Hospital of Medical College of Shantou UniversityShantouGuangdong 515000China

The role of microbiota in health and diseases is being highlighted by numerous studies since its *** on the localized regions,microbiota can be classified into gut,oral,respiratory,and skin *** microbial communities are in symbiosis with the host,contributing to homeostasis and regulating immune ***,microbiota dysbiosis can lead to dysregulation of bodily functions and diseases including cardiovascular diseases(CVDs),cancers,respiratory diseases.

关键词： diseases respiratory homeostasis

MET inhibitor tepotinib antagonizes multidrug resistance mediated by ABCG2 transporter:In vitro and in vivo study

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Acta Pharmaceutica Sinica B 2022年第5期12卷 2609-2618页

作者： Zhuo-Xun Wu Qiu-Xu Teng Yuqi Yang Nikita Acharekar Jing-Quan Wang Min He Sabesan Yoganathan Jun Lin Jian Wang zhe-sheng chen Department of Pharmaceutical Sciences College of Pharmacy and Health SciencesSt.John’s UniversityQueensNY 11439USA Department of Anesthesiology Stony Brook University Health Sciences CenterStony BrookNY 11794USA Department of Radiotherapy the Afﬁliated Jiangyin People’s Hospital of Nantong UniversityJiangyin 214400China

Overexpression of ABCG2 transporter in cancer cells has been linked to the development of multidrug resistance(MDR), an obstacle to cancer therapy. Our recent study uncovered that the MET inhibitor,tepotinib, is a potent reversal agent for ABCB1-mediated MDR. In the present study, we reported for the first time that the MET inhibitor tepotinib can also reverse ABCG2-mediated MDR in vitro and in vivo by directly binding to the drug-binding site of ABCG2 and reversibly inhibiting ABCG2 drug efflux activity, therefore enhancing the cytotoxicity of substrate drugs in drug-resistant cancer cells. Furthermore, the ABCB1/ABCG2 double-transfected cell model and ABCG2 gene knockout cell model demonstrated that tepotinib specifically inhibits the two MDR transporters. In mice bearing drug-resistant tumors, tepotinib increased the intratumoral accumulation of ABCG2 substrate drug topotecan and enhanced its antitumor effect. Therefore, our study provides a new potential of repositioning tepotinib as an ABCG2 inhibitor and combining tepotinib with substrate drugs to antagonize ABCG2-mediated MDR.

关键词： MET inhibitor Tepotinib Multidrug resistance ABCG2 transporter Reversal agent Combination treatment Chemotherapy In vivo study

Influences of shale microstructure on mechanical properties and bedding fractures distribution

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Petroleum Science 2024年第3期21卷 1944-1954页

作者： Ming-zhe Gu Mao sheng Shi-Zhong cheng Fan-Hao Gong Gen-sheng Li State Key Laboratory of Petroleum Resources and Engineering China University of Petroleum-BeijingBeijing2249China College of Petroleum Engineering China University of Petroleum-BeijingBeijing102249China Shenyang Center of China Geological Survey ShenyangLiaoning110034China

The difference in microstructure leads to the diversity of shale mechanical properties and bedding fractures distribution *** this paper,the microstructure and mechanical properties of Longmaxi marine shale and Qingshankou continental shale were studied by X-ray diffractometer(XRD),field emission scanning electron microscope(FE-SEM)with mineral analysis system,and ***,the typical bedding layers area was properly stratified using Focused Ion Beam(FIB),and the effects of microstructure and mechanical properties on the distribution patterns of bedding fractures were *** results show that the Longmaxi marine shale sample contains more clay mineral grains,while the Qingshankou continental shale sample contains more hard brittle mineral grains such as *** Longmaxi marine shale sample,hard brittle minerals with grain sizes larger than 20μm is18.24%and those with grain sizes smaller than 20μm is 16.22%.For Qingshankou continental shale sample,hard brittle minerals with grain sizes larger than 20μm is 40.7%and those with grain sizes smaller than 20μm is 11.82%.In comparison to the Qingshankou continental shale sample,the Longmaxi marine shale sample has a lower modulus,hardness,and *** shales are formed by alternating coarse-grained and fine-grained layers during *** average single-layer thickness of Longmaxi marine shale sample is greater than Qingshankou continental shale *** two types of shale have similar bedding fractures distribution patterns and fractures tend to occur in the transition zone from coarse-grained to fine-grained *** orientation of the fracture is usually parallel to the bedding plane and detour occurs in the presence of hard brittle *** fracture distribution density of the Longmaxi marine shale sample is lower than that of the Qingshankou continental shale sample due to the strong heterogeneity of the Qingshankou continental *** current resea

关键词： Shale Nanoindentation Microstructure Mechanical property Fracture