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Novel biomarkers and the future of targeted therapies in cholangiocarcinoma:a narrative review

Hepatobiliary Surgery and Nutrition 2022年第2期11卷 253-266页

作者： Nishant Munugala Shishir K.Maithel Rachna T.Shroff Department of Medicine University of ArizonaTucsonAZUSA Division of Surgical Oncology Emory UniversityWinship Cancer InstituteAtlantaGAUSA Division of Hematology and Oncology Department of GI Medical OncologyUniversity of Arizona Cancer CenterTucsonAZUSA

Background and Objectives:Cholangiocarcinoma is a highly aggressive and heterogenous group of biliary malignancies arising from any site in the biliary tree,comprising 15%of all primary liver cancers.The nature of the disease and nonspecific presentation leads to late diagnosis and ultimately poor outcomes for patients.Combination gemcitabine and cisplatin has been the standard of care for cholangiocarcinoma(CCA)since 2010,with a median overall survival of 11.7 months.The five-year survival for CCA remains 5-10%,revealing a clear need for improved treatment options.Methods:This targeted review highlights the role of next generation sequencing in CCA and the clinically relevant tumor biomarkers that have become the focus of therapeutic development.Key Content and Findings:These tumor biomarkers or actionable mutations hold the potential to enable earlier diagnosis,provide prognostic information,and guide treatment decisions for patients with CCA.Specifically,the FGFR2 fusion and IDH1 mutation have shown considerable promise in development of targeted therapies.Clinical trials with inhibitors targeting FGFR2 fusion and IDH1 mutation have created expectations that these drugs will soon enter clinical practice.Other biomarkers including KRAS and B-raf protooncogenes,Her2/neu genes,and BRCA1 and 2 tumor-suppressor genes have also been touted as potential targets for future therapies,with early data showing promise for new drug development.Conclusions:The discovery of these actionable mutations and identification of targeted therapies have challenged the notion of a“one-size fits all”for treatment of CCA,and generated optimism that these novel treatments will soon be available for patients with CCA.

关键词： Cholangiocarcinoma(CCA) targeted therapies IDH FGFR2 fusion tumor biomarkers

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Role of glioma stem cells in promoting tumor chemo- and radioresistance: A systematic review of potential targeted treatments

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World Journal of Stem Cells 2024年第5期16卷 604-614页

作者： Edoardo Agosti Marco Zeppieri Mattia Ghidoni Tamara Ius Alessandro Tel Marco Maria Fontanella Pier Paolo Panciani Division of Neurosurgery Department of Medical and Surgical SpecialtiesRadiological Sciences and Public HealthUniversity of BresciaBrescia 25123Italy Department of Ophthalmology University Hospital of UdineUdine 33100Italy Neurosurgery Unit Department of Head-Neck and NeuroScienceUniversity Hospital of UdineUdine 33100Italy Clinic of Maxillofacial Surgery Department of Head-Neck and NeuroScienceUniversity Hospital of UdineUdine 33100Italy

BACKGROUND Gliomas pose a significant challenge to effective treatment despite advancements in chemotherapy and radiotherapy.Glioma stem cells(GSCs),a subset within tumors,contribute to resistance,tumor heterogeneity,and plasticity.Recent studies reveal GSCs’role in therapeutic resistance,driven by DNA repair mechanisms and dynamic transitions between cellular states.Resistance mechanisms can involve different cellular pathways,most of which have been recently reported in the literature.Despite progress,targeted therapeutic approaches lack consensus due to GSCs’high plasticity.AIM To analyze targeted therapies against GSC-mediated resistance to radio-and chemotherapy in gliomas,focusing on underlying mechanisms.METHODS A systematic search was conducted across major medical databases(PubMed,Embase,and Cochrane Library)up to September 30,2023.The search strategy utilized relevant Medical Subject Heading terms and keywords related to including“glioma stem cells”,“radiotherapy”,“chemotherapy”,“resistance”,and“targeted therapies”.Studies included in this review were publications focusing on targeted therapies against the molecular mechanism of GSC-mediated re-sistance to radiotherapy resistance(RTR).RESULTS In a comprehensive review of 66 studies on stem cell therapies for SCI,452 papers were initially identified,with 203 chosen for full-text analysis.Among them,201 were deemed eligible after excluding 168 for various reasons.The temporal breakdown of studies illustrates this trend:2005-2010(33.3%),2011-2015(36.4%),and 2016-2022(30.3%).Key GSC models,particularly U87(33.3%),U251(15.2%),and T98G(15.2%),emerge as significant in research,reflecting their representativeness of glioma characteristics.Pathway analysis indicates a focus on phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin(mTOR)(27.3%)and Notch(12.1%)pathways,suggesting their crucial roles in resistance development.targeted molecules with mTOR(18.2%),CHK1/2(15.2%),and ATP binding cassette G2(12.1%)as frequent targets underscore their im

关键词： Glioma stem cells Chemoresistance Radioresistance Molecular pathways targeted therapies Systematic review

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Knockdown of HE4 suppresses tumor growth and invasiveness in lung adenocarcinoma through regulation of EGFR signaling

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Oncology Research 2024年第6期32卷 1119-1128页

作者： YUE ZHANG WENYU YANG XIAOWANG HAN YUE QIAO HAITAO WANG TING CHEN TIANYING LI WEN-BIN OU Department of Biopharmaceutics College of Life Sciences and MedicineZhejiang Provincial Key Laboratory of Silkworm Bioreactor and BiomedicineZhejiang Sci-Tech UniversityHangzhou310018China Department of Thoracic Surgery Zhejiang Provincial People’s HospitalHangzhou310014China

It has been shown that the high expression of human epididymis protein 4(HE4)in most lung cancers is related to the poor prognosis of patients,but the mechanism of pathological transformation of HE4 in lung cancer is still unclear.The current study is expected to clarify the function and mechanism of HE4 in the occurrence and metastasis of lung adenocarcinoma(LUAD).Immunoblotting evaluated HE4 expression in lung cancer cell lines and biopsies,and through analysis of The Cancer Genome Atlas(TCGA)dataset.Frequent HE4 overexpression was demonstrated in LUAD,but not in lung squamous cell carcinoma(LUSC),indicating that HE4 can serve as a biomarker to distinguish between LUAD and LUSC.HE4 knockdown significantly inhibited cell growth,colony formation,wound healing,and invasion,and blocked the G1-phase of the cell cycle in LUAD cell lines through inactivation of the EGFR signaling downstream including PI3K/AKT/mTOR and RAF/MAPK pathways.The first-line EGFR inhibitor gefitinib and HE4 shRNA had no synergistic inhibitory effect on the growth of lung adenocarcinoma cells,while the third-line EGFR inhibitor osimertinib showed additive anti-proliferative effects.Moreover,we provided evidence that HE4 regulated EGFR expression by transcription regulation and protein interaction in LUAD.Our findings suggest that HE4 positively modulates the EGFR signaling pathway to promote growth and invasiveness in LUAD and highlight that targeting HE4 could be a novel strategy for LUAD treatment.

关键词： Lung adenocarcinoma Human epididymis protein 4 Epidermal growth factor receptor Biomarker targeted therapies

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Senescence in chronic wounds and potential targeted therapies

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Burns & Trauma 2022年第1期10卷 742-756页

作者： Xuerong Wei Minxiong Li Zijun Zheng Jun Ma Yanbin Gao Lianglong Chen Yujie Peng Shengxiang Yu Lei Yang Department of Burns Nanfang HospitalSouthern Medical UniversityJingxi StreetBaiyun DistrictGuangzhou510515China Department of Plastic and Reconstructive Surgery Shanghai Ninth People’s HospitalShanghai JiaoTong University School of Medicine639 Zhizaoju Road200011ShanghaiChina

Chronic wounds(e.***.diabetic wounds,pressure wounds,vascular ulcers,etc.)do not usually heal in a timely and orderly manner but rather last for years and may lead to irreversible adverse events,resulting in a substantial financial burden for patients and society.Recently,a large amount of evidence has proven that cellular senescence has a crucial influence on chronic nonhealing wounds.As a defensive mechanism,cell senescence is a manner of cell-cycle arrest with increased secretory phenotype to resist death,preventing cells from stress-induced damage in cancer and noncancer diseases.A growing amount of research has advanced the perception of cell senescence in various chronic wounds and focuses on pathological and physiological processes and therapies targeting senescent cells.However,previous reviews have failed to sum up novel understandings of senescence in chronic wounds and emerging strategies targeting senescence.Herein,we discuss the characteristics and mechanisms of cellular senescence and the link between senescence and chronic wounds as well as some novel antisenescence strategies targeting other diseases that may be applied for chronic wounds.

关键词： Chronic wounds Senescence Senolytics targeted therapies Diabetic wound Pressure wound Vascular ulcer

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Current concepts in ameloblastoma-targeted therapies in B-raf proto-oncogene serine/threonine kinase V600E mutation: Systematic review

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World Journal of Clinical Oncology 2020年第1期11卷 31-42页

作者： Rogelio González-González Sandra López-Verdín Jesús Lavalle-Carrasco Nelly Molina-Frechero Mario Isiordia-Espinoza Ramón G Carreón-Burciaga Ronell Bologna-Molina Department of Research School of DentistryUniversidad Juárez del Estado de DurangoDurango 34000Mexico Research Institute of Dentistry Health Science CenterUniversidad de GuadalajaraGuadalajara 4430Mexico Department of Health Care Xochimilco UnitUniversidad Autónoma Metropolitana XochimilcoMéxico 04960Mexico Department of Clinics Biomedical Sciences DivisionCentro Universitario de los AltosUniversidad de GuadalajaraTepetitlán de Morelos 47620Mexico Molecular Pathology Area School of DentistryUniversidad de la RepúblicaMontevideo 11600Uruguay

BACKGROUND Ameloblastomas are common benign epithelial odontogenic neoplasms that present an aggressive and unpredictable behavior that may modify treatment strategies.Different signaling pathways that participate in the progression of these tumors have been identified.B-raf proto-oncogene serine/threonine kinase(BRAF)is a protein involved in the behavior of ameloblastomas,and it is related to many cell mechanisms.BRAF gene mutations have been identified in ameloblastomas,of which the BRAF V600E(valine substituted by glutamic acid at amino acid 600)mutation has been the most common and can be present concomitantly with other mutations that may be involved in its behavior.targeted therapies have been used as an alternative in the case of resistance or contraindications to conventional treatments.AIM To document the presence of BRAF V600E and additional mutations,their behavior,and targeted therapies in these tumors.METHODS An electronic literature search was conducted according to PRISMA guidelines in PubMed/MEDLINE,Cochrane,EMBASE,and SpringerLink using the terms“ameloblastomas”,“BRAF V600E”,“additional mutations”,and“targeted therapies”.Ameloblastomas were classified according to WHO guidelines.Inclusion criteria were articles in English,published not more than 10 years ago,and studies with laboratory works related to BRAF V600E.Articles were evaluated by two independent reviewers and retrieved for full-text evaluation.The EBLIP Critical Appraisal Checklist was used to evaluate the quality of the eligible studies.Descriptive statistical analysis was performed.RESULTS Two independent reviewers,with a substantial concordance indicated by a kappa coefficient of k=0.76,evaluated a total of 19 articles that were included in this study.The analysis registered 521 conventional ameloblastomas(AM),81 unicystic ameloblastomas(UA),13 ameloblastic carcinomas(AC),three metastatic ameloblastomas(MA),and six peripheral ameloblastomas(PA),of which the histopathological type,anatomic location,laboratory tests,expression of BRAF

关键词： Ameloblastoma B-raf proto-oncogene serine/threonine kinase B-raf protooncogene serine/threonine kinase V600E Additional mutations targeted therapies

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Treatment Sequencing Strategies in Lung Cancer

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中国肺癌杂志 2022年第5期25卷 323-336页

作者： Daniel Humberto Pozza Ramon Bezerra Andrade de Mello Department of Biomedicine Faculty of Medicine and i3sUniversity of Porto4200-319 PortoPortugal Discipline of Medical Oncology Post-graduation Program in MedicineNine of July University(UNINOVE)São PauloBrazil./Nine of July HospitalSão PauloBrazi

Background and objective The advances in the lung cancer screening methods and therapeutics,together with awareness towards deleterious habits,such as smoking,is increasing the overall survival with better quality of life for the patients.However,lung cancer is still one of the most common and fatal neoplasm with a high incidence and consequently burden to public health worldwide.Thus,based on guidelines and recent phasesⅡandⅢclinical trials studies,this manuscript summarizes the current treatment sequencing strategies in lung cancer.Methods A comprehensive search of related articles was performed focused on phasesⅡandⅢclinical trials studies.Results The lung cancer management should take into consideration the tumor characteristics,histology,molecular pathology and be discussed in a multidisciplinary team.Lung cancer treatment options comprises surgery whenever possible,radiotherapy associate with/or chemotherapy and immunotherapy as monotherapy,or combined with chemotherapy and best palliative care.Conclusions The screening predictability in more patients,smoking reduction,early diagnosis,better disease understanding and individualized,more effective and tolerable therapeutics are related to an increasing in overall survival and quality of life.In the near future improvement of personalized therapy in precision medicine is expected,enhancing new predictive biomarkers,optimal doses and optimal treatment sequencing as well as anti-cancer vaccines development.

关键词： Lung neoplasms Immunotherapy Clinical trials targeted therapies Pembrolizumab Nivolumab Atezolizumab Necitumumab Brigatinib

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DNA polymerase θ (POLQ):A druggable DNA polymerase for homologous recombination-deficient cancer cells

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BIOCELL 2023年第3期47卷 441-444页

作者： MERAN KESHAWA EDIRIWEERA Department of Biochemistry and Molecular Biology Faculty of MedicineUniversity of ColomboColombo 08Sri Lanka

Irregularities in the DNA repair pathways are frequently observed in cancer.Dysregulated DNA repair pathways support growth advantages to tumor cells.DNA polymerase-theta(POLQ)is an error-prone DNA polymerase involved in double-strand break repair through microhomology-mediated end joining(MMEJ).POLQ also mediates translesion DNA synthesis and it is largely not expressed in normal cells.POLQ is overexpressed in a range of cancer cells,including homologous recombination(HR)deficient cancer cells.In HR deficient cells,MMEJ is crucial as a backup DNA repair pathway,indicating the indispensable role of POLQ-mediated MMEJ in HR deficient cancer cells.In addition,POLQ is synthetic lethal with a number of oncogenes.This viewpoint highlights the potential role of POLQ as a new target in the treatment of HR-deficient tumors and aims to develop enthusiasm to introduce fundamental aspects of Molecular Biology and Biochemistry to basic research related to Molecular Life Sciences,Cell Biology and Genetics in Sri Lanka as Molecular Biology and Biochemistry fundamentals can still do wonders in modern research.

关键词： POLQ Cancer MMEJ targeted therapies

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Moving towards the chemo-free treatment of lymphoma:hype or reality?

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Journal of Cancer Metastasis and Treatment 2022年第1期8卷 631-636页

作者： Bruce D.Cheson Scientific Advisor Lymphoma Research FoundationNew YorkNY 10005USA

A new generation of novel,effective targeted drugs and cellular therapies include monoclonal antibodies directed at the cell surface,such as the anti-CD-19 tafasitamab which,combined with lenalidomide,is the first therapy approved by the Food and Drug Administration for second-line treatment of diffuse large B-cell lymphoma.Other agents interfere with pro-survival intracellular signaling pathways including drugs that inhibit Bruton tyrosine kinase,phosphatidylinositol-3 kinase(PI3-kinase),and bcl-2.An increasing number of therapies impact the microenvironment,notably checkpoint inhibitors and bispecific antibodies.Chimeric antigen receptor-T cell therapy has improved the outcome of patients with a variety of histologies of lymphoma.Whereas in the past,such therapies would be used inrelapsed and refractory settings,they are now being evaluated as initial treatment in selected patients.With an improved ability to individualize treatment approaches,chemo-free will be a reality for lymphoma patients.

关键词： Lymphoma targeted therapies chemo-free bispecifics BTK inhibitors PI3k inhibitors CAR-T cell

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Contemporary treatment approaches for metastatic colorectal cancer driven by BRAF V600 mutations

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World Journal of Gastrointestinal Oncology 2020年第10期12卷 1080-1090页

作者： Ozkan Kanat Hulya Ertas Burcu Caner Department of Medical Oncology Acıbadem Bursa HospitalBursa 16059Turkey Department of Medical Oncology Bursa City HospitalBursa 16059Turkey Department of Medical Oncoloy Balıkesir Ataturk City HospitalBursa 16059Turkey

The treatment of metastatic colorectal cancer(mCRC)harboring BRAF V600 mutations is challenging.These tumors are often refractory to standard treatment.Therefore,the patients may exhibit rapid clinical deterioration,depriving them of the chance to receive salvage therapy.In newly diagnosed patients with good performance status,the administration of an intensive chemotherapy regimen like FOLFOXIRI(5-fluorouracil,leucovorin,oxaliplatin,and irinotecan)along with the antiangiogenic agent bevacizumab can modify this aggressive behavior of the disease and improve patient clinical outcomes.The recently published results of the BEACON(Binimetinib,Encorafenib,and Cetuximab Combined to Treat BRAF-Mutant Colorectal Cancer)study demonstrated that a combination therapy consisting of BRAF,epidermal growth factor receptor,and mitogen-activated protein kinase kinase inhibitors could be a useful second-or third-line alternative.This review summarizes the current treatment strategies for BRAF-mutant mCRC.

关键词： BRAF mutation V600 mutations Metastatic colorectal cancer targeted therapies

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Molecular markers of systemic therapy response in urothelial carcinoma

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Asian Journal of Urology 2021年第4期8卷 376-390页

作者： Francesco Claps Maria Carmen Mir Homayoun Zargar Department of Urology Fundacion Instituto Valenciano de OncologiaValenciaSpain Urological Clinic Department of MedicineSurgery and Health SciencesUniversity of TriesteTriesteItaly Department of Urology Royal Melbourne HospitalMelbourneVictoriaAustralia Department of Surgery University of MelbourneMelbourneVictoriaAustralia

Identification of reliable molecular biomarkers that can complement clinical practice represents a fascinating challenge in any cancer field.Urothelial carcinoma is a very heterogeneous disease and responses to systemic therapies,and outcomes after radical cystectomy are difficult to predict.Advances in molecular biology such as next generation sequencing and whole genome or transcriptomic analysis provide promising platforms to achieve a full understanding of the biology behind the disease and can identify emerging predictive biomarkers.Moreover,the ability to categorize patients’risk of recurrence after curative treatment,or even predict benefit from a conventional or targeted therapies,represents a compelling challenge that may reshape both selection for tailored treatment and disease monitoring.Progress has been made but currently no molecular biomarkers are used in the clinical setting to predict response to systemic agents in either neoadjuvant or adjuvant settings highlighting a relevant unmet need.Here,we aim to present the emerging role of molecular biomarkers in predicting response to systemic agents in urothelial carcinoma.

关键词： Urothelial carcinoma Biomarkers Neoadjuvant chemotherapy Adjuvant chemotherapy targeted therapies Precision oncology

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