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Development of gemcitabine-resistant patient-derived xenograft models of pancreatic ductal adenocarcinoma

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Cancer Drug Resistance 2020年第3期3卷 572-585页

作者： Aubrey L.Miller Patrick L.Garcia Tracy L.Gamblin Rebecca B.Vance Karina J.Yoon Department of Pharmacology and Toxicology University of Alabama at BirminghamBirminghamAL 35294 USA.

Aim:Gemcitabine is a frontline agent for locally-advanced and metastatic pancreatic ductal adenocarcinoma(PDAC),but neither gemcitabine alone nor in combination produces durable remissions of this tumor type.We developed three PDAC patient-derived xenograft(PDX)models with gemcitabine resistance(gemR)acquired in vivo,with which to identify mechanisms of resistance relevant to drug exposure in vivo and to evaluate novel therapies.Methods:Mice bearing independently-derived PDXs received 100 mg/kg gemcitabine once or twice weekly.Tumors initially responded,but regrew on treatment and were designated gemR.We used immunohistochemistry to compare expression of proteins previously associated with gemcitabine resistance[ribonucleotide reductase subunit M1(RRM1),RRM2,human concentrative nucleoside transporter 1(hCNT1),human equilibrative nucleoside transporter 1(hENT1),cytidine deaminase(CDA),and deoxycytidine kinase(dCK)]in gemR and respective gemcitabine-naïve parental tumors.Results:Parental and gemR tumors did not differ in tumor cell morphology,amount of tumor-associated stroma,or expression of stem cell markers.No consistent pattern of expression of the six gemR marker proteins was observed among the models.Increases in RRM1 and CDA were consistent with in vitro-derived gemR models.However,rather than the expected decreases of hCNT1,hENT1,and dCK,gemR tumors expressed no change in or higher levels of these gemR marker proteins than parental tumors.Conclusion:These models are the first PDAC PDX models with gemcitabine resistance acquired in vivo.The data indicate that mechanisms identified in models with resistance acquired in vitro are unlikely to be the predominant mechanisms when resistance is acquired in vivo.Ongoing work focuses on characterizing unidentified mechanisms of gemR and on identifying agents with anti-tumor efficacy in these gemR models。

关键词： Gemcitabine resistance patient-derived xenograft ribonucleotide reductase subunit M1 ribonucleotide reductase subunit M2 human concentrative nucleoside transporter 1 human equilibrative nucleoside transporter 1 cytidine deaminase deoxycytidine kinase

The evolution of cancer genomic medicine in Japan and the role of the National Cancer Center Japan

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Cancer Biology & Medicine 2024年第1期21卷 29-44页

作者： Teruhiko Yoshida Yasushi Yatabe Ken Kato Genichiro Ishii Akinobu Hamada Hiroyuki Mano Kuniko Sunami Noboru Yamamoto Takashi Kohno Department of Genetic Medicine and Services National Cancer Center HospitalTokyo 104-0045Japan Department of Diagnostic Pathology National Cancer Center HospitalTokyo 104-0045Japan Clinical Research Support Offce Clinical Research Coordinating SectionBiobank Translational Research Support SectionNational Cancer Center HospitalTokyo 104-0045Japan Department of Pathology and Clinical Laboratories National Cancer Center Hospital EastChiba 277-8577Japan Division of Molecular Pharmacology National Cancer Center Research InstituteTokyo 104-0045Japan National Cancer Center Research Institute Tokyo 104-0045Japan Department of Laboratory Medicine National Cancer Center HospitalTokyo 104-0045Japan Department of Experimental Therapeutics National Cancer Center HospitalTokyo 104-0045Japan Division of Genome Biology National Cancer Center Research InstituteTokyo 104-0045Japan

The journey to implement cancer genomic medicine(CGM)in oncology practice began in the 1980s,which is considered the dawn of genetic and genomic cancer research.At the time,a variety of activating oncogenic alterations and their functional significance were unveiled in cancer cells,which led to the development of molecular targeted therapies in the 2000s and beyond.Although CGM is still a relatively new discipline and it is difficult to predict to what extent CGM will benefit the diverse pool of cancer patients,the National Cancer Center(NCC)of Japan has already contributed considerably to CGM advancement for the conquest of cancer.Looking back at these past achievements of the NCC,we predict that the future of CGM will involve the following:1)A biobank of paired cancerous and non-cancerous tissues and cells from various cancer types and stages will be developed.The quantity and quality of these samples will be compatible with omics analyses.All biobank samples will be linked to longitudinal clinical information.2)New technologies,such as whole-genome sequencing and artificial intelligence,will be introduced and new bioresources for functional and pharmacologic analyses(e.g.,a patient-derived xenograft library)will be systematically deployed.3)Fast and bidirectional translational research(bench-to-bedside and bedside-to-bench)performed by basic researchers and clinical investigators,preferably working alongside each other at the same institution,will be implemented;4)Close collaborations between academia,industry,regulatory bodies,and funding agencies will be established.5)There will be an investment in the other branch of CGM,personalized preventive medicine,based on the individual's genetic predisposition to cancer.

关键词： Cancer genomic medicine biobank patient-derived xenograft multi-gene panel test whole genome sequencing

patient-derived xenograft models for oncology drug discovery

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Journal of Cancer Metastasis and Treatment 2015年第1期1卷 8-15页

作者： Gang Li Ignyta Inc. San DiegoCA 92121USA.

The success of targeted therapies for cancer patients rests on three major components:the right target(s),the right drug and drug combination,and the right patient population.Although much progress has been made in understanding the mechanism of disease and in refi ning pharmaceutical properties of therapeutic agents,the attrition rates between target discovery and drug marketing approval have been high,especially in oncology.One of the main reasons underlying this undesirable statistics is believed to be the lack of predictive power of the model systems used in the preclinical setting.Several strategies have been employed with the aim of improving the predictive value of the preclinical studies,such as incorporating genomic profi ling and molecular segmentation into model selection,and enhancing the development and application of patient-derived xenograft models even during early stage of drug discovery.This brief review will summarize some of the recent concept and practice in incorporating patient-derived models into all stages of drug discovery process,from target to clinical development.

关键词： Animal models drug discovery oncology patient-derived xenograft translational research

Repurposed benzydamine targeting CDK2 suppresses the growth of esophageal squamous cell carcinoma

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Frontiers of Medicine 2023年第2期17卷 290-303页

作者： Yubing Zhou Xinyu He Yanan Jiang Zitong Wang Yin Yu Wenjie Wu Chenyang Zhang Jincheng Li Yaping Guo Xinhuan Chen Zhicai Liu Jimin Zhao Kangdong Liu Zigang Dong The Pathophysiology Department School of Basic Medical SciencesAcademy of Medical SciencesZhengzhou UniversityZhengzhou 450000China The China-US(Henan)Hormel Cancer Institute Zhengzhou 450000China State Key Laboratory of Esophageal Cancer Prevention and Treatment Zhengzhou 450000China Provincial Cooperative Innovation Center for Cancer Chemoprevention Zhengzhou UniversityZhengzhou 450000China Cancer Chemoprevention International Collaboration Laboratory Zhengzhou 450000China Oncology Department The Tumor Hospital of Linzhou CityLinzhou 456500China

Esophageal squamous cell carcinoma (ESCC) is one of the leading causes of cancer death worldwide. It is urgent to develop new drugs to improve the prognosis of ESCC patients. Here, we found benzydamine, a locally acting non-steroidal anti-inflammatory drug, had potent cytotoxic effect on ESCC cells. Benzydamine could suppress ESCC proliferation in vivo and in vitro. In terms of mechanism, CDK2 was identified as a target of benzydamine by molecular docking, pull-down assay and in vitro kinase assay. Specifically, benzydamine inhibited the growth of ESCC cells by inhibiting CDK2 activity and affecting downstream phosphorylation of MCM2, c-Myc and Rb, resulting in cell cycle arrest. Our study illustrates that benzydamine inhibits the growth of ESCC cells by downregulating the CDK2 pathway.

关键词： benzydamine cyclin-dependent kinase 2 patient-derived xenograft esophageal squamous cell carcinoma

Discovery of a first-in-class ANXA3 degrader for the treatment of triple-negative breast cancer

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Acta Pharmaceutica Sinica B 2023年第4期13卷 1686-1698页

作者： Yongxi Liang Delin Min Hulin Fan Kunlin Liu Juchuanli Tu Xueyan He Bingjie Liu Lu Zhou Suling Liu Xun Sun School of Pharmacy Fudan UniversityShanghai 201203China The Institutes of Integrative Medicine of Fudan University Shanghai 200040China Fudan University Shanghai Cancer Center&Institutes of Biomedical Sciences State Key Laboratory of Genetic EngineeringFudan UniversityShanghai 200032China

Triple-negative breast cancer(TNBC)is a nasty disease with extremely high malignancy and poor prognosis.Annexin A3(ANXA3)is a potential prognosis biomarker,displaying an excellent correlation of ANXA3 overexpression with patients'poor prognosis.Silencing the expression of ANXA3effectively inhibits the proliferation and metastasis of TNBC,suggesting that ANXA3 can be a promising therapeutic target to treat TNBC.Herein,we report a first-in-class ANXA3-targeted small molecule(R)-SL18,which demonstrated excellent anti-proliferative and anti-invasive activities to TNBC cells.(R)-SL18 directly bound to ANXA3 and increased its ubiquitination,thereby inducing ANXA3 degradation with moderate family selectivity.Importantly,(R)-SL18 showed a safe and effective therapeutic potency in a high ANXA3-expressing TNBC patient-derived xenograft model.Furthermore,(R)-SL18 could reduce theβ-catenin level,and accordingly inhibit the Wnt/β-catenin signaling pathway in TNBC cells.Collectively,our data suggested that targeting degradation of ANXA3 by(R)-SL18 possesses the potential to treat TNBC.

关键词： Annexin A3(ANXA3) Degrader Triple-negative breast cancer Ubiquitination patient-derived xenograft

Candidate therapeutic agents in a newly established triple wild-typemucosalmelanoma cell line

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Cancer Communications 2022年第7期42卷 627-647页

作者： Chaoji Shi Ziyue Gu Shengming Xu Houyu Ju Yunteng Wu Yong Han Jiayi Li Chuwen Li Jing Wu Lizhen Wang Jiang Li Guoyu Zhou Weimin Ye Guoxin Ren Zhiyuan Zhang Rong Zhou Department of Oral and Maxillofacial-Head Neck Oncology Shanghai Ninth People’s HospitalCollege of StomatologyShanghai Jiao Tong University School of MedicineShanghai 200011P.R.China National Clinical Research Center for Oral Diseases Shanghai 200011P.R.China Shanghai Key Laboratory of Stomatology&Shanghai Research Institute of Stomatology Shanghai 200011P.R.China Research Unit of Oral and Maxillofacial Regenerative Medicine Chinese Academy of Medical SciencesShanghai 200011P.R.China Department of Oral Pathology Ninth People’s HospitalShanghai Jiao Tong UniversitySchool of MedicineShanghai 200011P.R.China

Background:Mucosalmelanoma has characteristically distinct genetic features and typically poor prognosis.The lack of representativemucosal melanoma models,especially cell lines,has hindered translational research on this melanoma subtype.In this study,we aimed to establish and provide the biological properties,genomic features and the pharmacological profiles of a mucosal melanoma cell line that would contribute to the understanding and treatment optimization of molecularly-defined mucosal melanoma subtype.Methods:The sample was collected from a 67-year-old mucosal melanoma patient and processed into pieces for the establishment of cell line and patientderived xenograft(PDX)model.The proliferation and tumorigenic property of cancer cells from different passageswere evaluated,andwhole-genome sequencing(WGS)was performed on the original tumor,PDX,established cell line,and the matched blood to confirm the establishment and define the genomic features of this cell line.AmpliconArchitect was conducted to depict the architecture of amplified regions detected by WGS.High-throughput drug screening(HTDS)assay including a total of 103 therapeutic agents was implemented on the established cell line,and selected candidate agents were validated in the corresponding PDX model.Results:A mucosal melanoma cell line,MM9H-1,was established which exhibited robust proliferation and tumorigenicity after more than 100 serial passages.Genomic analysis of MM9H-1,corresponding PDX,and the original tumor showed genetic fidelity across genomes,and MM9H-1 was defined as a triple wild-type(TWT)melanoma subtype lacking well-characterized“driver mutations”.Instead,the amplification of several oncogenes,telomerase reverse transcriptase(TERT),v-Rafmurine sarcoma viral oncogene homolog B1(BRAF),melanocyte Inducing transcription factor(MITF)and INO80 complex ATPase subunit(INO80),via large-scale genomic rearrangement potentially contributed to oncogenesis of MM9H-1.Moreover,HTDS identified proteasome inhibitors,especially bortezomib,as promising th

关键词： bortezomib cell line extrachromosomal DNA high-throughput drug screening mucosal melanoma patient derived tumor cells patient-derived xenograft whole-genome sequencing

A comparison of next-generation sequencing analysis methods for cancer xenograft samples

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Journal of Genetics and Genomics 2018年第7期45卷 345-350页

作者： Wentao Dai Jixiang Liu Quanxue Li Wei Liu Yi-Xue Li Yuan-Yuan Li shanghai center for bioinformation technology Shanghai 201203China shanghai engineering research center of pharmaceutical translation&shanghai industrial technology institute Shanghai 201203China school of biotechnology east china university of science and technologyShanghai 201203China shanghai industrial technology institute Shanghai 200237China

The application of next-generation sequencing （NGS） technology in cancer is influenced by the quality and purity of tissue samples. This issue is especially critical for patient-derived xenograft （PDX） models, which have proven to be by far the best preclinical tool for investigating human tumor biology, because the sensitivity and specificity of NGS analysis in xenograft samples would be compromised by the contamination of mouse DNA and RNA. This definitely affects downstream analyses by causing inaccurate mutation calling and gene expression estimates. The reliability of NGS data analysis for cancer xenograft samples is therefore highly dependent on whether the sequencing reads derived from the xenograft could be distinguished from those originated from the host. That is, each sequence read needs to be accurately assigned to its original species. Here, we review currently available methodologies in this field, including Xenome, Disambiguate, bamcmp and pdxBlacklist, and provide guidelines for users.

关键词： patient-derived xenograft Next-generation sequencing Host contamination control Alignment

A novel inhibitor of MDM2 oncogene blocks metastasis of hepatocellular carcinoma and overcomes chemoresistance

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Genes & Diseases 2019年第4期6卷 419-430页

作者： Wei Wang Bo Hu Jiang-Jiang Qin Jian-Wen Cheng Xin Li Mehrdad Rajaei Jia Fan Xin-Rong Yang Ruiwen Zhang Department of Pharmacological and Pharmaceutical Sciences College of PharmacyUniversity of HoustonHoustonTX77204USA Drug Discovery Institute University of HoustonHoustonTX77204USA Department of Liver Surgery and Transplantation Liver Cancer InstituteZhongshan HospitalFudan UniversityShanghai200032China Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education Fudan UniversityShanghai200032China

Overexpression of the MDM2 oncogene and mutations in the p53 tumor suppressor commonly occur in hepatocellular carcinoma(HCC)and are associated with increased mortality due to this disease.Inhibiting MDM2 has been demonstrated to be a valid approach for the treatment of HCC.However,most of the MDM2 inhibitors evaluated to date have been designed to block the MDM2 and p53 binding,and have limited efficacy against tumors with mutant or deficient p53.In the present study,we developed a novel MDM2 inhibitor(termed SP141)that has direct effects on MDM2 and exerts anti-HCC activity independent of the p53 status of the cancer cells.We demonstrate that SP141 inhibits cell growth and prevents cell migration and invasion,independent of p53.Mechanistically,SP141 directly binds the MDM2 protein and promotes MDM2 degradation.The inhibition of MDM2 by SP141 also increases the sensitivity of HCC cells to sorafenib.In addition,in orthotopic and patient-derived xenograft models,SP141 inhibits MDM2 expression and suppresses tumor growth and metastasis,without any host toxicity.Furthermore,the inhibition of MDM2 by SP141 is essential for its anti-HCC activities.These results provide support for the further development of SP141 as a lead candidate for the treatment of HCC.

关键词： CRISPR/Cas9 Hepatocellular carcinoma MDM2 p53-independent patient-derived xenograft