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| 1 | Characterization of drug responses of mini patient-derived xenografts in mice for predicting cancer patient clinical therapeutic response显示文摘Background:Patient-derived organoids and xenografts(PDXs)have emerged as powerful models in functional diag-nostics with high predictive power for anticancer drug response.However,limitations such as engraftment failure and time-consuming for establishing and expanding PDX models followed by testing drug efficacy,and inability to subject to systemic drug administration for ex vivo organoid culture hinder realistic and fast decision-making in selecting the right therapeutics in the clinic.The present study aimed to develop an advanced PDX model,namely MiniPDX,for rapidly testing drug efficacy to strengthen its value in personalized cancer treatment.Methods:We developed a rapid in vivo drug sensitivity assay,OncoVee®MiniPDX,for screening clinically relevant regimens for cancer.In this model,patient-derived tumor cells were arrayed within hollow fiber capsules,implanted subcutaneously into mice and cultured for 7 days.The cellular activity morphology and pharmacokinetics were systematically evaluated.MiniPDX performance(sensitivity,specificity,positive and negative predictive values)was examined using PDX as the reference.Drug responses were examined by tumor cell growth inhibition rate and tumor growth inhibition rate in PDX models and MiniPDX assays respectively.The results from MiniPDX were also used to evaluate its predictive power for clinical outcomes.Results:Morphological and histopathological features of tumor cells within the MiniPDX capsules matched those both in PDX models and in original tumors.Drug responses in the PDX tumor graft assays correlated well with those in the corresponding MiniPDX assays using 26 PDX models generated from patients,including 14 gastric cancer,10 lung cancer and 2 pancreatic cancer.The positive predictive value of MiniPDX was 92%,and the negative predictive value was 81%with a sensitivity of 80%and a specificity of 93%.Through expanding to clinical tumor samples,Min-iPDX assay showed potential of wide clinical application.Conclusions:Fast in vivo MiniPDX assay based on capsule implantation was developed-to assess drug responses of both PDX tumor grafts and clinical cancer specimens.The high correlation between drug responses of paired MiniPDX and PDX tumor graft assay,as well as translational data suggest that MiniPDX assay is an advanced tool for personalized cancer treatment. | Feifei Zhang Wenjie Wang Yuan Long Hui Liu Jijun Cheng Lin Guo Rongyu Li Chao Meng Shan Yu Qingchuan Zhao Shun Lu Lili Wang Haitao Wang Danyi Wen | 2018 | Cancer Communications2018，38，1： | 20 |
| 2 | Personalized treatment based on mini patient-derived xenografts and WES/RNA sequencing in a patient with metastatic duodenal adenocarcinoma显示文摘Background:Treatment guidelines for a variety of cancers have been increasingly used in clinical practice,and have resulted in major improvement in patient outcomes.However,recommended regimens(even first-line treat-ments)are clearly not ideal for every patients.In the present study,we used mini patient-derived xenograft(mini-PDX)and next-generation sequencing to develop personalized treatment in a patient with metastatic duodenal adenocarcinoma.Methods:Resected metachronous metastatic tumor tissues were implanted into SCID mice to determine the sensitivity to a variety of drug regimens.Mutation profiles were assessed using both DNA whole-exome sequencing(DNA-WES)and RNA sequencing.The results of the analyses were used to select optimal treatment for the patient with metastatic duodenal adenocarcinoma.Results:Assessment with mini-PDX models took only 7 days.The results showed high sensitivity to S-1 plus cis-platin,gemcitabine plus cisplatin and everolimus alone.The patient received gemcitabine plus cisplatin initially,but the treatment was terminated due to toxicity.The patient was then switched to treatment with S-1 alone.The overall disease-free survival was 34 months.DNA-WES and RNA sequencing identified KRAS mutation(A146T),TP53(C229Yfs*10)and RICTOR amplification in the metastatic duodenal adenocarcinoma.These findings provided further support to the results of the mini-PDX,and suggest mTOR inhibitors should be used if and when relapse eventually occurs in this patient.Conclusions:Mini-PDX model combined with WES/RNA sequencing can rapidly assess drug sensitivity in cancer patients and reveal key genetic alterations.Further research on this technology for personalized therapy in patients with refractory malignant tumors is warranted. | Peng Zhao Hui Chen Danyi Wen Shuo Mou Feifei Zhang Shusen Zheng | 2018 | Cancer Communications2018，38，1： | 11 |
| 3 | Xenograft tumors derived from malignant pleural effusion of the patients with non-small-cell lung cancer as models to explore drug resistance显示文摘Background:Non-small cell lung cancer(NSCLC)patients with epidermal growth factor receptor(EGFR)mutations or anaplastic lymphoma kinase(ALK)fusions show dramatic responses to specific tyrosine kinase inhibitors(TKIs);however,after 10-12 months,secondary mutations arise that confer resistance.We generated a murine xenograft model using patient-derived NSCLC cells isolated from the pleural fluid of two patients with NSCLC to investigate the mechanisms of resistance against the ALK-and EGFR-targeted TKIs crizotinib and osimertinib,respectively.Methods:Genotypes of patient biopsies and xenograft tumors were determined by whole exome sequencing(WES),and patients and xenograft-bearing mice received targeted treatment(crizotinib or osimertinib)accordingly.Xenograft mice were also treated for prolonged periods to identify whether the development of drug resistance and/or treatment responses were associated with tumor size.Finally,the pathology of patients biopsies and xenograft tumors were compared histologically.Results:The histological characteristics and chemotherapy responses of xenograft tumors were similar to the actual patients.WES showed that the genotypes of the xenograft and patient tumors were similar(an echinoderm microtu-bule-associated protein-like 4-ALK(EML4-ALK)gene fusion(patient/xenograft:CTC15035EML4-ALK)and EGFR L858R and T790M mutations(patient/xenograft:CTC15063EGFR L858R,T790M)).After continuous crizotinib or osimertinib treatment,WES data suggested that acquired ALK E1210K mutation conferred crizotinib resistance in the CTC15035EML4-ALK xenograft,while decreased frequencies of EGFR L858R and T790M mutations plus the appearance of v-RAF murine sarcoma viral oncogene homolog B(BRAF)G7V mutations and phosphatidylinositol-4-phosphate 3-kinase catalytic subunit type 2 alpha(PIK3C2A)A86fs frame shift mutations led to osimertinib resistance in the CTC15063EGFR L858R,T790M xenografts.Conclusions:We successfully developed a new method of generating drug resistance xenograft models from liquid biopsies using microfluidic technology,which might be a useful tool to investigate the mechanisms of drug resist-ance in NSCLC. | Yunhua Xu Feifei Zhang Xiaoqing Pan Guan Wang Lei Zhu Jie Zhang Danyi Wen Shun Lu | 2018 | Cancer Communications2018，38，1： | 7 |
| 4 | Intrinsic gemcitabine resistance in a novel pancreatic cancer cell lineis associated with cancer stem cell-like phenotype显示文摘 | Gang Hu Fu Li Kedong Ouyang Fubo Xie Xuzhen Tang Ke Wang Sufang Han Zhenzhou Jiang Minghua Zhu Danyi Wen Xiaoran Qin Luyong Zhang | 2012 | International Journal of Oncology2012，，3： | 1 |
| 5 | Transactivation of the human NME5 gene by Sp1 in pancreatic cancer cells显示文摘 | Fu Li Zhenzhou Jiang Ke Wang Jingjing Guo Gang Hu Lixin Sun Tao Wang Xuzhen Tang Ling He Jincheng Yao Danyi Wen Xiaoran Qin Luyong Zhang | 2012 | Gene2012，，2： | 1 |
| 6 | 用于预测癌症患者临床治疗方案的小鼠mini人源肿瘤异种移植模型的建立显示文摘背景与目的患者来源的类器官(patient-derived organoids,PDOs)和异种移植物(patientderivedxenografts,PDXs)具有较强的预测抗癌药物药效的能力,是功能检测的重要模型。然而,移植失败、构建PDX模型和随后检测药效的耗时过长、体外器官培养无法进行系统性给药等限制因素严重阻碍了其在临床上的应用,无法快速地筛选正确、可行的治疗方案。本研究旨在开发一种名为'miniPDX'的改良的PDX模型,用于快速检测药效,提高其在个体化癌症治疗中的应用价值。方法我们开发了一种快速检测体内药物敏感性的方法——OncoVee?MiniPDX,用于筛选癌症临床治疗方案。本模型将患者来源的肿瘤细胞注入中空纤维胶囊内,皮下植入小鼠体内培养7 d。系统评价了细胞的活性形态和药代动力学。以PDX为对照评估miniPDX的性能(敏感性、特异性、阳性和阴性预测值)。分别采用PDX和miniPDX模型以肿瘤生长抑制率和肿瘤细胞生长抑制率为指标检测药物反应。评价miniPDX模型对临床疗效的预测能力。结果MiniPDX胶囊内肿瘤细胞的形态学和组织病理学特征与PDX模型和原发肿瘤细胞的形态学和组织病理学特征均保持一致。26例(包括14例胃癌、10例肺癌和2例胰腺癌)来自患者的PDX肿瘤移植试验的药物反应与相应的miniPDX试验的药物反应结果具有良好的相关性。MiniPDX阳性预测值为92%,阴性预测值为81%,敏感性为80%,特异性为93%。通过扩大临床肿瘤样本,miniPDX检测显示出广泛的临床应用潜力。结论我们建立了基于胶囊植入技术的miniPDX快速体内检测方法,用于评估PDX肿瘤移植物和临床肿瘤标本的药物反应。PDX模型和其对应的miniPDX药效结果具有良好的相关性,结合转化研究数据最终表明miniPDX模型是一种先进的个体化癌症治疗工具。 | Feifei Zhang Wenjie Wang Yuan Long Hui Liu Jijun Cheng Lin Guo Rongyu Li Chao Meng Shan Yu Qingchuan Zhao Shun Lu Lili Wang Haitao Wang Danyi Wen | 2019 | 癌症2019，38，4： | 0 |
| 7 | Mini患者来源异种移植和WES/RNA测序指导一例转移性十二指肠腺癌患者的个体化治疗显示文摘背景与目的各种癌症的治疗指南已越来越多地应用于临床实践,并已极大地改善了患者预后。然而,医生推荐的治疗方案(甚至一线治疗)并非对每位患者都是最佳的。在本研究中,我们应用mini患者来源的异种移植(mini patient-derived xenograft,mini-PDX)和二代测序技术指导了一例转移性十二指肠腺癌患者的个体化治疗。方法将切除的异位转移瘤组织植入SCID小鼠体内,来确定对各种药物的敏感性。采用DNA全外显子测序(DNA whole-exome sequencing,DNA-WES)和RNA测序分析突变谱。所得分析结果用于选择对转移性十二指肠腺癌的最佳治疗方案。结果使用mini-PDX模型进行评估只用了7 d。结果表明,对S-1+顺铂、吉西他滨+顺铂、依维莫司单药具有高敏感性。患者最初接受吉西他滨联合顺铂治疗,但由于毒性而终止治疗。随后,该患者单独使用S-1进行治疗。总无病生存期为34个月。DNA-WES和RNA测序鉴定了转移性十二指肠腺癌中KRAS突变(A146T)、TP53(C229Yfs*10)和RICTOR扩增。这些发现进一步为mini-PDX的结果提供了支持,并建议当该患者最终复发时应使用m TOR抑制剂治疗。结论联合WES/RNA测序的mini-PDX模型可以快速检测癌症患者的药物敏感性,揭示关键的基因变异。有必要进一步研究该技术用以对难治性恶性肿瘤患者进行个体化治疗。 | Peng Zhao Hui Chen Danyi Wen Shuo Mou Feifei Zhang Shusen Zheng | 2019 | 癌症2019，38，7： | 0 |
| 8 | Identification of cancer stem cells provides novel tumor models for drug discovery显示文摘Cancer stem cells(CSCs)have received considerable attention from the research community since they were first reported in human acute myeloid leukemia 15 years ago.Accumulating evidence suggests that CSCs are responsible for tumor initiation and progression,drug resistance,and metastasis in both liquid and solid tumors.These findings lead to the development of novel compounds targeting CSC populations that is becoming increasingly important for eradicating CSCs in heterogeneous tumor masses and to cure the cancer.Since 2003,we have participated in CSC studies and encountered crucial early events in the field.This article reviews the history of CSC biology,clarifies the term and its definition,and further addresses the issue of how to utilize CSCs in therapeutic target discovery and drug development based on our substantial experience. | Douglas D.Fang Danyi Wen Yajun Xu | 2012 | Frontiers of Medicine2012，6，2： | 0 |
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