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Application of patient-derived tumor models in anticancer drug development and individualized medicine
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作者 Kai-Ling Chen Yu-Fei Deng +1 位作者 Xiao-Ying Hou Yu-Chen Liu 《Life Research》 2024年第1期3-9,共7页
Malignant tumor is the second leading cause of death due to its high incidence, lack of effective treatment and poor prognosis. The evaluation of anticancer drugs used to based on NCI-60 cell line models, but the limi... Malignant tumor is the second leading cause of death due to its high incidence, lack of effective treatment and poor prognosis. The evaluation of anticancer drugs used to based on NCI-60 cell line models, but the limited heterogeneity and the divorce from clinical practice of models lead to extremely low success rate of novel anticancer drugs during clinical trials (less than 10%). In recent years, because of the high heterogeneity and human derived tumor matrix, patient-derived tumor models have been gradually applied to the preclinical evaluation of various antitumor drugs, which shows certain advantages in predicting the clinical efficacy of antitumor drugs. Optimize the drug combination through patient-derived tumor models to achieve individualized medicine has gradually become an indispensable strategy in clinical cancer therapy. The current review summarized the development of patient-derived tumor models, characterized the application, advantages and challenges of them in preclinical antitumor drug evaluation and clinical precise medicine, which will provide a scientific basis and novel insights for further basic research, drug development and clinical application. 展开更多
关键词 patient-derived xenograft(PDX) patient-derived organoid(PDO) patient-derived cell(PDC) individualized medicine
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Patient-derived xenograft model in colorectal cancer basic and translational research
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作者 Xiaofeng Liu Zechang Xin Kun Wang 《Animal Models and Experimental Medicine》 CAS CSCD 2023年第1期26-40,共15页
Colorectal cancer(CRC)is one of the most popular malignancies globally,with 930000 deaths in 2020.The evaluation of CRC-related pathogenesis and the discovery of po-tential therapeutic targets will be meaningful and h... Colorectal cancer(CRC)is one of the most popular malignancies globally,with 930000 deaths in 2020.The evaluation of CRC-related pathogenesis and the discovery of po-tential therapeutic targets will be meaningful and helpful for improving CRC treat-ment.With huge efforts made in past decades,the systematic treatment regimens have been applied to improve the prognosis of CRC patients.However,the sensitivity of CRC to chemotherapy and targeted therapy is different from person to person,which is an important cause of treatment failure.The emergence of patient-derived xenograft(PDX)models shows great potential to alleviate the straits.PDX models possess similar genetic and pathological characteristics as the features of primary tu-mors.Moreover,PDX has the ability to mimic the tumor microenvironment of the original tumor.Thus,the PDX model is an important tool to screen precise drugs for individualized treatment,seek predictive biomarkers for prognosis supervision,and evaluate the unknown mechanism in basic research.This paper reviews the recent advances in constructed methods and applications of the CRC PDX model,aiming to provide new knowledge for CRC basic research and therapeutics. 展开更多
关键词 colorectal cancer drug discovery patient-derived xenograft model precision medicine tumor microenvironment
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Patient-derived non-small cell lung cancer xenograft mirrors complex tumor heterogeneity 被引量:9
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作者 Xuanming Chen Cheng Shen +15 位作者 Zhe Wei Rui Zhang Yongsheng Wang Lili Jiang Ke Chen Shuang Qiu Yuanli Zhang Ting Zhang Bin Chen Yanjun Xu Qiyi Feng Jinxing Huang Zhihui Zhong Hongxia Li Guowei Che Kai Xiao 《Cancer Biology & Medicine》 SCIE CAS CSCD 2021年第1期184-198,共15页
Objective:Patient-derived xenograft(PDX)models have shown great promise in preclinical and translational applications,but their consistency with primary tumors in phenotypic,genetic,and pharmacodynamic heterogeneity h... Objective:Patient-derived xenograft(PDX)models have shown great promise in preclinical and translational applications,but their consistency with primary tumors in phenotypic,genetic,and pharmacodynamic heterogeneity has not been well-studied.This study aimed to establish a PDX repository for non-small cell lung cancer(NSCLC)and to further elucidate whether it could preserve the heterogeneity within and between tumors in patients.Methods:A total of 75 surgically resected NSCLC specimens were implanted into immunodeficient NOD/SCID mice.Based on the successful establishment of the NSCLC PDX model,we compared the expressions of vimentin,Ki67,EGFR,and PD-L1 proteins between cancer tissues and PDX models using hematoxylin and eosin staining and immunohistochemical staining.In addition,we detected whole gene expression profiling between primary tumors and PDX generations.We also performed whole exome sequencing(WES)analysis in 17 first generation xenografts to further assess whether PDXs retained the patient heterogeneities.Finally,paclitaxel,cisplatin,doxorubicin,atezolizumab,afatininb,and AZD4547 were used to evaluate the responses of PDX models to the standard-of-care agents.Results:A large collection of serially transplantable PDX models for NSCLC were successfully developed.The histology and pathological immunohistochemistry of PDX xenografts were consistent with the patients’tumor samples.WES and RNA-seq further confirmed that PDX accurately replicated the molecular heterogeneities of primary tumors.Similar to clinical patients,PDX models responded differentially to the standard-of-care treatment,including chemo-,targeted-and immuno-therapeutics.Conclusions:Our established PDX models of NSCLC faithfully reproduced the molecular,histopathological,and therapeutic characteristics,as well as the corresponding tumor heterogeneities,which provides a clinically relevant platform for drug screening,biomarker discovery,and translational research. 展开更多
关键词 patient-derived xenograft(PDX) non-small cell lung cancer(NSCLC) tumor heterogeneity
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Translational pancreatic cancer research:a comparative study on patient-derived xenograft models 被引量:2
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作者 Mercedes Rubio-Manzanares Dorado Luis Miguel Marín Gómez +7 位作者 Daniel Aparicio Sánchez Sheila Pereira Arenas Juan Manuel Praena-Fernández Juan Jose Borrero Martín Francisco Farfán López Miguel ángel Gómez Bravo Jordi Muntané Relat Javier Padillo Ruiz 《World Journal of Gastroenterology》 SCIE CAS 2018年第7期794-809,共16页
AIM To assess the viability of orthotopic and heterotopic patient-derived pancreatic cancer xenografts implanted into nude mice.METHODS This study presents a prospective experimental analytical follow-up of the develo... AIM To assess the viability of orthotopic and heterotopic patient-derived pancreatic cancer xenografts implanted into nude mice.METHODS This study presents a prospective experimental analytical follow-up of the development of tumours in mice upon implantation of human pancreatic adenocarcinoma samples. Specimens were obtained surgically from patients with a pathological diagnosis of pancreatic adenocarcinoma. Tumour samples from pancreatic cancer patients were transplanted into nude mice in three different locations(intraperitoneal, subcutaneous and pancreatic). Histological analysis(haematoxylin-eosin and Masson's trichrome staining) and immunohistochemical assessment of apoptosis(TUNEL), proliferation(Ki-67), angiogenesis(CD31) and fibrogenesis(α-SMA) were performed. When a tumour xenograft reached the target size, it was reimplanted in a new nude mouse. Three sequential tumour xenograft generations were generated(F1, F2 and F3).RESULTS The overall tumour engraftment rate was 61.1%. The subcutaneous model was most effective in terms of tissue growth(69.9%), followed by intraperitoneal(57.6%) and pancreatic(55%) models. Tumour development was faster in the subcutaneous model(17.7 ± 2.6 wk) compared with the pancreatic(23.1 ± 2.3 wk) and intraperitoneal(25.0 ± 2.7 wk) models(P = 0.064). There was a progressive increase in the tumour engraftment rate over successive generations for all three models(F1 28.1% vs F2 71.4% vs F3 80.9%, P < 0.001). There were no significant differences in tumour xenograft differentiation and cell proliferation between human samples and the three experimental models among the sequential generations of tumour xenografts. However, a progressive decrease in fibrosis, fibrogenesis, tumour vascularisation and apoptosis was observed in the three experimental models compared with the human samples. All three pancreatic patient-derived xenograft models presented similar histological and immunohistochemical characteristics.CONCLUSION In our experience, the faster development andgreatest number of viable xenografts could make the subcutaneous model the best option for experimentation in pancreatic cancer. 展开更多
关键词 Immunohistological analysis PANCREATIC cancer patient-derived XENOGRAFT Animal model NUDE mice
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Establishment,functional and genetic characterization of three novel patient-derived rectal cancer cell lines 被引量:1
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作者 Michael Gock Christina S Mullins +8 位作者 Carina Bergner Friedrich Prall Robert Ramer Anja Goder Oliver H Kramer Falko Lange Bernd J Krause Ernst Klar Michael Linnebacher 《World Journal of Gastroenterology》 SCIE CAS 2018年第43期4880-4892,共13页
AIM To establish patient-individual tumor models of rectal cancer for analyses of novel biomarkers, individual response prediction and individual therapy regimens.METHODS Establishment of cell lines was conducted by d... AIM To establish patient-individual tumor models of rectal cancer for analyses of novel biomarkers, individual response prediction and individual therapy regimens.METHODS Establishment of cell lines was conducted by direct in vitro culturing and in vivo xenografting with subsequent in vitro culturing. Cell lines were in-depth characterized concerning morphological features, invasive and migratory behavior, phenotype, molecular profile including mutational analysis, protein expression, and confirmation of origin by DNA fingerprint. Assessment of chemosensitivity towards an extensive range of current chemotherapeutic drugs and of radiosensitivity was performed including analysis of a combined radioand chemotherapeutic treatment. In addition, glucose metabolism was assessed with 18 F-fluorodeoxyglucose(FDG) and proliferation with 18 F-fluorothymidine.RESULTS We describe the establishment of ultra-low passage rectal cancer cell lines of three patients suffering from rectal cancer. Two cell lines(HROC126, HROC284 Met) were established directly from tumor specimens while HROC239 T0 M1 was established subsequent to xenografting of the tumor. Molecular analysis classified all three cell lines as CIMP-0/non-MSI-H(sporadic standard) type. Mutational analysis revealed following mutational profiles: HROC126: APC^(wt), TP53^(wt), KRAS^(wt), BRAF^(wt), PTEN^(wt); HROC239 T0 M1: APC^(mut), P53^(wt), KRAS^(mut), BRAF^(wt), PTEN^(mut) and HROC284 Met: APC^(wt), P53^(mut), KRAS^(mut), BRAF^(wt), PTEN^(mut). All cell lines could be characterized as epithelial(EpCAM+) tumor cells with equivalent morphologic features and comparable growth kinetics. The cell lines displayed a heterogeneous response toward chemotherapy, radiotherapy and their combined application. HROC126 showed a highly radio-resistant phenotype and HROC284 Met was more susceptible to a combined radiochemotherapy than HROC126 and HROC239 T0 M1. Analysis of 18 F-FDG uptake displayed a markedly reduced FDG uptake of all three cell lines after combined radiochemotherapy. CONCLUSION These newly established and in-depth characterized ultra-low passage rectal cancer cell lines provide a useful instrument for analysis of biological characteristics of rectal cancer. 展开更多
关键词 patient-derived tumor model Rectal cancer ^(18)F-fluorodeoxyglucose ^(18)F-fluorothymidine FOLFOX FOLFIRI Personalized medicine
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Spontaneous xenogeneic GvHD in Wilms'tumor Patient-Derived xenograft models and potential solutions 被引量:1
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作者 Seyed Mostafa Monzavi Ahad Muhammadnejad +3 位作者 Maryam Behfar Amir Arsalan Khorsand Samad Muhammadnejad Abdol-Mohammad Kajbafzadeh 《Animal Models and Experimental Medicine》 CAS CSCD 2022年第4期389-396,共8页
Severely immunocompromised NOD.Cg-PrkdcIl2rg(NOG)mice are among the ideal animal recipients for generation of human cancer models.Transplantation of human solid tumors having abundant tumor-i nfiltrating lymphocytes(T... Severely immunocompromised NOD.Cg-PrkdcIl2rg(NOG)mice are among the ideal animal recipients for generation of human cancer models.Transplantation of human solid tumors having abundant tumor-i nfiltrating lymphocytes(TILs)can induce xenogeneic graft-versus-host disease(xGvHD)following engraftment and expansion of the TILs inside the animal body.Wilms’tumor(WT)has not been recognized as a lymphocyte-predominant tumor.However,3 consecutive generations of NOG mice bearing WT patient-derived xenografts(PDX)xenotransplanted from a single donor showed different degrees of inflammatory symptoms after transplantation before any therapeutic intervention.In the initial generation,dermatitis,auto-amputation of digits,weight loss,lymphadenopathy,hepatitis,and interstitial pneumonitis were observed.Despite antibiotic treatment,no response was noticed,and thus the animals were prematurely euthanized(day 47 posttransplantation).Laboratory and histopathologic evaluations revealed lymphoid infiltrates positively immunostained with anti-human CD3 and CD8 antibodies in the xenografts and primary tumor,whereas no microbial infection or lymphoproliferative disorder was found.Mice of the next generation that lived longer(91 days)developed sclerotic skin changes and more severe pneumonitis.Cutaneous symptoms were milder in the last generation.The xenografts of the last 2 generations also contained TILs,and lacked lymphoproliferative transformation.The systemic immunoinflammatory syndrome in the absence of microbial infection and posttransplant lymphoproliferative disorder was suggestive of xGvHD.While there are few reports of xGvHD in severely immunodeficient mice xenotransplanted from lymphodominant tumor xenografts,this report for the first time documented serial xGvHD in consecutive passages of WT PDX-bearing models and discussed potential solutions to prevent such an undesired complication. 展开更多
关键词 graft-versus-host disease patient-derived xenograft models tumor-infiltrating lymphocytes Wilms’tumor
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Specific bone region localization of osteolytic versus osteoblastic lesions in a patient-derived xenograft model of bone metastatic prostate cancer 被引量:1
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作者 Takeshi Hirata Seung Chol Park +12 位作者 Michelle T.Muldong Christina N.Wu Tomonori Yamaguchi Amy Strasner Omer Raheem Hiromi Kumon Robert L.Sah Nicholas A.Cacalano Catriona H.M.Jamieson Christopher J.Kane Koichi Masuda Anna A.Kulidjian Christina A.M.Jamieson 《Asian Journal of Urology》 2016年第4期229-239,共11页
Objective:Bone metastasis occurs in up to 90%of men with advanced prostate cancer and leads to fractures,severe pain and therapy-resistance.Bone metastases induce a spectrum of types of bone lesions which can respond ... Objective:Bone metastasis occurs in up to 90%of men with advanced prostate cancer and leads to fractures,severe pain and therapy-resistance.Bone metastases induce a spectrum of types of bone lesions which can respond differently to therapy even within individual prostate cancer patients.Thus,the special environment of the bone makes the disease more complicated and incurable.A model in which bone lesions are reproducibly induced that mirrors the complexity seen in patients would be invaluable for pre-clinical testing of novel treatments.The microstructural changes in the femurs of mice implanted with PCSD1,a new patient-derived xenograft from a surgical prostate cancer bone metastasis specimen,were determined.Methods:Quantitative micro-computed tomography(micro-CT)and histological analyses were performed to evaluate the effects of direct injection of PCSD1 cells or media alone(Control)into the right femurs of Rag2/gc/male mice.Results:Bone lesions formed only in femurs of mice injected with PCSD1 cells.Bone volume(BV)was significantly decreased at the proximal and distal ends of the femurs(p<0.01)whereas BV(p<0.05)and bone shaft diameter(p<0.01)were significantly increased along the femur shaft.Conclusion:PCSD1 cells reproducibly induced bone loss leading to osteolytic lesions at the ends of the femur,and,in contrast,induced aberrant bone formation leading to osteoblastic lesions along the femur shaft.Therefore,the interaction of PCSD1 cells with different bone region-specific microenvironments specified the type of bone lesion.Our approach can be used to determine if different bone regions support more therapy resistant tumor growth,thus,requiring novel treatments. 展开更多
关键词 Bone metastatic prostate cancer patient-derived xenograft microenvironment Microstructural CT Osteolytic lesions Osteoblastic lesions
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Molecular phenotypes reveal heterogeneous engraftments of patient-derived hepatocellular carcinoma xenografts
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作者 Jianyong Zhuo Di Lu +8 位作者 Jianguo Wang Zhengxing Lian Jiali Zhang Huihui Li Beini Cen Xuyong Wei Qiang Wei Haiyang Xie Xiao Xu 《Chinese Journal of Cancer Research》 SCIE CAS CSCD 2021年第4期470-479,共10页
Objective:Patient-derived xenograft(PDX)models provide a promising preclinical platform for hepatocellular carcinoma(HCC).However,the molecular features associated with successful engraftment of PDX models have not be... Objective:Patient-derived xenograft(PDX)models provide a promising preclinical platform for hepatocellular carcinoma(HCC).However,the molecular features associated with successful engraftment of PDX models have not been revealed.Methods:HCC tumor samples from 76 patients were implanted in immunodeficient mice.The molecular expression was evaluated by immunohistochemistry.Patient and tumor characteristics as well as tumor molecular expressions were compared for PDX engraftment using the Chi-square test.The independent prediction parameters were identified by logistic regression analyses.Results:The engraftment rate for PDX models from patients with HCC was 39.47%(30/76).Tumors from younger patients and patients with elevated preoperative alpha-fetoprotein level had higher engraftment rates.Tumors with poor differentiation and vascular invasion were related to engraftment success.The positive expression of CK19,CD133,glypican-3(GPC3),and Ki67 in tumor samples was associated with engraftment success.Logistic regression analyses indicated that GPC3 and Ki67 were two of the strongest predictors of PDX engraftment.Tumors with GPC3/Ki67 phenotypes showed heterogeneous engraftment rates,with 71.9%in GPC3^(+)/Ki67^(+)tumors,30.8%in GPC3^(-)/Ki67^(+)tumors,15.0%in GPC3^(+)/Ki67^(-)tumors,and 0 in GPC3^(-)/Ki67^(-)tumors.Conclusions:Successful engraftment of HCC PDXs was significantly related to molecular features.Tumors with the GPC3+/Ki67+phenotype were the most likely to successfully establish HCC PDXs. 展开更多
关键词 Hepatocellular carcinoma patient-derived xenografts heterogeneous establishment molecular phenotype
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Advantages and limitations in the establishment and utilization of patient-derived xenografts in gastric cancer
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作者 Zuhua Chen Lin Shen 《Oncology and Translational Medicine》 2017年第1期3-9,共7页
Owing to the high genetic heterogeneity of tumors, small number of therapeutic strategies available, and frequent presentation of drug resistance, the prognosis for patients with advanced gastric cancer(AGC) are unsat... Owing to the high genetic heterogeneity of tumors, small number of therapeutic strategies available, and frequent presentation of drug resistance, the prognosis for patients with advanced gastric cancer(AGC) are unsatisfactory. The utility of traditional cancer cell lines in translational research is limited by their poor correspondence to the genomic alterations and expression profiles that occur in actual patient tumors. In the last decade, increasing attention has been given to patient-derived tumor xenografts(PDTXs), which can faithfully recapitulate the histopathology, molecular characteristics, and therapeutic responses of the patient's tumor. However, the widespread development and utilization of PDTXs is restricted by factors such as the timeframe of establishment, lymphoma transformation during passaging, the immunodeficient microenvironment, and pharmacokinetic differences between mice and humans. In this review, we summarize the establishment and characterization of PDTX models for gastric cancer(GC). We then weigh the advantages and limitations of PDTXs when used to evaluate novel compounds, identify effective biomarkers, demonstrate resistance mechanisms, and predict clinical outcomes. 展开更多
关键词 patient-derived tumor XENOGRAFT (PDTX) GASTRIC cancer (GC) PRECLINICAL research
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A multidimensional platform of patient-derived tumors identifies drug susceptibilities for clinical lenvatinib resistance
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作者 Lei Sun Arabella H.Wan +11 位作者 Shijia Yan Ruonian Liu Jiarui Li Zhuolong Zhou Ruirui Wu Dongshi Chen Xianzhang Bu Jingxing Ou Kai Li Xiongbin Lu Guohui Wan Zunfu Ke 《Acta Pharmaceutica Sinica B》 SCIE CAS CSCD 2024年第1期223-240,共18页
Lenvatinib,a second-generation multi-receptor tyrosine kinase inhibitor approved by the FDA for first-line treatment of advanced liver cancer,facing limitations due to drug resistance.Here,we applied a multidimensiona... Lenvatinib,a second-generation multi-receptor tyrosine kinase inhibitor approved by the FDA for first-line treatment of advanced liver cancer,facing limitations due to drug resistance.Here,we applied a multidimensional,high-throughput screening platform comprising patient-derived resistant liver tumor cells(PDCs),organoids(PDOs),and xenografts(PDXs)to identify drug susceptibilities for conquering lenvatinib resistance in clinically relevant settings.Expansion and passaging of PDCs and PDOs from resistant patient liver tumors retained functional fidelity to lenvatinib treatment,expediting drug repurposing screens.Pharmacological screening identified romidepsin,YM155,apitolisib,NVP-TAE684 and dasatinib as potential antitumor agents in lenvatinib-resistant PDC and PDO models.Notably,romidepsin treatment enhanced antitumor response in syngeneic mouse models by triggering immunogenic tumor cell death and blocking the EGFR signaling pathway.A combination of romidepsin and immunotherapy achieved robust and synergistic antitumor effects against lenvatinib resistance in humanized immunocompetent PDX models.Collectively,our findings suggest that patient-derived liver cancer models effectively recapitulate lenvatinib resistance observed in clinical settings and expedite drug discovery for advanced liver cancer,providing a feasible multidimensional platform for personalized medicine. 展开更多
关键词 Lenvatinib Drug resistance High-throughput screening Drug discovery patient-derived model ROMIDEPSIN EGFR Liver cancer
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Reduction-responsive nucleic acid nanocarrier-mediated miR-22 inhibition of PI3K/AKT pathway for the treatment of patient-derived tumor xenograft osteosarcoma 被引量:1
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作者 Dafu Chen Chengyue Lei +11 位作者 Weifeng Liu Meiyu Shao Meizhou Sun Jianxun Guo Jingjing Cao Jing-Jun Nie Peng Luo Yuwen Luo Bingran Yu Renxian Wang Shun Duan Fu-Jian Xu 《Bioactive Materials》 SCIE CSCD 2023年第10期376-385,共10页
miRNAs are important regulators of gene expression and play key roles in the development of cancer, including osteosarcoma. During the development of osteosarcoma, the expression of miR-22 is significantly downregulat... miRNAs are important regulators of gene expression and play key roles in the development of cancer, including osteosarcoma. During the development of osteosarcoma, the expression of miR-22 is significantly downregulated, making miR-22 as a promising therapeutic target against osteosarcoma. To design and fabricate efficient delivery carriers of miR-22 into osteosarcoma cells, a hydroxyl-rich reduction-responsive cationic polymeric nanoparticle, TGIC-CA (TC), was developed in this work, which also enhanced the therapeutic effects of Volasertib on osteosarcoma. TC was prepared by the ring-opening reaction between amino and epoxy groups by one-pot method, which had the good complexing ability with nucleic acids, reduction-responsive degradability and gene transfection performance. TC/miR-22 combined with volasertib could inhibit proliferation, migration and promote apoptosis of osteosarcoma cells in vitro. The anti-tumor mechanisms were revealed as TC/ miR-22 and volasertib could inhibit the PI3K/Akt signaling pathway synergistically. Furthermore, this strategy showed outstanding tumor suppression performance in animal models of orthotopic osteosarcoma, especially in patient-derived chemo-resistant and chemo-intolerant patient-derived xenograft (PDX) models, which reduced the risk of tumor lung metastasis and overcame drug resistance. Therefore, it has great potential for efficient treatment of metastasis and drug resistance of osteosarcoma by the strategy of localized, sustained delivery of miR-22 using the cationic nanocarriers combined with non-traditional chemotherapy drugs. 展开更多
关键词 Nucleic acid delivery Nanoparticle Gene therapy OSTEOSARCOMA Responsive patient-derived Xenograft(PDX)
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Characterization of drug responses of mini patient-derived xenografts in mice for predicting cancer patient clinical therapeutic response 被引量:23
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作者 Feifei Zhang Wenjie Wang +11 位作者 Yuan Long Hui Liu Jijun Cheng Lin Guo Rongyu Li Chao Meng Shan Yu Qingchuan Zhao Shun Lu Lili Wang Haitao Wang Danyi Wen 《Cancer Communications》 SCIE 2018年第1期643-654,共12页
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 failu... 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. 展开更多
关键词 Personalized cancer therapy Cancer precision medicine patient-derived xenograft(PDX) MiniPDX Drug response In vivo
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Personalized treatment based on mini patient-derived xenografts and WES/RNA sequencing in a patient with metastatic duodenal adenocarcinoma 被引量:14
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作者 Peng Zhao Hui Chen +3 位作者 Danyi Wen Shuo Mou Feifei Zhang Shusen Zheng 《Cancer Communications》 SCIE 2018年第1期586-592,共7页
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-m... 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. 展开更多
关键词 Duodenal adenocarcinoma Mini patient-derived xenograft Whole-exome sequencing RNA sequencing Somatic mutation Personalized therapy
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Delivery of triptolide with reduction-sensitive polymer nanoparticles for liver cancer therapy on patient-derived xenografts models 被引量:7
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作者 Mengxue He Ling Yu +7 位作者 Yuanyuan Yang Binhua Zou Wen Ma Meng Yu Jiandong Lu Guoliang Xiong Zhiqiang Yu Aimin Li 《Chinese Chemical Letters》 SCIE CAS CSCD 2020年第12期3178-3182,共5页
Hepatocellular carcinoma(HCC)has become the fourth predominant cause of cancer-related deaths worldwide,and HCC is still one of the worst prognoses for survival as it is poorly responsive to both chemotherapy and surg... Hepatocellular carcinoma(HCC)has become the fourth predominant cause of cancer-related deaths worldwide,and HCC is still one of the worst prognoses for survival as it is poorly responsive to both chemotherapy and surgical treatment due to drug resista nce and great toxic effects.Triptolide(TP),a key ingredient from the traditional Chinese medical herb,has been utilized to treat inflammation and antitumor for centuries.However,investigations of this potent agent have been met with only limited success due to the severe systemic toxicities in patients and low water solubility as well as its high toxicity over the past two decades.Herein,we reported the development of a reduction-responsive drug delive ry system loaded with TP fo r glutathione(GSH)-trigge red drug release for cancer therapy.With the GSH-sensitive TP loaded nanoparticles,the remarkable increases in tumor accumulation and amelioration of drug toxicity in animals are demonstrated,which is likely due to sustained stepwise release of active TP within cancer cells.Moreover,in a patient-derived tumor xenograft model of liver cancer,administration of tritolide nanoparticles enhances the antitumor efficacy relative to administration of free TP.These findings indicate that GSH-sensitive release of TP may be a promising strategy for cancer treatment. 展开更多
关键词 TRIPTOLIDE Hepatocellular carcinoma Reduction-sensitive polymer patient-derived xenografts Drug therapy
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Patient-derived xenograft platform of OSCC: a renewable human bio-bank for preclinical cancer research and a new co-clinical model for treatment optimization 被引量:5
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作者 Shuyang Sun Zhiyuan Zhang 《Frontiers of Medicine》 SCIE CAS CSCD 2016年第1期104-110,共7页
Advances in next-generation sequencing and bioinformatics have begun to reveal the complex genetic landscape in human cancer genomes, including oral squamous cell carcinoma (OSCC). Sophisticated preclinical models t... Advances in next-generation sequencing and bioinformatics have begun to reveal the complex genetic landscape in human cancer genomes, including oral squamous cell carcinoma (OSCC). Sophisticated preclinical models that fully represent intra- and inter-tumoral heterogeneity are required to understand the molecular diversity of cancer and achieve the goal of personalized therapies. Patient-derived xenograft (PDX) models generated from human tumor samples that can retain the histological and genetic features of their donor tumors have been shown to be the preferred preclinical tool in translational cancer research compared with other conventional preclinical models. Specifically, genetically well-defined PDX models can be applied to accelerate targeted antitumor drug development and biomarker discovery. Recently, we have successfully established and characterized an OSCC PDX panel as part of our tumor bio-bank for translational cancer research. In this paper, we discuss the establishment, characterization, and preclinical applications of the PDX models. In particular, we focus on the classification and applications of the PDX models based on validated annotations, including clinicopathological features, genomic profiles, and pharmacological testing information. We also explore the translational value of this well-annotated PDX panel in the development of co-clinical trials for patient stratification and treatment optimization in the near future. Although various limitations still exist, this preclinical approach should be further tested and improved. 展开更多
关键词 patient-derived xenograft models personalized medicine co-clinical trial patient stratification oral squamous cellcarcinoma
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Generation and application of patient-derived xenograft models in pancreatic cancer research 被引量:3
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作者 Cheng-Fang Wang Xian-Jie Shi 《Chinese Medical Journal》 SCIE CAS CSCD 2019年第22期2729-2736,共8页
Objective:Pancreatic ductal adenocarcinoma cancer(PDAC)is one of the leading causes of cancer-related death worldwide.Hence,the development of effective anti-PDAC therapies is urgently required.Patient-derived xenogra... Objective:Pancreatic ductal adenocarcinoma cancer(PDAC)is one of the leading causes of cancer-related death worldwide.Hence,the development of effective anti-PDAC therapies is urgently required.Patient-derived xenograft(PDX)models are useful models for developing anti-cancer therapies and screening drugs for pre&sion medicine.This review aimed to provide an updated summary of using PDX models in PDAC.Data sources:The author retrieved information from the PubMed database up to June 2019 using various combinations of search terms,including PDAC,pancreatic carcinoma,pancreatic cancer,patient-derived xenografts or PDX,and patient-derived tumor xenografts or PDTX.Study selection:Original articles and review articles relevant to the review's theme were selected.Results:PDX models are better than cell line-derived xenograft and other models.PDX models consistently demonstrate retained tumor morphology and genetic stability,are benefi&al in cancer research,could enhance drug discovery and oncologic mechanism development of PDAC,allow an improved understanding of human cancer cell biology,and help guide personalized treatmem.Conclusions:In this review,we outline the status and application of PDX models in both basic and pre-clinical pancreatic cancer researches.PDX model is one of the most appropriate pre-clinical tools that can improve the prognosis of patients with pancreatic cancer in the future. 展开更多
关键词 Cancer research PANCREATIC DUCTAL ADENOCARCINOMA patient-derived XENOGRAFTS Precision medicine
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Novel dual inhibitor for targeting PIM1 and FGFR1 kinases inhibits colorectal cancer growth in vitro and patient-derived xenografts in vivo 被引量:3
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作者 Fanxiang Yin Ran Zhao +11 位作者 Dhilli Rao Gorja Xiaorong Fu Ning Lu Hai Huang Beibei Xu Hanyong Chen Jung-Hyun Shim Kangdong Liu Zhi Li Kyle Vaughn Laster Zigang Dong Mee-Hyun Lee 《Acta Pharmaceutica Sinica B》 SCIE CAS CSCD 2022年第11期4122-4137,共16页
Colorectal cancer(CRC) is the second most common cause of cancer-related death in the world. The pro-viral integration site for Moloney murine leukemia virus 1(PIM1) is a proto-oncogene and belongs to the serine/threo... Colorectal cancer(CRC) is the second most common cause of cancer-related death in the world. The pro-viral integration site for Moloney murine leukemia virus 1(PIM1) is a proto-oncogene and belongs to the serine/threonine kinase family, which are involved in cell proliferation, migration,and apoptosis. Fibroblast growth factor receptor 1(FGFR1) is a tyrosine kinase that has been implicated in cell proliferation, differentiation and migration. Small molecule HCI-48 is a derivative of chalcone, a class of compounds known to possess anti-tumor, anti-inflammatory and antibacterial effects. However,the underlying mechanism of chalcones against colorectal cancer remains unclear. This study reports that HCI-48 mainly targets PIM1 and FGFR1 kinases, thereby eliciting antitumor effects on colorectal cancer growth in vitro and in vivo. HCI-48 inhibited the activity of both PIM1 and FGFR1 kinases in an ATPdependent manner, as revealed by computational docking models. Cell-based assays showed that HCI-48inhibited cell proliferation in CRC cells(HCT-15, DLD1, HCT-116 and SW620), and induced cell cycle arrest in the G2/M phase through modulation of cyclin A2. HCI-48 also induced cellular apoptosis, as evidenced by an increase in the expression of apoptosis biomarkers such as cleaved PARP, cleaved caspase 3 and cleaved caspase 7. Moreover, HCI-48 attenuated the activation of downstream components of the PIM1 and FGFR1 signaling pathways. Using patient-derived xenograft(PDX) murine tumor models,we found that treatment with HCI-48 diminished the PDX tumor growth of implanted CRC tissue expressing high protein levels of PIM1 and FGFR1. This study suggests that the inhibitory effect of HCI-48 on colorectal tumor growth is mainly mediated through the dual-targeting of PIM1 and FGFR1kinases. This work provides a theoretical basis for the future application of HCI-48 in the treatment of clinical CRC. 展开更多
关键词 PIM1 FGFR1 Colorectal cancer HCI-48 Targeted therapy Small moleculecompound ofchalcone patient-derived xenograft model ATPKinase activity
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Culture of patient-derived multicellular clusters in suspended hydrogel capsules for pre-clinical personalized drug screening 被引量:3
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作者 Haijiang Dong Zequn Li +8 位作者 Suchen Bian Guangyuan Song Wenfeng Song Mingqi Zhang Haiyang Xie Shusen Zheng Xuxu Yang Tiefeng Li Penghong Song 《Bioactive Materials》 SCIE 2022年第12期164-177,共14页
A personalized medication regimen provides precise treatment for an individual and can be guided by pre-clinical drug screening.The economical and high-efficiency simulation of the liver tumor microenvironment(TME)in ... A personalized medication regimen provides precise treatment for an individual and can be guided by pre-clinical drug screening.The economical and high-efficiency simulation of the liver tumor microenvironment(TME)in a drug-screening model has high value yet challenging to accomplish.Herein,we propose a simulation of the liver TME with suspended alginate-gelatin hydrogel capsules encapsulating patient-derived liver tumor multicellular clusters,and the culture of patient-derived tumor organoids(PDTOs)for personalized pre-clinical drug screening.The hydrogel capsule offers a 3D matrix environment with mechanical and biological properties similar to those of the liver in vivo.As a result,18 of the 28 patient-derived multicellular clusters were successfully cultured as PDTOs.These PDTOs,along with hepatocyte growth factor(HGF)of non-cellular components,preserve stromal cells,including cancer-associated fibroblasts(CAFs)and vascular endothelial cells(VECs).They also maintain stable expression of molecular markers and tumor heterogeneity similar to those of the original liver tumors.Drugs,including cabazitaxel,oxaliplatin,and sorafenib,were tested in PDTOs.The sensitivity of PDTOs to these drugs differs between individuals.The sensitivity of one PDTO to oxaliplatin was validated using magnetic resonance imaging(MRI)and biochemical tests after oxaliplatin clinical treatment of the corresponding patient.Therefore,this approach is promising for economical,accurate,and high-throughput drug screening for personalized treatment. 展开更多
关键词 Multicellular clusters Hydrogel capsules Tumor microenvironment Tumor heterogeneity patient-derived tumor organoids Personalized pre-clinical drug screening
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Integrating of lipophilic platinum(IV) prodrug into liposomes for cancer therapy on patient-derived xenograft model 被引量:2
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作者 Zibo Li Qing Xu +6 位作者 Xuefeng Lin Kunyi Yu Ling Lin Yangjia Liu Zhiqiang Yu Tiancai Liu Dixian Luo 《Chinese Chemical Letters》 SCIE CAS CSCD 2022年第4期1875-1879,共5页
Platinum-based anticancer agents such as cisplatin and its analogues are widely used for treating multiple cancers. However, due to the inferior water-solubility, chemoresistance and consequent adverse side effects, t... Platinum-based anticancer agents such as cisplatin and its analogues are widely used for treating multiple cancers. However, due to the inferior water-solubility, chemoresistance and consequent adverse side effects, their clinical applications are limited. Herein, choles Pt(IV), a lipophilic platinum(IV) prodrug was synthesized for manufacture of Choles Pt(IV)-Liposomes aiming to resolve the predefined obstacles encountered by platinum drugs. Following systematic screening, Choles Pt(IV)-Liposomes showed a small particle size(105.6 nm), the rapid release of platinum(Pt) ions, and notable apoptosis of cancer cells.In addition, according to the fluidity and safety results of animal experiments in mice, Choles Pt(IV)-Liposomes also showed better therapeutic effect, which significantly inhibited the growth of patientderived xenograft tumors of hepatocellular carcinoma with an inhibition ratio of 80.7%, and effectively alleviated the drug toxicity brought by traditional platinum drugs. Overall, this study provides a promising route to enhance the therapeutic efficiency of platinum drugs in cancer treatment. 展开更多
关键词 Lipophilic platinum(IV)prodrug Liposome Cancer therapy Drug delivery patient-derived xenograft
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Patient-derived organoids potentiate precision medicine in advanced clear cell renal cell carcinoma 被引量:1
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作者 Yizheng Xue Bingran Wang +5 位作者 Yiying Tao Jun Xia Kedi Yuan Junhua Zheng Wei Zhai Wei Xue 《Precision Clinical Medicine》 2022年第4期215-221,共7页
To investigate the role of patient-derived organoid(PDO)model in the precision medicine of advanced clear cell renal cell carcinoma(ccRCC),we retrospectively analyzed the clinical data of seven cases of ccRCC diagnose... To investigate the role of patient-derived organoid(PDO)model in the precision medicine of advanced clear cell renal cell carcinoma(ccRCC),we retrospectively analyzed the clinical data of seven cases of ccRCC diagnosed by operation and pathology in Renji Hospital from September 2021 to September 2022.The seven patients were diagnosed with advanced ccRCC with or without remote metastasis.Cytoreductive and radical nephrectomy was performed respectively.To predict the response to immunotherapy and provide personalized medicine recommendation,a PDO model based on air-liquid interface system was established from the surgical resected tumor and subsequent drug screening was performed.Hematoxylin and eosin(H&E)staining and immunohistochemistry revealed that the PDO recapitulated the histological feature of parent tumor.Immunofluorescence staining identified that CD3^(+)T cells,SMA^(+)cancer associated fibroblasts,and CD31^(+)endothelial cells were preserved in PDO models.Fluorescence activated cell sorter(FACS)revealed an evidently increased ratio of CD8^(+)/CD4^(+)T cells and apoptotic tumor cells in PDO treated with toripalimab than those treated with IgG4.The results showed that toripalimab is able to rescue the excessive death of CD8^(+)T cells by critically reversing the immune exhaustion state of ccRCC in PDO model.This research validated that PDO is a promising and faithful preclinical model for prediction of immunotherapy response in patients with ccRCC. 展开更多
关键词 patient-derived organoid air-liquid interface tumor microenvironment IMMUNOTHERAPY renal cell carcinoma
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