Application of patient-derived tumor models in anticancer drug development and individualized medicine

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.

Patient-derived xenograft model in colorectal cancer basic and translational research

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.

Translational pancreatic cancer research:a comparative study on patient-derived xenograft models

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.

Spontaneous xenogeneic GvHD in Wilms'tumor Patient-Derived xenograft models and potential solutions

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.

Patient-derived non-small cell lung cancer xenograft mirrors complex tumor heterogeneity

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.

Mouse models of colorectal cancer: Past, present and future perspectives

Colorectal cancer(CRC)is the third most common diagnosed malignancy among both sexes in the United States as well as in the European Union.While the incidence and mortality rates in western,high developed countries are declining,reflecting the success of screening programs and improved treatment regimen,a rise of the overall global CRC burden can be observed due to lifestyle changes paralleling an increasing human development index.Despite a growing insight into the biology of CRC and many therapeutic improvements in the recent decades,preclinical in vivo models are still indispensable for the development of new treatment approaches.Since the development of carcinogen-induced rodent models for CRC more than 80 years ago,a plethora of animal models has been established to study colon cancer biology.Despite tenuous invasiveness and metastatic behavior,these models are useful for chemoprevention studies and to evaluate colitis-related carcinogenesis.Genetically engineered mouse models(GEMM)mirror the pathogenesis of sporadic as well as inherited CRC depending on the specific molecular pathways activated or inhibited.Although the vast majority of CRC GEMM lack invasiveness,metastasis and tumor heterogeneity,they still have proven useful for examination of the tumor microenvironment as well as systemic immune responses;thus,supporting development of new therapeutic avenues.Induction of metastatic disease by orthotopic injection of CRC cell lines is possible,but the so generated models lack genetic diversity and the number of suited cell lines is very limited.Patient-derived xenografts,in contrast,maintain the pathological and molecular characteristics of the individual patient's CRC after subcutaneous implantation into immunodeficient mice and are therefore most reliable for preclinical drug development–even in comparison to GEMM or cell line-based analyses.However,subcutaneous patient-derived xenograft models are less suitable for studying most aspects of the tumor microenvironment and anti-tumoral immune responses.The authors review the distinct mouse models of CRC with an emphasis on their clinical relevance and shed light on the latest developments in the field of preclinical CRC models.

Cancer models in preclinical research:A chronicle review of advancement in effective cancer research

Cancer is a major stress for public well-being and is the most dreadful disease.The models used in the discovery of cancer treatment are continuously changing and extending toward advanced preclinical studies.Cancer models are either naturally existing or artificially prepared experimental systems that show similar features with human tumors though the heterogeneous nature of the tumor is very familiar.The choice of the most fitting model to best reflect the given tumor system is one of the real difficulties for cancer examination.Therefore,vast studies have been conducted on the cancer models for developing a better understanding of cancer invasion,progression,and early detection.These models give an insight into cancer etiology,molecular basis,host tumor interaction,the role of microenvironment,and tumor heterogeneity in tumor metastasis.These models are also used to predict novel can-cer markers,targeted therapies,and are extremely helpful in drug development.In this review,the potential of cancer models to be used as a platform for drug screening and therapeutic discoveries are highlighted.Although none of the cancer models is regarded as ideal because each is associated with essential caveats that restraint its application yet by bridging the gap between preliminary cancer research and transla-tional medicine.However,they promise a brighter future for cancer treatment.

Assessing the performance of different outcomes for tumor growth studies with animal models

The consistency of reporting results for patient-derived xenograft(PDX) studies is an area of concern. The PDX method commonly starts by implanting a derivative of a human tumor into a mouse, then comparing the tumor growth under different treatment conditions. Currently, a wide array of statistical methods(e.g., t-test, regression, chi-squared test) are used to analyze these data, which ultimately depend on the outcome chosen(e.g., tumor volume, relative growth, categorical growth). In this simulation study, we provide empirical evidence for the outcome selection process by comparing the performance of both commonly used outcomes and novel variations of common outcomes used in PDX studies. Data were simulated to mimic tumor growth under multiple scenarios, then each outcome of interest was evaluated for 10?000 iterations. Comparisons between different outcomes were made with respect to average bias, variance, type-1 error, and power. A total of 18 continuous, categorical, and time-to-event outcomes were evaluated, with ultimately 2 outcomes outperforming the others: final tumor volume and change in tumor volume from baseline.Notably, the novel variations of the tumor growth inhibition index(TGII)— a commonly used outcome in PDX studies— was found to perform poorly in several scenarios with inflated type-1 error rates and a relatively large bias. Finally, all outcomes of interest were applied to a real-world dataset.

SPA: A Quantitation Strategy for MS Data in Patient-derived Xenograft Models

With the development of mass spectrometry(MS)-based proteomics technologies,patient-derived xenograft(PDX),which is generated from the primary tumor of a patient,is widely used for the proteome-wide analysis of cancer mechanism and biomarker identification of a drug.However,the proteomics data interpretation is still challenging due to complex data deconvolution from the PDX sample that is a cross-species mixture of human cancerous tissues and immunodeficient mouse tissues.In this study,by using the lab-assembled mixture of human and mouse cells with different mixing ratios as a benchmark,we developed and evaluated a new method,SPA(shared peptide allocation),for protein quantitation by considering the unique and shared peptides of both species.The results showed that SPA could provide more convenient and accurate protein quantitation in human–mouse mixed samples.Further validation on a pair of gastric PDX samples(one bearing FGFR2 amplification while the other one not)showed that our new method not only significantly improved the overall protein identification,but also detected the differential phosphorylation of FGFR2 and its downstream mediators(such as RAS and ERK)exclusively.The tool pdx SPA is freely available at https://github.com/LiLab-Proteomics/pdx SPA.

Patient-derived xenograft models for oncology drug discovery

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.

Reduction-responsive nucleic acid nanocarrier-mediated miR-22 inhibition of PI3K/AKT pathway for the treatment of patient-derived tumor xenograft osteosarcoma

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.

结直肠癌人源性肿瘤组织异种移植模型(PDX)的构建及^(18)F-FDG PET/CT活体成像监测

目的构建结直肠癌人源性肿瘤组织异种移植模型(Patient-derived Xenograft,PDX),并探讨18F-FDG PET/CT成像技术用于监测结直肠癌PDX模型肿瘤生长的有效性。方法取外科手术切除的新鲜结直肠癌组织,接种到免疫缺陷小鼠皮下构建PDX模型。采用HE染色法、免疫组织化学染色法进行模型评价。选取部分构建成功的PDX模型进行PET/CT活体成像监测。结果接种结直肠癌患者新鲜肿瘤组织35例,成功构建PDX模型20例,成功率为57%;成瘤所需的中位时间为54.5天,四分位间距为47.5天。HE染色结果表明结直肠癌PDX模型可以较好地保留原发肿瘤的组织学特性。Ki67、p53在第一代PDX模型移植瘤与原发肿瘤组织中均呈强阳性表达,具有高度相似性。结直肠癌的成瘤能力与患者的性别、年龄、以及肿瘤的部位、大小、分期、分化程度等均没有相关性。PDX模型的PET/CT活体显像表明,18F-FDG PET/CT可以获得较好的显像效果。结论结直肠癌PDX模型构建成功率较高,模型可以较好地保留原发肿瘤的组织学、生物学特性。18F-FDG PET/CT成像技术可用于监测结直肠癌PDX模型肿瘤的生长情况。

人体肿瘤PDX移植模型的优与劣

介绍人体肿瘤移植(patient-derived tumor xenograft model,PDX)模型的基本特征和在生物医学研究中的应用;比较该类模型应用于肿瘤研究的优点和存在的问题。目的是正确应用PDX模型开展研究工作,分析相应的实验结果,加快肿瘤药物研发进程。

Patient-derived xenograft platform of OSCC： a renewable human bio-bank for preclinical cancer research and a new co-clinical model for treatment optimization

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.

Characterization of drug responses of mini patient-derived xenografts in mice for predicting cancer patient clinical therapeutic response

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.

A nanocomposite competent to overcome cascade drug resistance in ovarian cancer via mitochondria dysfunction and NO gas synergistic therapy

Ovarian cancer(OC)is one of the most common and recurring malignancies in gynecology.Patients with relapsed OC always develop"cascade drug resistance"(CDR)under repeated chemotherapy,leading to subsequent failure of chemotherapy.To overcome this challenge,amphiphiles(P1)carrying a nitric oxide(NO)donor(Isosorbide 5-mononitrate,ISMN)and high-density disulfide are synthesized for encapsulatingmitochondria-targeted tetravalent platinum prodrug(TPt)to construct a nanocomposite(INP@TPt).Mechanism studies indicated that INP@TPt significantly inhibited drug-resistant cells by increasing cellular uptake and mitochondrial accumulation of platinum,depleting glutathione,and preventing apoptosis escape through generating highly toxic peroxynitrite anion(ONOO−).To better replicate the microenvironmental and histological characteristics of the drug resistant primary tumor,an OC patient-derived tumor xenograft(PDXOC)model in BALB/c nude mice was established.INP@TPt showed the best therapeutic effects in the PDXOC model.The corresponding tumor tissues contained high ONOO−levels,which were attributed to the simultaneous release of O_(2)^(·−)and NO in tumor tissues.Taken together,INP@TPtbased systematic strategy showed considerable potential and satisfactory biocompatibility in overcoming platinum CDR,providing practical applications for ovarian therapy.

Novel dual inhibitor for targeting PIM1 and FGFR1 kinases inhibits colorectal cancer growth in vitro and patient-derived xenografts in vivo

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.

人源肿瘤异种移植模型在精准肿瘤医学中的研究进展

癌症是由于物理、化学、病毒等致癌因子导致的原癌基因和抑癌基因突变从而引发的一系列异质性疾病的统称。尽管近年来高通量测序技术与靶向治疗取得了突破性的进展,但是临床转化研究的高失败率使得抗肿瘤药物的创新发展十分有限。人源肿瘤异种移植模型(patient-derived xenograft model,PDX模型)是指直接将病人的新鲜肿瘤组织移植到免疫缺陷小鼠上,依靠小鼠提供的环境生长的一种异种移植模型。这种模型保留了原代肿瘤的基质异质性、组织学特性、分子多样性以及微环境,为临床前药效的个性化筛选评估以及生物标志物的鉴定提供了有效的研发资源。PDX模型结合临床数据,基因组图谱以及药效数据可以增加药物特异性,应用于肿瘤患者个体化治疗,提高临床治疗成功率。本文就PDX模型研究进展进行综述,包括其在肿瘤新疗法中的应用、挑战性与局限性、以及在精准肿瘤医学中的应用前景。

近红外荧光染料在胃癌人源性肿瘤组织异种移植模型研究中的应用

目的建立胃癌人源性肿瘤组织异种移植(patient-derived tumor xenograft,PDX)裸鼠模型,探讨近红外荧光(near infrared fluorescence,NIRF)染料IR-783在胃癌PDX模型活体成像研究中的应用。方法取临床胃癌新鲜手术切除标本,裸鼠肾包膜移植建立PDX模型,HE染色比较移植肿瘤组织与患者肿瘤组织形态结构的一致性。将移植肿瘤组织裸鼠皮下接种,20 d后,荷瘤小鼠腹腔注射NIRF染料IR-783(每只10 nmol/L),活体成像连续测定肿瘤部位近红外荧光强度并分析肿瘤体积与荧光强度的相关性;免疫组织化学检测移植肿瘤组织中HIF1α与OATP1B3的表达强度。结果成功建立了3个人胃癌PDX模型,移植肿瘤组织较好的保持了原发肿瘤的特征,NIRF活体成像早期检测到肾包膜部位荧光信号。PDX模型中肿瘤体积与荧光强度的相关性均在98%以上。移植肿瘤组织中HIF1α与OATP1B3表达呈强阳性。结论 NIRF染料IR-783可在PDX模型肿瘤部位特异性聚集,用于PDX模型的早期检测,这种肿瘤靶向性可能与HIF1α和OATP1B3的表达相关。

人源化免疫肺癌小鼠模型的建立及其在程序性死亡受体1抑制剂疗效评估中的作用

目的·建立表达程序性死亡配体1(programmed death-ligand 1,PD-L1)的人源化免疫肺癌动物模型,并研究该模型在评估程序性死亡受体1(programmed death-1,PD-1)抑制剂疗效中的作用。方法·取晚期非小细胞肺癌患者新鲜的活检组织样本,或恶性胸腔积液中的肿瘤细胞,接种至CB17-SCID小鼠(重症联合免疫缺陷小鼠)皮下,建立患者来源异种移植物模型(patient-derived xenograft model,PDX模型),通过免疫组织化学法检测PDX模型肿瘤PD-L1的表达情况。将成熟的人外周血单个核细胞与PDX模型肿瘤细胞混合后接种NCG小鼠(高度免疫缺陷小鼠),建立人源化免疫的肺癌PDX模型,并在该模型上验证PD-1抑制剂的疗效。结果·在16个临床来源样本建立的PDX模型中,有2个PD-L1表达为强阳性,4个表达为阳性,其余均为阴性。在PD-L1强阳性的人源化免疫肺癌PDX模型中,PD-1抑制剂信迪利单抗在初次给药后21 d的肿瘤生长抑制率为82.6%;在PD-L1阴性的人源化免疫肺癌PDX模型中,PD-1抑制剂未显示出抗肿瘤活性。结论·成功建立了表达PD-L1的人源化免疫肺癌小鼠模型,且能在该模型上评估PD-1抑制剂的疗效。