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Clinical utility of pdx cohorts to reveal biomarkers of intrinsic resistance and clonal architecture changes underlying acquired resistance to cetuximab in HNSCC

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Signal Transduction and Targeted Therapy 2022年第4期7卷 1202-1218页

作者： Yanli Yao Yujue Wang Lan Chen Zhen Tian Guizhu Yang Rui Wang Chong Wang Qi Wu Yaping Wu Jiamin Gao Xindan Kang Shengzhong Duan Zhiyuan Zhang Shuyang Sun Department of Oral and Maxillofacial-Head Neck Oncology Shanghai Ninth People’s HospitalShanghai Jiao Tong University School of MedicineShanghaiChina College of Stomatology Shanghai Jiao Tong UniversityNational Center for StomatologyNational Clinical Research Center for Oral DiseasesShanghai Key Laboratory of StomatologyShanghaiChina Department of Oral Pathology Shanghai Ninth People’s HospitalShanghai Jiao Tong University School of MedicineShanghaiChina Laboratory of Oral Microbiota and Systemic Diseases Shanghai Ninth People’s HospitalShanghai Jiao Tong University School of MedicineShanghaiChina

Cetuximab is a widely used drug for treating head and neck squamous cell carcinomas(HNSCCs);however,it provides restricted clinical benefits,and its response duration is limited by drug resistance.Here,we conducted randomized“Phase II-like clinical trials”of 49 HNSCC pdx models and reveal multiple informative biomarkers for intrinsic resistance to cetuximab(e.g.,amplification of ANKH,up-regulation of PARP3).After validating these intrinsic resistance biomarkers in another HNSCC pdx cohort(61 pdx models),we generated acquired cetuximab resistance pdx models and analyzed them to uncover resistance mechanisms.Whole exome sequencing and transcriptome sequencing revealed diverse patterns of clonal selection in acquired resistant pdxs,including the emergence of subclones with strongly activated RAS/MAPK.Extending these insights,we show that a combination of a RAC1/RAC3 dual-target inhibitor and cetuximab could overcome acquired cetuximab resistance in vitro and in vivo.Beyond revealing intrinsic resistance biomarkers,our pdx-based study shows how clonal architecture changes underlying acquired resistance can be targeted to expand the therapeutic utility of this important drug to more HNSCC patients.

关键词： resistance pdx intrinsic

Discovery of novel KRAS-PDEδ inhibitors with potent activity in patient-derived human pancreatic tumor xenograft models

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Acta Pharmaceutica Sinica B 2022年第1期12卷 274-290页

作者： Long Chen Jing Zhang Xinjing Wang Yu Li Lu Zhou Xiongxiong Lu Guoqiang Dong Chunquan Sheng School of Pharmacy Second Military Medical UniversityShanghai 200433China Department of Pathology Changzheng HospitalSecond Military Medical UniversityShanghai 200003China Department of General Surgery Pancreatic Disease CenterRuijin HospitalShanghai Jiao Tong UniversityShanghai 200025China Research Institute of Pancreatic Diseases Shanghai Jiao Tong University School of MedicineShanghai 200025China Department of Medicinal Chemistry School of PharmacyFudan UniversityShanghai 201203China

KRAS-PDEδ interaction is revealed as a promising target for suppressing the function of mutant KRAS. The bottleneck in clinical development of PDEδ inhibitors is the poor antitumor activity of known chemotypes. Here, we identified novel spiro-cyclic PDEδ inhibitors with potent antitumor activity both in vitro and in vivo. In particular, compound 36 l(KD= 127 ± 16 nmol/L) effectively bound to PDEδ and interfered with KRAS-PDEδ interaction. It influenced the distribution of KRAS in Mia PaCa-2 cells, downregulated the phosphorylation of t-ERK and t-AKT and promoted apoptosis of the cells. The novel inhibitor 36 l exhibited significant in vivo antitumor potency in pancreatic cancer patient-derived xenograft(pdx) models. It represents a promising lead compound for investigating the druggability of KRAS-PDEδ interaction.

关键词： KRAS-PDEδinteraction pdx Spiro-cyclic inhibitors Lead optimization SBDD Anti-pancreatic cancer activity

Progress in building clinically relevant patient-derived tumor xenograft models for cancer research

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Animal Models and Experimental Medicine 2023年第5期6卷 381-398页

作者： Weijing Wang Yongshu Li Kaida Lin Xiaokang Wang Yanyang Tu Zhenjian Zhuo Department of Clinical Medicine Shantou University Medical CollegeShantouChina College of Life Sciences Hubei Normal UniversityHuangshiChina Shenzhen Institute for Technology Innovation National Institute of MetrologyShenzhenChina Department of Pharmacy Shenzhen Longhua District Central HospitalShenzhenChina Research Center Huizhou Central People's HospitalGuangdong Medical UniversityHuizhou CityChina State Key Laboratory of Chemical Oncogenomics School of Chemical Biology and BiotechnologyPeking University Shenzhen Graduate SchoolShenzhenChina Laboratory Animal Center School of Chemical Biology and BiotechnologyPeking University Shenzhen Graduate SchoolShenzhenChina

Patient-derived tumor xenograft(pdx)models,a method involving the surgical extraction of tumor tissues from cancer patients and subsequent transplantation into immunodeficient mice,have emerged as a pivotal approach in translational research,particularly in advancing precision medicine.As the first stage of pdx development,the patient-derived orthotopic xenograft(PDOX)models implant tumor tissue in mice in the corresponding anatomical locations of the patient.The PDOX models have several advantages,including high fidelity to the original tumor,heightened drug sensitivity,and an elevated rate of successful transplantation.However,the PDOX models present significant challenges,requiring advanced surgical techniques and resourceintensive imaging technologies,which limit its application.And then,the humanized mouse models,as well as the zebrafish models,were developed.Humanized mouse models contain a human immune environment resembling the tumor and immune system interplay.The humanized mouse models are a hot topic in pdx model research.Regarding zebrafish patient-derived tumor xenografts(zpdx)and patient-derived organoids(PDO)as promising models for studying cancer and drug discovery,zpdx models are used to transplant tumors into zebrafish as novel personalized medical animal models with the advantage of reducing patient waiting time.PDO models provide a cost-effective approach for drug testing that replicates the in vivo environment and preserves important tumor-related information for patients.The present review highlights the functional characteristics of each new phase of pdx and provides insights into the challenges and prospective developments in this rapidly evolving field.

关键词： animal model cancer pdx precision medicine

Theoretical study of CO2 hydrogenation to methanol on isolated small pdx clusters

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Journal of Energy Chemistry 2019年第8期28卷 79-87,I0004页

作者： Adhitya G.Saputro Refaldi I.D.Putra Arifin L.Maulana Muhammad U.Karami Mochamad R.Pradana Mohammad K.Agusta Hermawan K.Dipojono Hideaki Kasai Engineering Physics Research Group Institut Teknologi BandungBandung 40132 Indonesia Research Center for Nanosciences and Nanotechnology Institut Teknologi BandungBandung 40132 Indonesia Akashi College National Institute of TechnologyHyogo 674-8501 Japan Graduate School of Engineering Osaka UniversityOsaka 565-0871 Japan Department of Applied Physics Osaka UniversityOsaka 565-0871 Japan

CO2 hydrogenation to methanol on small size pdxclusters(x = 7, 9 and 13) has been studied using density functional theory calculations. It has been found that in contrast to metallic Pd system, these small pdxclusters can interact well with CO2 molecule. CO2 molecule can be adsorbed with a bidendate configuration on the pdxclusters. The formation of CO2 bidendate adsorption configuration facilitates the first step of CO2 hydrogenation reaction on the clusters. The energy profiles for formate pathway and reverse water gas shift + CO hydrogenation pathways on pdxclusters are quite similar with Cu(111) surface, except for the first and last hydrogenation steps where the pdxclusters have lower activation energies. This improvement causing the pdxclusters to have a tolerable turn over frequencies values. In general, the usage of Pd in the form of small size cluster can improve the catalytic performance of metallic Pd for the CO2 hydrogenation to methanol because small size Pd cluster can act not only as an H2 dissociation center but also as a CO2 hydrogenation center.

关键词： pdx clusters CO2 Adsorption Hydrogenation Methanol Density functional theory

Experimental models of endocrine responsive breast cancer: strengths, limitations, and use

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Cancer Drug Resistance 2021年第4期4卷 762-783页

作者： Robert Clarke Brandon C.Jones Catherine M.Sevigny Leena A.Hilakivi-Clarke Surojeet Sengupta The Hormel Institute and Department of Biochemistry Molecular Biology and BiophysicsUniversity of MinnesotaAustinMN 55912USA Department of Oncology Georgetown University Medical CenterWashingtonDC 20057USA The Jackson Laboratory 600 Main StreetBar HarborME 04609USA

Breast cancers characterized by expression of estrogen receptor-alpha(ER;ESR1)represent approximately 70%of all new cases and comprise the largest molecular subtype of this disease.Despite this high prevalence,the number of adequate experimental models of ER+breast cancer is relatively limited.Nonetheless,these models have proved very useful in advancing understanding of how cells respond to and resist endocrine therapies,and how the ER acts as a transcription factor to regulate cell fate signaling.We discuss the primary experimental models of ER+breast cancer including 2D and 3D cultures of established cell lines,cell line-and patient-derived xenografts,and chemically induced rodent models,with a consideration of their respective general strengths and limitations.What can and cannot be learned easily from these models is also discussed,and some observations on how these models may be used more effectively are provided.Overall,despite their limitations,the panel of models currently available has enabled major advances in the field,and these models remain central to the ability to study mechanisms of therapy action and resistance and for hypothesis testing that would otherwise be intractable or unethical in human subjects.

关键词： Breast cancer experimental models pdx xenografts study design

MicroRNA-217在骨巨细胞瘤pdx模型中对LC3、Beclin-1表达影响的实验研究

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MicroRNA-217在骨巨细胞瘤PDX模型中对LC3、Beclin-1表达影响的实...

作者：对红内蒙古医科大学

学位级别：硕士

目的骨巨细胞瘤(Giant cell tumor of bone,GCTB)的发病机制尚不明确,其具有侵袭性及复发率高是治疗该疾病的难题。大量研究证实了LC3、Beclin-1在细胞发生自噬时起到重要作用,且MicroRNA-217可能通过调控LC3、Beclin-1相关基因使GCTB... 详细信息

目的骨巨细胞瘤(Giant cell tumor of bone,GCTB)的发病机制尚不明确,其具有侵袭性及复发率高是治疗该疾病的难题。大量研究证实了LC3、Beclin-1在细胞发生自噬时起到重要作用,且MicroRNA-217可能通过调控LC3、Beclin-1相关基因使GCTB细胞发生自噬,从而影响GCTB的进展,但是具体的作用机制仍待进一步研究。本课题组使用造模方式——建立人源肿瘤异种移植(Patient-Derived tumor Xenograft,pdx)模型来探究MicroRNA-217与GCTB发展之间的关联、及其皮下瘤中LC3、Beclin-1相关基因表达的改变,从而进一步研究MicroRNA-217是否通过调控LC3、Beclin-1相关基因促进或抑制GCTB自噬的发展。方法使用课题组前期体外培养过表达或干扰miR-217的人GCTB细胞系并注射植入免疫缺陷的裸鼠皮下,从而建立6组pdx模型后使皮下瘤体自然增值。实验过程中比对分析不同分组中的皮下瘤体增值情况、体积及重量的改变并记录。通过免疫组化、定量PCR、Western blot检测各组皮下瘤标本中LC3、Beclin-1的表达变化,分析miR-217对皮下瘤中LC3、Beclin-1表达变化的影响。实验数据均采用SPSS19.0统计软件包处理,统计分析实验组与对照组有无统计学意义。结果miR-217mimics组与Control组相比裸鼠皮下瘤体生长较慢,而miR-217inhibitor组与Control组相比生长较快,miR-217 mimics组裸鼠皮下结瘤体积及重量明显降低,相反miR-217 inhibitor组裸鼠皮下结瘤体积及重量明显增加;免疫组化实验结果示,与Control组相比,miR-217 mimic组中LC3、Beclin-1的蛋白表达水平均显著降低,miR-217 inhibitor组中LC3、Beclin-1的蛋白表达水平均显著升高;定量PCR结果示,与Control组相比,miR-217 mimic组中LC3、Beclin-1的m RNA表达水平均显著降低,miR-217inhibitor组中LC3、Beclin-1的m RNA表达水平均显著升高;Western blot结果示,与Control组相比,miR-217 mimic组中LC3、Beclin-1的蛋白表达水平均显著降低,miR-217 inhibitor组中LC3、Beclin-1的蛋白表达水平均显著升高。结论MicroRNA-217可能调控GCTB的进展过程,可通过稳定过表达MicroRNA-217对瘤体生长进行抑制;瘤体病理组织切片免疫组化结果显示,过表达MicroRNA-217可能对GCTB组织中的自噬相关因子LC3、Beclin-1的表达进行了下调,从而提示可能减少自噬的发生;GCTB裸鼠结瘤后通过检测蛋白、m RNA表达情况,提示过表达MicroRNA-217可能对自噬相关基因LC3、Beclin-1有下调作用并减少自噬的发生,从而抑制肿瘤的进展和增值。

关键词：骨巨细胞瘤 LC3 Beclin-1 pdx MicroRNA-217

阿魏酸乙酯抑制食管鳞癌增殖的作用及其机制研究

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阿魏酸乙酯抑制食管鳞癌增殖的作用及其机制研究

作者：庞梦君郑州大学

学位级别：硕士

背景和目的食管癌(EC)是全球范围内最严重的恶性肿瘤之一,严重威胁着人们的健康,其中鳞状细胞癌和腺癌占食管癌的95%以上。食管鳞状细胞癌(ESCC)是食管癌的主要组织病理学亚型之一,其特征是发病率和死亡率高。ESCC在非工业化国家更常见... 详细信息

背景和目的食管癌(EC)是全球范围内最严重的恶性肿瘤之一,严重威胁着人们的健康,其中鳞状细胞癌和腺癌占食管癌的95%以上。食管鳞状细胞癌(ESCC)是食管癌的主要组织病理学亚型之一,其特征是发病率和死亡率高。ESCC在非工业化国家更常见,重要的危险因素包括吸烟、饮酒和贲门失弛缓症。食管腺癌(EAC)是发达国家的主要食管癌类型,重要的危险因素包括慢性胃食管反流病、肥胖和吸烟。目前,手术切除、放疗和化疗是食管癌的主要临床治疗方法,但治疗过程中的不良反应和疗效不理想依然是食管癌临床治疗面对的巨大挑战。靶向治疗作为一种新型的治疗手段,已被证实在食管癌的治疗中发挥着重要作用。针对表皮生长因子受体(EGFR)、血管内皮生长因子(VEGF)、人表皮生长因子受体2(HER-2)和PD-L1的靶向治疗药物和抑制剂已被美国食品和药物管理局(FDA)批准作为ESCC患者的治疗药物,但是在治疗中患者不可避免的出现了耐药性,我们亟待寻求疗效更好的靶向药物。肿瘤细胞通过重新编码其新陈代谢以获得营养物质,支持它们的生长和增殖。肿瘤的发生与肿瘤细胞的代谢相关,细胞生长信号通路的激活对合成代谢有着深远的影响。mTOR通路是细胞代谢过程中的中枢信号通路,调节多种基本细胞过程,包括蛋白质合成、生长、代谢、衰老、再生、自噬等。mTOR在人类癌症中经常被解除调控,mTOR信号通路的激活在多种类型的人类癌症被发现,因此mTOR是一种值得关注的治疗靶点。许多源自中草药的天然产物及化合物都表现出了抗癌活性,包括抗增殖、抗转移、促凋亡、抗血管生成等作用,以及调节自噬、平衡免疫力、逆转药物耐药性、增强化疗效果。阿魏酸乙酯是从传统药用植物阿魏中分离得到的苯丙烷类单体化合物,它的抗炎作用被广泛报道,然而,阿魏酸乙酯的抗癌活性及其潜在的分子机制尚不清楚。在此,我们研究了阿魏酸乙酯在体内外对食管鳞状细胞癌恶性生长的抗癌作用。方法1.探究阿魏酸乙酯对食管鳞癌的抑制作用首先,通过细胞毒性实验检测不同浓度的阿魏酸乙酯对正常食管上皮细胞SHEE增殖活力的影响;然后,通过细胞增殖实验、平板克隆形成实验和软琼脂糖克隆形成实验检测不同浓度的阿魏酸乙酯对食管鳞癌细胞KYSE30,KYSE70,KYSE450和KYSE510的生长抑制作用;利用类器官实验检测阿魏酸乙酯对ESCC类器官生长的影响。2.探索阿魏酸乙酯对食管鳞癌细胞周期的影响首先,通过细胞周期实验分析阿魏酸乙酯是否对ESCC细胞周期有阻滞作用;利用免疫蛋白印记实验检测阿魏酸乙酯对ESCC细胞周期标记蛋白的影响。3.阐明阿魏酸乙酯在食管鳞癌中作用的分子机制利用免疫蛋白印记实验分析阿魏酸乙酯在JB6和ESCC细胞中潜在的分子靶点;通过体外结合实验确定阿魏酸乙酯与mTOR是否直接结合;体外激酶实验检测阿魏酸乙酯对mTOR激酶活性的影响;再利用激酶筛选试验探索其他信号蛋白的活性是否受到阿魏酸乙酯的影响。4.研究敲低mTOR对食管鳞癌细胞生长的影响利用病毒感染的方法建立了稳定的mTOR敲低细胞系,通过免疫蛋白印记实验检测敲低的细胞系中mTOR蛋白的表达水平;通过细胞增殖实验、平板克隆形成实验和软琼脂糖克隆形成实验验证敲低mTOR对ESCC细胞生长的影响。5.探究阿魏酸乙酯对食管鳞癌细胞增殖的影响是否依赖于mTOR的表达利用细胞增殖实验、平板克隆形成实验和软琼脂糖克隆形成实验检测阿魏酸乙酯对敲低mTOR细胞增殖的影响。6.验证阿魏酸乙酯在体内对食管鳞癌肿瘤生长的作用首先,利用动物毒性实验确定在体内研究中使用的阿魏酸乙酯浓度;在食管癌患者异种移植瘤小鼠模型(patient-derived xenograft model,pdx)中验证阿魏酸乙酯在体内对ESCC肿瘤生长的影响;免疫组织化学实验检测肿瘤细胞增殖标志蛋白Ki-67的表达;利用免疫蛋白印记实验检测阿魏酸乙酯对pdx肿瘤组织中通路信号蛋白表达的影响;通过ALT、AST活性实验检测阿魏酸乙酯对pdx小鼠肝脏毒性的影响;HE染色观察阿魏酸乙酯对小鼠肝、肾和脾组织形态的影响。结果1.阿魏酸乙酯抑制食管鳞癌的生长阿魏酸乙酯对SHEE正常食管上皮细胞的活力没有影响;阿魏酸乙酯能够抑制食管鳞癌细胞KYSE30,KYSE70,KYSE450、KYSE510和ESCC类器官的生长,并且呈浓度依赖性。2.阿魏酸乙酯阻滞食管鳞癌细胞周期在G1期阿魏酸乙酯促进ESCC细胞G1期周期阻滞,并增加了细胞周期标记蛋白p21的表达,降低了Cyclin D1的表达。3.阿魏酸乙酯通过mTOR信号通路作用于食管鳞癌阿魏酸乙酯能够显著降低JB6和ESCC细胞中mTOR及其下游信号通路AKT、GSK3β和p70S6K的磷酸化水平,并且阿魏酸乙酯能与mTOR直接结合,以剂量依赖的方式直接抑制mTOR的激酶活性。4.敲低mTOR可抑制食管鳞癌细胞的生长敲低细胞系中mTOR蛋白的表达水平被显著抑制,并且敲低mTOR对ESCC细胞生长有抑

关键词：食管鳞癌 mTOR pdx 阿魏酸乙酯

pdx模型在妇科恶性肿瘤靶向治疗方面的应用

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现代妇产科进展 2020年第4期29卷 308-312页

作者：周君涵邹双微(综述) 朱雪琼(审校) 温州医科大学附属第二医院妇产科温州325000

人源性肿瘤异种移植(pdx)模型是将患者的肿瘤组织或细胞经处理后移植到免疫缺陷小鼠上所建立的模型。pdx模型能较好保留原始肿瘤的组织学、分子学及遗传学特性,因此具有优于传统体外细胞系及其衍生物的特点,常被作为癌症患者的替代模型... 详细信息

人源性肿瘤异种移植(pdx)模型是将患者的肿瘤组织或细胞经处理后移植到免疫缺陷小鼠上所建立的模型。pdx模型能较好保留原始肿瘤的组织学、分子学及遗传学特性,因此具有优于传统体外细胞系及其衍生物的特点,常被作为癌症患者的替代模型用于临床前药物筛选。本文从pdx模型的建立及其在妇科恶性肿瘤的靶向治疗方面进行综述,明确其在妇科恶性肿瘤靶向治疗方面的应用价值。

关键词：人源性肿瘤异种移植 pdx 靶向治疗妇科恶性肿瘤

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人源性肝癌组织移植模型研究进展

中国药理学通报 2020年第4期36卷 475-478页

作者：刘世芳李宜航陈德力苏晶吕亚娜丁璇李光孙晓波中国医学科学院北京协和医学院药用植物研究所云南分所药理中心云南景洪666100 西双版纳州傣药南药重点实验室云南景洪666100 中国医学科学院北京协和医学院药用植物研究所海南分所植物化学中心海南海口570311 中国医学科学院北京协和医学院药用植物研究所药理毒理中心北京100093

人源性肿瘤组织移植(Patient-derived human tumor xenograft,pdx)模型能很好的保持原代肿瘤的组织病理学、生长及转移特性,并在多次传代后仍然能够在较大程度上保留原代肿瘤的这些特性,与原始患者肿瘤密切相关,具有重要科研价值。肝癌... 详细信息

人源性肿瘤组织移植(Patient-derived human tumor xenograft,pdx)模型能很好的保持原代肿瘤的组织病理学、生长及转移特性,并在多次传代后仍然能够在较大程度上保留原代肿瘤的这些特性,与原始患者肿瘤密切相关,具有重要科研价值。肝癌pdx模型已用于患者的个性化药物筛选、药物疗效的评价、治疗方向的探索、肝癌的发生发展机制等,具有良好的应用前景。该文对肝癌pdx模型的方法、应用以及成瘤因素等方面进行综述。

关键词： pdx 肝癌方法应用成瘤因素研究进展