Pancreatic-Cancer Imageable Patient-Derived Orthotopic Xenografts (iPDOX)

胰腺癌可成像患者来源的原位异种移植物 (iPDOX)

• 批准号: 8780448
• 负责人: MENG YANG
• 金额: $ 22.47万
• 依托单位: ANTICANCER, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-15 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8780448
• 关键词: Animals; Area; Cancer Patient; Cells; Coin; Colon Carcinoma; Cyan Fluorescent Protein; Disease; Future; Goals; Green Fluorescent Proteins; Growth; Human; Imaging technology; Immunodeficient Mouse; Individual; Label; Laboratories; Life; Malignant Neoplasms; Malignant neoplasm of pancreas; Modeling; Monitor; Mus; Names; Neoplasm Metastasis; Neoplasm Transplantation; Nude Mice; Organ; Organ Transplantation; Outcome; Patients; Pharmaceutical Preparations; Phase; Preclinical Drug Evaluation; Primary Neoplasm; Probability; Proteins; Skin; Therapeutic; Time; Transgenic Mice; Transgenic Organisms; Tumor Volume; Tumor Weights; Xenograft Model; Xenograft procedure; base; cancer cell; cancer therapy; chemotherapy; cohort; effective therapy; fluorescence imaging; immunodeficient mouse model; improved; in vivo imaging; interest; mouse model; novel; pancreatic neoplasm; public health relevance; red fluorescent protein; response; screening; subcutaneous; tumor; tumor growth

DESCRIPTION (provided by applicant): Individualized cancer treatment is an important goal, in particular, for pancreatic cancer, which is the most lethal human cancer. Novel transformative therapeutics are also urgently needed to cure this disease. Our laboratory pioneered the orthotopic growth of patient tumors, including colon cancer (1) and pancreatic cancer (2), in nude-mouse models where the tumors grow and metastasize as they did in the patient. Although there is presently much interest in growth of patient tumors in immunodeficient mouse models to individualize therapy and new names for these models have been coined, such as "tumorgraft" and "xenopatients", the current models are still subcutaneous ectopic xenografts in various types of immunodeficient mice. Such ectopic models do not metastasize and therefore do not sufficiently represent the patient. The present application, takes advantages of the patient-like orthotopic models our laboratory pioneered (1-6) as well as the in vivo imaging technology our laboratory also pioneered, based on fluorescent proteins (7), to develop imageable orthotopic models of patient pancreatic tumors for rapid screening for effective and individualized therapy. We have termed these models imageable patient-derived orthotopic xenografts (iPDOX). We have initially demonstrated that pancreatic cancer patient tumors can be made imageable by passage in transgenic nude mice expressing either green fluorescent protein (GFP), red fluorescent protein (RFP) or cyan fluorescent protein (CFP) whereby the patient tumors acquire and maintain the fluorescent stroma of the transgenic mice, even though tumor growth and passage (8-10). The current application proposes to develop the iPDOX models for screening for effective individualized therapy for pancreatic cancer patients whereby response to therapy can be monitored non-invasively in real time by fluorescence imaging. The new iPDOX derived from pancreatic cancer patients will individualize therapy and increase the probability of improved outcome and provide the opportunity to discover transformative therapeutics for this disease. The specific aims of the Phase I application are as follows: 1) Establish a cohort of pancreatic-cancer iPDOX models by labeling the stroma with fluorescent proteins; 2) Validate the imageable model by correlating fluorescence imaging area with both tumor weight and volume during iPDOX growth and metastasis. In the Phase II application, the pancreatic-cancer iPDOX models will be validated for rapid screening for transformative novel chemotherapy for pancreatic cancer.

描述（由申请人提供）：个体化癌症治疗是一个重要的目标，特别是对于胰腺癌，这是最致命的人类癌症。也迫切需要新的变革疗法来治愈这种疾病。我们的实验室率先在裸鼠模型中原位生长患者肿瘤，包括结肠癌（1）和胰腺癌（2），在裸鼠模型中肿瘤生长和转移与患者一样。尽管目前对患者肿瘤在免疫缺陷小鼠模型中的生长以个体化治疗有很大兴趣，并且已经为这些模型创造了新的名称，例如“肿瘤移植物”和“异种移植物”，但目前的模型仍然是各种类型免疫缺陷小鼠中的皮下异位异种移植物。这种异位模型不会转移，因此不能充分代表患者。本申请利用我们实验室开创的患者样原位模型（1-6）以及我们实验室也开创的基于荧光蛋白的体内成像技术（7），以开发患者胰腺肿瘤的可成像原位模型，用于快速筛选有效和个体化的治疗。我们将这些模型称为可成像的患者来源的原位异种移植物（iPDOX）。我们已经初步证明，胰腺癌患者肿瘤可以通过在表达绿色荧光蛋白（GFP）、红色荧光蛋白（RFP）或青色荧光蛋白（CFP）的转基因裸鼠中传代而变得可成像，由此患者肿瘤获得并维持转基因小鼠的荧光基质，即使肿瘤生长和传代（8-10）。本申请提出开发用于筛选胰腺癌患者的有效个体化治疗的iPDOX模型，由此可以通过荧光成像真实的时间非侵入性地监测对治疗的响应。来自胰腺癌患者的新iPDOX将使治疗个性化，增加改善结果的可能性，并为发现这种疾病的变革性疗法提供机会。I期申请的具体目标如下：1）通过用荧光蛋白标记基质来建立胰腺癌iPDOX模型的队列; 2）通过在iPDOX生长和转移期间将荧光成像面积与肿瘤重量和体积两者相关联来验证可成像模型。在II期申请中，胰腺癌iPDOX模型将被验证用于快速筛选胰腺癌的变革性新化疗。

项目成果

Patient-derived orthotopic xenograft (PDOX) nude mouse model of soft-tissue sarcoma more closely mimics the patient behavior in contrast to the subcutaneous ectopic model.

与皮下异位模型相比，患者来源的软组织肉瘤原位异种移植（PDOX）裸鼠模型更接近地模拟患者行为。

• 发表时间: 2015
• 期刊: Anticancer research
• 影响因子: 2
• 作者: Hiroshima,Yukihiko;Zhang,Yong;Zhang,Nan;Uehara,Fuminari;Maawy,Ali;Murakami,Takashi;Mii,Sumiyuki;Yamamoto,Mako;Miwa,Shinji;Yano,Shuya;Momiyama,Masashi;Mori,Ryutaro;Matsuyama,Ryusei;Chishima,Takashi;Tanaka,Kuniya;Ichikawa,Yasu
• 通讯作者: Ichikawa,Yasu

Efficacy of Tumor-Targeting Salmonella A1-R on a Melanoma Patient-Derived Orthotopic Xenograft (PDOX) Nude-Mouse Model.

• DOI: 10.1371/journal.pone.0160882
• 发表时间: 2016
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Yamamoto M;Zhao M;Hiroshima Y;Zhang Y;Shurell E;Eilber FC;Bouvet M;Noda M;Hoffman RM
• 通讯作者: Hoffman RM

Tumor-Targeting Salmonella typhimurium A1-R Arrests a Chemo-Resistant Patient Soft-Tissue Sarcoma in Nude Mice.

• DOI: 10.1371/journal.pone.0134324
• 发表时间: 2015
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Hiroshima Y;Zhao M;Zhang Y;Zhang N;Maawy A;Murakami T;Mii S;Uehara F;Yamamoto M;Miwa S;Yano S;Momiyama M;Mori R;Matsuyama R;Chishima T;Tanaka K;Ichikawa Y;Bouvet M;Endo I;Hoffman RM
• 通讯作者: Hoffman RM