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

描述（由申请人提供）：个体化的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。迫切需要新的转化疗法来治愈这种疾病。我们的实验室开创了病人肿瘤的原位生长，包括结肠癌(1)和胰腺癌(2)，在裸鼠模型中，肿瘤像在病人身上一样生长和转移。尽管目前人们对免疫缺陷小鼠模型中患者肿瘤的生长非常感兴趣，并为这些模型创造了新的名称，如“肿瘤移植”和“异种患者”，但目前的模型仍然是各种类型免疫缺陷小鼠的皮下异位异种移植。这种异位模型不会转移，因此不能充分代表患者。目前的应用，利用了我们实验室首创的患者样原位模型（1-6）以及我们实验室首创的基于荧光蛋白的体内成像技术(7)，开发了患者胰腺肿瘤的可成像原位模型，用于快速筛查有效的个体化治疗。我们将这些模型命名为可想象的患者来源的原位异种移植物（iPDOX）。我们已经初步证明，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，胰腺癌患者肿瘤可以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）。目前的应用建议开发iPDOX模型，用于筛选胰腺癌患者的有效个体化治疗，通过荧光成像可以无创地实时监测对治疗的反应。来自胰腺癌患者的新iPDOX将个性化治疗，增加改善预后的可能性，并为发现这种疾病的变革性治疗方法提供机会。I期申请的具体目的如下：1)通过荧光蛋白标记基质，建立胰腺癌iPDOX模型队列；2)通过iPDOX生长和转移过程中荧光成像面积与肿瘤重量和体积的相关性来验证可成像模型。在II期申请中，胰腺癌iPDOX模型将被验证用于胰腺癌变革性新型化疗的快速筛选。

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.