Dual-color tumor-host imaging models

描述（由申请人提供）：该II期申请将进一步开发在I期申请中开发的双色可成像肿瘤-宿主相互作用裸鼠模型，用于III期发现和评估新的有效基质治疗药物，包括血管生成。宿主模型是在β -肌动蛋白启动子（BAD-GFP）控制下普遍表达绿色荧光蛋白（GFP）的裸鼠（Yang， M., et al., Proc. Natl.）。学会科学。Yang， M.等，癌症研究，64,8651- 8656,2004)和用GFP标记新生血管的巢蛋白驱动GFP （ND-GFP）裸鼠（Amoh， Y.等，癌症研究，65,5352-5357,2005）。除红细胞和毛发外，BAD-GFP小鼠的所有组织在蓝色激发光下都发出绿色荧光。ND-GFP小鼠新生血管表达GFP。在BAD-GFP模型中，移植的表达红色荧光蛋白（RFP）的肿瘤和表达GFP的基质细胞可以同时清晰地成像。将在BAD-GFP和ND-GFP模型中开发人类乳腺癌、结肠癌和前列腺癌的双色原位模型，以显示原发性和由此引起的转移中肿瘤与宿主的相互作用。双色成像使肿瘤和宿主组织的分辨率下降到单细胞水平。所有与肿瘤相互作用的宿主基质细胞都可以在BAD-GFP模型中唯一成像，包括活小鼠。基质细胞是新的基质治疗的靶点。新生肿瘤血管生成可以在ND- GFP模型中独特地成像。新生血管生成是抗肿瘤和抗转移治疗的潜在关键靶点，并且在活的ND-GFP裸鼠的人类肿瘤中被独特地观察到。这些颜色编码的人类癌症裸鼠模型将用于可视化新的靶点，这将极大地促进基质靶向和抗血管生成药物的发现。具体目的包括：(1)利用原位表达rfp的人肿瘤的BAD-GFP裸鼠建立双色肿瘤-宿主模型，发现基质靶向治疗药物。(2)用ND-GFP裸鼠和原位表达rfp的肿瘤模型建立双色肿瘤-宿主模型，发现靶向新生血管生成的特异性药物。这些模型对于基质靶向药物和抗血管生成药物的发现和开发具有重要的商业潜力。

DESCRIPTION (provided by applicant): This Phase II application will further develop dual-color imageable tumor-host-interaction nude mouse models, developed in the Phase I application, to be used in Phase III to discover and evaluate new effective agents for stromal therapy, including angiogenesis. The host models are the ubiquitously-expressing green fluorescent protein (GFP)-nude mouse with GFP under control of the beta-actin promoter (BAD-GFP) (Yang, M., et al., Proc. Natl. Acad. Sci. USA 98, 2616-2621, 2001 and Yang, M., et al., Cancer Research, 64, 8651- 8656, 2004) and the nestin-driven-GFP (ND-GFP) nude mouse in which nascent blood vessels are labeled with GFP (Amoh, Y., et al., Cancer Res. 65, 5352-5357, 2005). All of the tissues of the BAD-GFP mice, with the exception of erythrocytes and hair, fluoresce green under blue excitation light. In ND-GFP mice, nascent blood vessels express GFP. Transplanted red fluorescent protein (RFP)-expressing tumors and GFP- expressing stromal cells can be clearly imaged simultaneously in the BAD-GFP models. Dual-color orthotopic models of human breast, colon and prostate cancer will be developed in both the BAD-GFP and ND-GFP models to image tumor-host interaction in both primary and resulting metastases. Dual-color imaging enables resolution of the tumor and the host tissues down to the single cell level. All tumor- interacting host stromal cells can be uniquely imaged in the BAD-GFP model including live mice. The stromal cells are targets for new stromal therapy. Nascent tumor angiogenesis can be uniquely imaged in the ND- GFP model. Nascent angiogenesis is a potentially critical target for antitumor and antimetastatic therapy and is uniquely visualized in human tumors in the live ND-GFP nude mouse. These color-coded nude mouse models of human cancer will be used to visualize new targets which should greatly enhance the discovery of stromal-targeting and anti-angiogenesis drugs. The specific aims include: (1) Development of dual-color tumor-host models with the BAD-GFP nude mouse with orthotopic RFP-expressing human tumors for discovery of stroma-targeted therapeutic agents. (2) Development of dual-color tumor-host models with the ND-GFP nude mouse with orthotopic RFP-expressing tumor models for discovery of specific agents which target nascent angiogenesis. These models have significant commercial potential for discovery and development of stroma-targeted and anti-angiogenesis drugs.