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 i nclude: (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. ? ? ?
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