Area of Science: 03 Using embryonic stem cells to re-create a human tumor microenvironment to develop ovarian cancer therapeutic and diagnostic tools. ABSTRACT Tumor vasculature expresses unique markers that represent novel immunotherapeutic targets. Development of anti-vascular immunotherapeutics, with few exceptions, has been hindered by the absence of a tumor model with human tumor vessels. A new tumor model, combining human embryonic stem cells (ESC) and tumor cells, develops abundant human vessels. It is unknown if these are `normal' or `tumor' vessels, expressing tumor vascular markers (TVMs). We hypothesize that ovarian cancer cells will induce human ovarian TVM expression. We propose (1) to characterize ovarian TVM expression in an ESC-ovarian cancer model for the development of anti-vascular immunotherapeutics. We recently identified over 70 ovarian TVMs. Many ovarian TVMs are not expressed in normal tissues or other tumors. Tumor specific expression, expression at the earliest stages of tumor development, and direct exposure to blood, suggest that TVMs are ideal biomarkers for both ovarian cancer diagnosis and targeted immunotherapy. We propose (2a) to test anti-ovarian TVM antibodies as diagnostic tools and, (2b) to couple anti-ovarian TVM antibodies with toxic nanoparticles and test them as immunotherapeutics using the ESC ovarian tumor model. Finally, our preliminary data suggest that the ESC-ovarian tumor model has human tumor vascular cells. Tumor vascular cells are critical for the growth of tumor stem cells, which reside within the vascular niche. One challenge with characterizing tumor stem cells has been finding appropriate conditions for in vivo growth. We hypothesize that the ESC ovarian tumor model, with human vascular cells, will provide an ideal microenvironment to support human stem cell growth. We therefore propose (3) to isolate ovarian tumor stem cells and grow them in vivo using the ESC ovarian cancer model. If successfully, this will create a murine tumor model that nearly completely reproduces the human tumor microenvironment with human tumor stroma, vessels and tumor stem cells.
