Microbubbles are encapsulated gaseous particles that compress and expand their shape in response to an insonation source and generate strong acoustic signals that exceed conventional ultrasound backscatter. Ranging in size from 2 to 6 um, microbubbles persist in the blood stream for several minutes enabling assessment of their presence at the tissue microvascular level. Microbubbles have found their way into clinical application as ultrasound contrast agents - e.g. for imaging of liver lesions or echocardiography. Important to this proposal is the finding that microbubbles can be targeted to specific antigens on the surface of vascular endothelial cells by attaching ligands to the microbubble shell. Microbbubles functionalized in this way provide detailed information on the vasculature at a molecular level. Angiogenesis, the recruitment of new blood vessels, occurs at a very early stage in ovarian cancer development and activation ofthe VEGFA/EGFR2 axis plays a crucial role in the process. Our preliminary data demonstrates that VEGFR2 is up-regulated in tumor vessels from ovarian cancer including occult cancer identified at the time of risk-reduction salpingo-oophorectomy. In small animal tumor models we validated non-invasive tumor angiogenesis imaging using contrast enhanced ultrasound (CEUS) with VEGFR2- and/or OvPs-targeted microbubbles and demonstrated that these microbubbles have a high specificity for binding to VEGFR2- and OvPs-expressing cells, respectively, in cell culture and living mice. We also show that ultrasound signal amplification is possible using dual-targeted microbubbles.
In Aim 1 of this proposal we will translate our findings from small animal models to the clinic by conducting the first ever Phase 1 clinical trial of VEGFR2 targeted microbubble CEUS to image the ovarian cancer vascular network. Because the molecular phenotype of vascular endothelial cells varies by tissue site and activation state selecting the best antigens for targeting is a critical step in optimizing the approach.
In Aim 2 we wilt identify and validate novel endothelial cell surface proteins that may be better markers than or complementary to VEGR2 and validate these markers as in-vivo angiogenesis imaging targets in mouse models.

Public Health Relevance

(See Instructions): The primary objective of this proposal is to validate and refine molecularly targeted microbubble contrast enhanced ultrasound (CEUS) for non-invasive, in-vivo imaging ofthe ovarian cancer vascular network. The approach has the potential to improve outcomes for all women with ovarian cancer through early detection and diagnosis ofthe disease and selecting and monitoring the response of ovarian cancer to anti-angiogenic therapy.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center (P50)
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Fred Hutchinson Cancer Research Center
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