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)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-RPRB-M)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Fred Hutchinson Cancer Research Center
United States
Zip Code
Stephan, Sirkka B; Taber, Alexandria M; Jileaeva, Ilona et al. (2015) Biopolymer implants enhance the efficacy of adoptive T-cell therapy. Nat Biotechnol 33:97-101
Karlan, Beth Y; Thorpe, Jason; Watabayashi, Kate et al. (2014) Use of CA125 and HE4 serum markers to predict ovarian cancer in elevated-risk women. Cancer Epidemiol Biomarkers Prev 23:1383-93
Cecil, Denise L; Holt, Gregory E; Park, Kyong Hwa et al. (2014) Elimination of IL-10-inducing T-helper epitopes from an IGFBP-2 vaccine ensures potent antitumor activity. Cancer Res 74:2710-8
Palanca-Wessels, Maria Corinna; Press, Oliver W (2014) Advances in the treatment of hematologic malignancies using immunoconjugates. Blood 123:2293-301
Miller, Chris P; Thorpe, Jason D; Kortum, Amanda N et al. (2014) JAK2 expression is associated with tumor-infiltrating lymphocytes and improved breast cancer outcomes: implications for evaluating JAK2 inhibitors. Cancer Immunol Res 2:301-6
Topp, Monique D; Hartley, Lynne; Cook, Michele et al. (2014) Molecular correlates of platinum response in human high-grade serous ovarian cancer patient-derived xenografts. Mol Oncol 8:656-68
Pennington, Kathryn P; Walsh, Tom; Harrell, Maria I et al. (2014) Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas. Clin Cancer Res 20:764-75
Cheon, Dong-Joo; Orsulic, Sandra (2014) Ten-gene biomarker panel: a new hope for ovarian cancer? Biomark Med 8:523-6
Duggan, Catherine; Wang, Ching-Yun; Xiao, Liren et al. (2014) Aspirin and serum estrogens in postmenopausal women: a randomized controlled clinical trial. Cancer Prev Res (Phila) 7:906-12
Emori, Megan M; Drapkin, Ronny (2014) The hormonal composition of follicular fluid and its implications for ovarian cancer pathogenesis. Reprod Biol Endocrinol 12:60

Showing the most recent 10 out of 129 publications