It is well known that tumors dramatically distort microvasculature throughout the angiogenic process. Data show that substantial changes in microvasculature structure occur after the arrival of only 100s of tumor cells, that these changes extend to vessels that are relatively large (hundreds of microns in diameter), and that microvascular changes extend well beyond tumor margins, even soon after the onset of disease. These unique microvascular "cancer signatures" are a biomarker which provides us with a means to overcome traditional resolution limitations which otherwise impair micro-tumor detection. Thus, our innovative response to improving imaging sensitivity to micro-cancers is to detect these microvascular changes, rather than the solid tumor itself. Prior groups have illustrated the potential for this concept using optical microscopy, however optical microscopy is inherently non-clinically translatable for this application, and hence we are using a novel ultrasound approach. Although previously, ultrasound has not provided utility in assessing changes in microvascular structure, our group has recently implemented a new US imaging technique called "Acoustic Angiography" which provides supreme signal-to-noise and high resolution for imaging microvessel structure. This new imaging technique thus enables microvessel segmentation and tortuosity quantification. Encouraging preliminary pre-clinical data in have already illustrated our ability use acoustic angiography to discriminate small tumors and healthy tissue based on an analysis of microvessel morphology alone. The parent grant involves a comprehensive development of this promising new technology, including both optimizations of the imaging technique, as well as preclinical in-vivo studies using clinically-relevant genetically engineered rodent models of breast cancer to establish sensitivity and specificity in assessing the biomarker of tumor associated angiogenesis as a function of tumor size for early detection. In this supplement/revision application, we propose to carry the technology from the parent grant into a pilot clinical trial. Our goal is to demonstrate that this new imaging technology, Acoustic Angiography, will be effective in human patients. Our approach involves a 60 patient clinical study on patients with suspected breast cancer. Results will be compared for sensitivity and specificity against traditional ultrasound imaging (standard of care), as well as gold standard pathology provided as each patient will receive a biopsy or excision of the lesion. Although this small clinical pilot study will not be able to fully evaluatethe role of Acoustic Angiography in early cancer detection, the results of this study will provide necessary comparison data against gold standards to evaluate the potential efficacy of this new biomarker imaging technique, and help us optimize the technology and design a larger scale clinical trial as we move towards translation.

Public Health Relevance

Breast ultrasound is already a clinical standard of care for younger women, women with dense breasts, or women who have had breast augmentation, as mammography performs poorly in these populations. However, traditional ultrasound also has poor specificity and has a high false positive rate. In this project, our team will evaluate a new ultrasound imaging technology that could more effectively identify cancer and reduce false positive tests in a significant subset of women.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
3R01CA170665-03S1
Application #
8699388
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Zhang, Yantian
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Biomedical Engineering
Type
Schools of Medicine
DUNS #
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Shelton, Sarah E; Lindsey, Brooks D; Tsuruta, James K et al. (2016) Molecular Acoustic Angiography: A New Technique for High-resolution Superharmonic Ultrasound Molecular Imaging. Ultrasound Med Biol 42:769-81
Rao, Sneha R; Shelton, Sarah E; Dayton, Paul A (2016) The "Fingerprint" of Cancer Extends Beyond Solid Tumor Boundaries: Assessment With a Novel Ultrasound Imaging Approach. IEEE Trans Biomed Eng 63:1082-6
Lindsey, Brooks D; Rojas, Juan D; Dayton, Paul A (2015) On the relationship between microbubble fragmentation, deflation and broadband superharmonic signal production. Ultrasound Med Biol 41:1711-25
Ma, Jianguo; Martin, K Heath; Li, Yang et al. (2015) Design factors of intravascular dual frequency transducers for super-harmonic contrast imaging and acoustic angiography. Phys Med Biol 60:3441-57
Lindsey, Brooks D; Shelton, Sarah E; Dayton, Paul A (2015) Optimization of Contrast-to-Tissue Ratio Through Pulse Windowing in Dual-Frequency "Acoustic Angiography" Imaging. Ultrasound Med Biol 41:1884-95
Shelton, Sarah E; Lee, Yueh Z; Lee, Mike et al. (2015) Quantification of Microvascular Tortuosity during Tumor Evolution Using Acoustic Angiography. Ultrasound Med Biol 41:1896-904
Dunleavey, James M; Xiao, Lin; Thompson, Joshua et al. (2014) Vascular channels formed by subpopulations of PECAM1+ melanoma cells. Nat Commun 5:5200
Lindsey, Brooks D; Rojas, Juan D; Martin, K Heath et al. (2014) Acoustic characterization of contrast-to-tissue ratio and axial resolution for dual-frequency contrast-specific acoustic angiography imaging. IEEE Trans Ultrason Ferroelectr Freq Control 61:1668-87
Dayton, Paul A; Gessner, Ryan C; Phillips, Linsey et al. (2014) The implementation of acoustic angiography for microvascular and angiogenesis imaging. Conf Proc IEEE Eng Med Biol Soc 2014:4283-5
Martin, K Heath; Lindsey, Brooks D; Ma, Jianguo et al. (2014) Dual-frequency piezoelectric transducers for contrast enhanced ultrasound imaging. Sensors (Basel) 14:20825-42

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