Breast cancer early detection can substantially improve patient survival. Ultrasound is one of the primary imaging approaches to diagnose breast diseases and fulfills many prerequisites as an ideal imaging and screening tool for breast cancer early detection: It is non-invasive and relatively cheap compared to other imaging modalities;it does not use ionizing irradiation;it has a high spatial and temporal resolution and is routinely available in most clinical imaging departments worldwide. However, ultrasound often lacks the sensitivity and specificity to detect breast cancer at an early stage. In this proposed study, we will combine the advantages of ultrasound with the advantages of molecular imaging through use of molecularly targeted ultrasound contrast microbubbles. This modified targeted contrast-enhanced ultrasound imaging strategy (molecular ultrasound imaging), may provide a quantitative and objective imaging approach for earlier detection of breast cancer. We will test newly developed clinically translatable micro bubbles that are targeted to the human kinase insert domain receptor (KDR), which has been shown to be over expressed on angiogenic vessels in breast cancer. In longitudinal screening exams in transgenic mice with mammary glands progressing from normal breast tissue to invasive breast cancer, diagnostic accuracy of screening ultrasound using KDR-targeted contrast micro bubbles will be assessed in vivo. Molecular ultrasound imaging data will be quantitatively correlated with KDR expression in tumor vessels and with tumor histology. Following ongoing toxicity studies on KDR-targeted micro bubbles in patients, we will perform a first ever clinical feasibility and efficacy trial on KDR-targeted molecular ultrasound imaging in women with various breast pathologies, using histology as the gold standard. Finally, we will further develop and refine molecular ultrasound imaging for early breast cancer detection by designing next generation contrast micro bubbles targeted to breast cancer specific molecular targets. Based on successful study results, we anticipate rapid translation of this technique into the clinic to improve patient survival and patient care by diagnosing breast cancer at an earlier stage.

Public Health Relevance

Current strategies for the diagnosis of early breast cancer have major limitations leading to delayed or missed diagnoses. In this research proposal, we will test the accuracy of a new targeted ultrasound imaging approach that allows detection of molecular alterations in tumor vessels of early stage breast cancer. The successful completion of our aims will lead to the development of a new imaging approach that can be used to more accurately diagnose breast cancer at an early, still curable stage.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA155289-01A1
Application #
8115571
Study Section
Clinical Molecular Imaging and Probe Development (CMIP)
Program Officer
Baker, Houston
Project Start
2011-09-13
Project End
2016-07-31
Budget Start
2011-09-13
Budget End
2012-07-31
Support Year
1
Fiscal Year
2011
Total Cost
$326,467
Indirect Cost
Name
Stanford University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Zhou, Jianhua; Zhang, Huiping; Wang, Huaijun et al. (2017) Early prediction of tumor response to bevacizumab treatment in murine colon cancer models using three-dimensional dynamic contrast-enhanced ultrasound imaging. Angiogenesis 20:547-555
Wang, Huaijun; Lutz, Amelie M; Hristov, Dimitre et al. (2017) Intra-Animal Comparison between Three-dimensional Molecularly Targeted US and Three-dimensional Dynamic Contrast-enhanced US for Early Antiangiogenic Treatment Assessment in Colon Cancer. Radiology 282:443-452
Wilson, Katheryne E; Bachawal, Sunitha V; Abou-Elkacem, Lotfi et al. (2017) Spectroscopic Photoacoustic Molecular Imaging of Breast Cancer using a B7-H3-targeted ICG Contrast Agent. Theranostics 7:1463-1476
Mullick Chowdhury, Sayan; Lee, Taehwa; Willmann, Jürgen K (2017) Ultrasound-guided drug delivery in cancer. Ultrasonography 36:171-184
Willmann, Jürgen K; Bonomo, Lorenzo; Carla Testa, Antonia et al. (2017) Ultrasound Molecular Imaging With BR55 in Patients With Breast and Ovarian Lesions: First-in-Human Results. J Clin Oncol 35:2133-2140
Zhou, Jianhua; Wang, Huaijun; Zhang, Huiping et al. (2016) VEGFR2-Targeted Three-Dimensional Ultrasound Imaging Can Predict Responses to Antiangiogenic Therapy in Preclinical Models of Colon Cancer. Cancer Res 76:4081-9
Abou-Elkacem, Lotfi; Wilson, Katheryne E; Johnson, Sadie M et al. (2016) Ultrasound Molecular Imaging of the Breast Cancer Neovasculature using Engineered Fibronectin Scaffold Ligands: A Novel Class of Targeted Contrast Ultrasound Agent. Theranostics 6:1740-52
Valluru, Keerthi S; Willmann, Juergen K (2016) Clinical photoacoustic imaging of cancer. Ultrasonography 35:267-80
Valluru, Keerthi S; Wilson, Katheryne E; Willmann, Jürgen K (2016) Photoacoustic Imaging in Oncology: Translational Preclinical and Early Clinical Experience. Radiology 280:332-49
Mullick Chowdhury, Sayan; Wang, Tzu-Yin; Bachawal, Sunitha et al. (2016) Ultrasound-guided therapeutic modulation of hepatocellular carcinoma using complementary microRNAs. J Control Release 238:272-280

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