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.
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.
|Lee, John J; Perera, Rushika M; Wang, Huaijun et al. (2014) Stromal response to Hedgehog signaling restrains pancreatic cancer progression. Proc Natl Acad Sci U S A 111:E3091-100|
|Lutz, Amelie M; Bachawal, Sunitha V; Drescher, Charles W et al. (2014) Ultrasound molecular imaging in a human CD276 expression-modulated murine ovarian cancer model. Clin Cancer Res 20:1313-22|
|Wilson, Katheryne E; Bachawal, Sunitha V; Tian, Lu et al. (2014) Multiparametric spectroscopic photoacoustic imaging of breast cancer development in a transgenic mouse model. Theranostics 4:1062-71|
|Panje, Cedric M; Wang, David S; Willmann, Jurgen K (2013) Ultrasound and microbubble-mediated gene delivery in cancer: progress and perspectives. Invest Radiol 48:755-69|
|Kamaya, Aya; Machtaler, Steven; Safari Sanjani, Sahinaz et al. (2013) New technologies in clinical ultrasound. Semin Roentgenol 48:214-23|
|Wilson, Katheryne E; Wang, Tzu Yin; Willmann, Jurgen K (2013) Acoustic and photoacoustic molecular imaging of cancer. J Nucl Med 54:1851-4|
|Bachawal, Sunitha V; Jensen, Kristin C; Lutz, Amelie M et al. (2013) Earlier detection of breast cancer with ultrasound molecular imaging in a transgenic mouse model. Cancer Res 73:1689-98|
|Foygel, Kira; Wang, Huaijun; Machtaler, Steven et al. (2013) Detection of pancreatic ductal adenocarcinoma in mice by ultrasound imaging of thymocyte differentiation antigen 1. Gastroenterology 145:885-894.e3|
|Tzu-Yin, Wang; Wilson, Katheryne E; Machtaler, Steven et al. (2013) Ultrasound and microbubble guided drug delivery: mechanistic understanding and clinical implications. Curr Pharm Biotechnol 14:743-52|