Antiangiogenic therapy has been shown to be an effective strategy to control metastatic disease, but eventually resistance is developed in most cases and therefore, it is important to evaluate and track treatment efficacy for appropriate personalized medicine. New contrast-enhanced ultrasonography techniques such as Ultrasound Molecular Imaging (USMI), which allows for the quantification of biomarker expression, have been proposed as a safe, low-cost, bedside approach assessment of tumor response to therapy. For optimal performance in USMI, an ideal contrast agent could be detected with high sensitivity and would accumulate substantially at a target site. Ultrasound molecular imaging is currently performed with microbubble contrast agents, which have a short circulation half-life and thus do not accumulate ideally, and are only moderately echogenic. Our group has developed a novel low-boiling-point phase change contrast agent (PCCA), which has substantial advantages over currently used microbubble agents. Notably, it has long circulation time in-vivo and produces a stronger acoustic signature than microbubble agents that is unique from background. These properties suggest that this novel agent might present substantial advantages in molecular imaging. PCCAs have a liquid core that is not echogenic, but can be vaporized (activated) into highly echogenic microbubbles during imaging. The central hypothesis of this proposal is that novel PCCAs can be used for USMI in order to track renal cell carcinoma disease progression and evaluate response to antiangiogenic therapy. To test this hypothesis I will optimize ultrasound parameters for the activation and imaging of low-boiling- point PCCAs and develop a technique to detect and discriminate the acoustic signal produce by the activation of PCCAs. I will then I will test the sensitivity and specificity of USMI with low-boiling-point PCCAs for the detection of cancer. I will accomplish this aim by imaging mice with growing RCC tumors and using a blinded reader-study to calculate sensitivity and specificity of detection. Finally, I will use PCCA USMI to evaluate response to therapy using USMI with low-boiling-point PCCAs by imaging mice with RCC tumors that are being treated with the antiangiogenic drug Sutent. I will evaluate the ability of both methods to track response to therapy accurately, compared to the long term growth curve, which is the gold-standard. At the conclusion of this project, I will have developed a new USMI technique based on PCCAs, evaluated the sensitivity and specificity of this technique in detection of cancer, and assessed it ability to accurately track tumor response to therapy.
Studies have shown that around 40% of patients with advanced clear-cell Renal Cell Carcinoma (ccRCC) initially show positive response to antiangiogenic therapy, but around 95% of these patients eventually exhibit disease progression and succumb to their disease. For this reason, it is important to assess and monitor the response to treatment, in order to allow modifications therapy for maximum treatment efficacy and minimize exposure to nontherapeutic treatments.
