The goal of treating an individual patient based on their personal response to therapy is tantalizingly close. Therapy that is not efficacious may result in unnecessary morbidity and a high cost without benefit. Of importance to this project, the widespread clinical introduction of anti-angiogenic therapies is stimulating the search for surrogate imaging biomarkers for monitoring treatment response. One promising approach takes advantage of the ability of ultrasound (US) contrast agents to be targeted to specific biomarkers located inside the tumor vascularity. These contrast agents can be engineered to selectively bind to overly abundant biomarkers associated with the angiogenic process to permit in vivo US imaging of tumor angiogenesis at the cellular and molecular level. Molecular US imaging is an emerging technology that exhibits all the advantages of US including broad clinical availability, lack of ionizing radiation, portability, and relatively low costs. Traditionlly, the molecular imaging signal is determined using a contrast agent destruction/replenishment technique and image processing to differentiate attached from freely circulating contrast agents. While our group has shown that this approach is robust, the US pressure necessary for contrast agent destruction is not standardized for different agent types and high-powered destructive pulses for diagnostic purposes may cause unwarranted biological effects that are still not fully characterized. Therefore, new image processing algorithms that can isolate the targeted contrast agent signal without use of destruction techniques are needed. While US imaging has traditionally been a 2-dimensional spatial imaging modality, 3-dimensional contrast-enhanced US imaging strategies for monitoring whole tumor response to drug therapy have recently been pioneered by our group. In order to fully appreciate molecular US imaging for cancer applications, whole tumor angiogenesis imaging and treatment monitoring through real-time volumetric strategies need to be developed and validated. To that end, the proposed research project will address these limitations and is defined by the following specific aims (1) Develop image processing algorithms and software for isolating targeted US contrast agents that have bound to tumor vascularity biomarkers in US images from the unbound (systemically free flowing) contrast agents. Test new US image processing methods using an in vitro flow phantom. (2) Assess volumetric molecular US imaging of a tumor-targeted contrast agent using an established animal of renal cancer. Radiolabel US contrast agents to determine biomarker bound contrast agent levels via in vivo biodistribution assays and correlate to molecular US imaging results. (3) Evaluate volumetric molecular US imaging of renal cell carcinoma response to the anti-angiogenic drug sorafenib. Determine if baseline US measurements of tumor biomarker density correlate to tumor response to anti-angiogenic therapy. Successful completion of this research project will introduce a whole tumor molecular US imaging technique for monitoring anti-angiogenic therapy during the critical early phase after drug dosing.
This project is a tailored combination of professional development activities and a detailed research study that will evaluate the use of whole tumor molecular ultrasound imaging for monitoring early renal cancer response or resistance to anti-angiogenic therapy.
|Mahoney, Marshall; Sorace, Anna; Warram, Jason et al. (2014) Volumetric contrast-enhanced ultrasound imaging of renal perfusion. J Ultrasound Med 33:1427-37|