PROJECT SUMMARY/ABSTRACT The ability to non-invasively predict or monitor early patient response to cancer therapy will have significant implications for patient care with the potential to spare non-responding patients the high morbidity and cost associated with failed treatments. Due to its wide accessibility, lack of radiation, relatively low cost, and excellent visualization of the liver, ultrasound is a demonstrated and potentially ideal modality to repeatedly image and monitor patient responses over the course of therapy. In the first phase of this work, we demonstrated that current 2D dynamic contrast-enhanced ultrasound (DCE-US) is fundamentally limited in quantification due to tumor heterogeneities, resulting in consecutive sampling errors with substantial over- or underestimation of treatment response in patients. We then showed that these limitations could be overcome by a novel 3D DCE-US imaging approach using innovative matrix array transducer technology to provide motion-compensated, accurate quantitative and volumetric assessment of tissue perfusion of liver metastases. In this competitive renewal proposal, framed as an industry-academic partnership with Philips who is committed to our proposal, our aim to clinically advance 3D multi-parametric tissue and perfusion characterization with ultrasound (3D MPUS) to predict or monitor early response in patients with metastatic colorectal cancers to the liver (mCRC). For this, we have proposed a set of specific aims where we will: i) work with Philips to enhance 3D DCE-US data acquisition to overcome previously reported limitations, enable simultaneous acquisition of raw RF/Bmode data for tissue characterization, and develop an analysis software suite for MPUS quantification, ii) carry-out a multi-site clinical feasibility, acquisition repeatability and quantification reproducibility assessment of 3D MPUS in 300 patients, and iii) determine whether 3D MPUS quantification can predict or monitor early therapy response. For this, baseline and early changes of tumor perfusion and tissue parameters (obtained before and at 2-3 weeks after initiation of therapy) will be correlated to treatment response. Treatment response as defined on abdominal radiological scans acquired at 2 months following treatment initiation will be determined using standard RECIST 1.1 reporting. Our proposal builds on the recent FDA approval of ultrasound contrast agents for liver tumor imaging, increased clinical availability of commercial 3D US abdominal probes, and our initial clinical validation of 3D DCE-US and extensive experiences in QUS.