Early Detection, Accurate Staging, and Biologic Characterization of HCC with Hybrid 68Ga-PSMA-Dual-Contrast PET/MRI Using Cyclotron-Produced 68Ga

We address the Fiscal Year 2019 (FY19) Peer Reviewed Cancer Research Program (PRCRP) topic: Liver Cancer. Specifically, our proposal addresses the gaps in the early detection/diagnosis and treatment of liver cancer that may impact mission readiness and the health and wellbeing of military members, Veterans, their beneficiaries, and the general public. Unmet needs: Hepatocellular carcinoma (HCC) is the most common type of liver cancer. It is the second most common cause of death due to cancer worldwide. It more frequently affects Service members compared to the civilian population. In US Veterans, the number of HCC cases and deaths have increased dramatically—nearly a three-fold increase between 2001 and 2013. Long-standing liver disease resulting in liver fibrosis or cirrhosis is the biggest HCC risk factor. The VA medical system serves approximately 2.6 million patients with long-standing liver disease. Causes of long-standing liver disease include viral hepatitis, alcoholic liver disease, and nonalcoholic fatty liver disease. The number of Service members affected by these diseases has leapt over the years. For instance, the number of Service members with nonalcoholic fatty liver disease has increased 12-fold between 2000 and 2017. Early detection and accurate mapping of disease burden are crucial because success in HCC treatment depends upon the stage at which it is detected. Current options for imaging of HCC have significant shortcomings. It is imperative to overcome these shortcomings so that we can improve screening for HCC of the population that is at-risk for HCC, timely detection of small HCCs, assessment of response of HCC to treatments, and for the development of safer and more precise treatments for HCC. Proposed Research: Our proposal, to develop a novel imaging technique for HCC targets a protein called Prostate Specific Membrane Antigen (PSMA), which has been detected in HCC very recently. Advantages of this novel technique are that it is (1) noninvasive, (2) uses a novel imaging agent called Gallium-68 (68Ga)-PSMA, (3) combines imaging information obtained simultaneously from two different imaging techniques, namely positron enhanced tomography (PET) and magnetic resonance imaging (MRI), and (4) can potentially detect HCC both in the liver and in other parts of the body (i.e., metastases) in one combined exam. The unique imaging agent for the proposed study, 68Ga-PSMA, will be produced in-house with the use of a Food and Drug Administration-approved innovative technology that is also more cost-effective compared to purchasing this agent commercially. We expect that this unique hybrid imaging technique will be superior to current imaging options for early detection of HCC. Over a 2-year period, we will enroll approximately 60 patients with HCC who are expected to undergo either surgical removal of their tumor or a liver transplant. Using tissue from surgical specimens as the benchmark, we will evaluate the performance of this novel imaging technique, 68Ga-PSMA PET/MRI, for HCC, and compare its performance to current imaging techniques. In addition, we will also evaluate the performance of this technique in detecting the spread of HCC outside the liver. Finally, we will correlate data obtained from this technique with features of HCC as seen in pathology specimens, which will generate new knowledge that is needed for designing future research studies in patients with HCC or who are at risk of developing HCC. Impact of Proposed Research: Our innovative technique may impact HCC diagnosis and treatment. Through early and timely HCC detection, our proposal seeks to directly benefit millions of Service members, Veterans, and their family members at risk of HCC due to long-standing liver disease. Secondly, our proposed technique can impact the care of patients with HCC who are candidates for liver transplant. In such patients, it is critical to know about any disease outside the liver, which can lead to H