Novel PET Imaging to Guide Therapy in Hepatocellular Carcinoma

PROJECT SUMMARY/ABSTRACT: Novel PET Imaging to Guide Therapy in Hepatocellular Carcinoma Liver cancer is the third leading cause of cancer death worldwide, with hepatocellular carcinoma (HCC) constituting more than 75% of all liver cancers. Locoregional therapies (LRTs), such as transcatheter arterial radioembolization (TARE) with Yttrium-90 (Y90), play a critical role in the care of patients with HCC. For patients undergoing LRT, time is of the essence; the time required to determine how an HCC responds to LRT is a critical determinant in the overall care algorithm and outcome for these patients. Current methods to predict response to Y90 LRT rely on standard-of-care (SOC) anatomical imaging, such as magnetic resonance imaging (MRI) or computed tomography (CT), which remain ambiguous for months following treatment. During this critical waiting, physicians and patients face uncertainty with respect to disease status, with eligibility for future interventions frequently compromised by ambiguities associated with determining treatment outcomes. In this project, we propose to evaluate an innovative molecular imaging approach to predict response to Y90 LRT much earlier than SOC imaging. We have previously evaluated 18F-FSPG PET in liver cancer and found it to be highly suitable for lesion detection and evaluation of response to therapy. Cancer cell accumulation of 18F-FSPG is mediated by xCT (SLC7A11) transporter activity, which is highly correlated with resistance to radiation. Thus, we hypothesize that 18F-FSPG PET represents an ideal biomarker to predict the response of HCC to Y90 LRT at baseline or soon after therapy, to identify residual, Y90-resistant disease and early recurrence. Complementary to imaging, liquid biopsy involves the collection of blood or other body fluids for the detection of tumor-derived molecular specimens, including circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA). In this application, we propose to determine if ctDNA levels are actionable in the setting of patients with HCC undergoing Y90 LRT, triggering future 18F-FSPG PET/CT examinations in these patients. Our overall objective is to evaluate 18F-FSPG PET as a means to predict early response and recurrence following Y90 therapy and to determine whether PET imaging and ctDNA are correlated. Our overarching hypothesis is that 18F-FSPG PET will predict response to Y90 therapy and tumor recurrence sooner than standard-of-care (SOC) imaging and will be highly correlated with ctDNA liquid biopsy. We will test our hypothesis, in two Specific Aims. Aim 1. To evaluate the relationship between 18F-FSPG uptake in HCC lesions, ctDNA in blood, and clinical response to Y90 radioembolization therapy by SOC imaging. Aim 2. To evaluate voxel-wise correlations between post-treatment 18F-FSPG intra-tumoral accumulation and SOC imaging in patients with HCC who have undergone TARE. Clinical Impact: This study holds the potential to improve HCC disease management by providing novel imaging and liquid biopsy approaches that predict response to Y90 LRT much earlier than conventional means.