Project Summary The Translational Imaging Core (TIC) is a technologically advanced state-of-the-art radiology Core characterized by the breadth of its scope and versatility. Its adaptability to the needs of the SPORE is illustrated by the prior and current SPORE proposals. In Years 1 – 5, the TIC developed and deployed novel tools to support investigators centering on magnetic resonance imaging (MRI). We advanced novel applications of multiparametric MRI in kidney cancer to evaluate a broad range of areas central to the projects including tumor aggressiveness, angiogenesis, and heterogeneity. For the renewal, the TIC will support SPORE investigators through the development of innovative radiotracers to query oncogenic drivers and tumor/microenvironment interactions using positron emission tomography (PET). For Project 1, we have developed a novel radiotracer, [18F]PT2385, to visualize what is arguably the most important driver of clear cell renal cell carcinoma (ccRCC), the HIF2α protein. Of note, we showed that PT2385, a first-in-class HIF2α inhibitor, exclusively binds HIF2α. This offers a unique opportunity to turn this drug into a radiotracer that, for the first time, enables visualization of HIF2α in patients. In July 2021, we obtained an investigational new drug (IND) approval from the Food and Drug Administration (FDA; IND 156933). In Project 2, the TIC will support the In Vivo Metabolism Lab with pre-clinical MRI imaging of patient-derived tumorgrafts and enable new research directions through the generation of PET imaging methods to query tumor metabolism using nutrient-derived radiotracers. For instance, PET imaging with L-[5-11C]glutamine provides a noninvasive method for real-time monitoring of glutamine metabolism and assessment of the impact of drug inhibitors. For Project 3, the TIC has generated a PET radiotracer to enable a deeper understanding of the interplay between the tumor and its microenvironment, particularly the interaction between tumor cells and the immune system. The TIC turned the therapeutic anti-PD-L1 antibody, atezolizumab, into a specific imaging biomarker for PD-L1. After evaluation in our tumorgraft platform, we conducted dosimetry studies and obtained an IND in 2019. Since then, we have successfully initiated the first immunoPET (iPET) trial in the U.S. of 89Zr-labeled atezolizumab in patients with locally advanced and metastatic kidney cancer (NCT04006522). The TIC goals are: Aim 1: To develop and evaluate a novel radiotracer, [18F]PT2385, to monitor expression of the most important driver of ccRCC, HIF2α (Project 1). Aim 2: To enable real-time evaluation of novel immunotherapy combinations through iPET (Project 3). Aim 3: To expand metabolic experiments with novel metabolic radiotracers and support the In Vivo Metabolism Lab with preclinical imaging (Project 2). Aim 4: To empower SPORE investigators with novel image-based services. We will offer image-based targeted tissue procurement, expert image analysis,...