Novel Dual Agent HP C-13 MRI for Quantitative Imaging of Prostate Cancer Aggressiveness for Improved Biopsy Guidance - Project Summary/Abstract Over the past 20+ years, our group and others have worked to make multiparametric (mp) MRI a valuable tool for detecting prostate cancer (PC) and guiding diagnostic & treatment decisions. While mpMRI provides a whole gland assessment with a high patient-level sensitivity, it still misses clinically significant PC in up to 20% of patients with a negative mpMRI (12). Furthermore, the Prostate Imaging Reporting & Data System (PI-RADS), which is qualitative in nature, is associated with significant inter-reader variability and generally poor correlations with tumor grade. Radionuclide FDG or PSMA PET are not clinically reliable in the setting of localized PC. These limitations, together with the increased use of focal therapies for intermediate risk disease, highlight the need for improved and quantitative biomarkers of aggressive PC especially for guiding biopsies and treatment planning. This resubmission project is designed to translate new safe, non-radioactive hyperpolarized (HP) 13C dual-agent molecular MRI techniques with ~10x higher sensitivity to guide prostate biopsies in PC patients in order to address the unmet clinical need of reliably detecting aggressive prostate cancer for improved patient care. HP pyruvate-to-lactate conversion rates (kPL) have been shown to provide quantitative metabolic measures that correlate with prostate cancer aggressiveness (Figure 1). Also, HP 13C-urea MR, using a small molecular weight (0.08 of Gd contrast), metabolically-inert, safe, endogenous, positive-contrast stable-isotope probe, has been shown in preclinical animal studies (and in an initial human study) to provide unique tissue/tumor perfusion information that is altered with aggressive prostate cancers (Figures 1-3). HP 13C-urea detects decreased tumor urea distribution volume and perfusion that are hallmarks of high-grade disease (Figure 2-4), providing unique information synergistic with HP 13C-pyruvate MRI for detecting aggressive PC. HP [1-13C]pyruvate+urea MRI was able to detect clinically occult prostate cancer not seen on conventional multiparametric MRI (Figure 3). This novel project, improved in response to the prior critiques, is designed by highly experienced academic- industry PC MRI researchers to translate new dual agent HP acquisition & analysis methods and integrate this new biomarker-driven guided biopsy approach into a 1H & HP 13C mpMRI exam with: A) Specialized hardware and methods for novel, cost-effective high-concentration HP urea+pyruvate contrast-agent sterile doses and greatly-advanced HP 13C MR acquisition & analysis techniques (Aim 1), B) Pre-prostatectomy studies with correlations of the non-invasive biomarker of tumor tissue-perfusion & metabolism, kUR, with “gold standard” step-sectioned histopathology, immunohistochemical staining and genomic sequencing to correlate the imaging markers to histological and genomic signatures of aggressive cancers with associated highly proliferative, lethal phenotypes (Aim 2), and C) Specialized kinetic modeling and MRI-TRUS fusion biopsy-guidance methods (Aim 3) to provide a novel solution to a significant & persistant challenge in PC clinical research & management, constantly faced by our urologists & oncologists, namely, the accurate detection of aggressive tumors.
