Measuring Metabolic Activity in Prostate Cancer Bone Metastases Using Hyperpolarized 13C Pyruvate MRI for Improved Targeted Therapy Monitoring

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Project Summary/Abstract Prostate cancer is a major US health concern with over 160,000 new cases and 30,000 deaths per year. More than 90% of patients with advanced disease have bone metastases with a median survival of a year. Patients with metastatic bone disease suffer from bone pain, fractures, hypercalcemia, cytopenias, and ultimately death. The goal of this early phase “feasibility” imaging “biomarker-driven” trial is to investigate novel 3D hyperpolarized (HP) 13C-pyruvate MRI techniques to quantitatively measure lactate dehydrogenase (LDH) catalyzed pyruvate- to-lactate (kPL) conversion rates in prostate cancer bone metastases to enable early and rapid metabolic response monitoring to treatment response and development of therapeutic resistance, as well assess on-target treatment effects for new targeted drug development, thus addressing current unmet clinical needs. This clinical trial is required because current imaging modalities for bone metastases are inadequate for quantifying response to therapeutic interventions. This can result in significant delays in determining treatment effectiveness, and subjecting patients to prolonged periods of side-effects of ineffective therapies, too often causing excess morbidity without benefit. Hyperpolarized (HP) 13C-pyruvate MRI is a safe, non-radioactive, quantitative MR stable-isotope imaging approach that can provide early, real-time metabolic response monitoring of prostate cancer bone metastases. Added to conventional mpMRI exams, the rapid 2 minute HP MRI measurement of pyruvate-to-lactate conversion rate, kPL, a potentially valuable “biomarker”, reflects changes in metabolic reprogramming and early response to targeted therapies (e.g. AR, MYC inhibitors). While PSMA-PET improves detection of metastatic disease, PSMA expression is not directly affected by targeted therapies including androgen pathway inhibitors and novel MYC-targeted therapies in clinical trial evaluation, and therefore is not able to reliably capture bone metastasis response at early time points. HP 13C-pyruvate MR studies have demonstrated that MYC-mediated increased HP 13C pyruvate-to-lactate metabolic conversion rate, kPL, is associated with key oncogenomic alterations that occur with the progression to advanced prostate cancer and decreased in response to treatment. Initial studies also demonstrated that higher kPL is associated with intrinsic resistance to androgen pathway inhibitors (e.g. enzalutamide). Our multidisciplinary research team translated these findings into patient feasibility studies and performed first-ever HP 13C-pyruvate metabolic MR imaging of patients with prostate cancer bone metastases demonstrating feasibility and supporting the scientific rigor of this approach. This new biomarker- driven trial is designed to apply new HP 13C-pyruvate MRI technology for monitoring androgen-receptor and MYC targeted drug therapies with the goal of investigating kPL as a quantitative in vivo marker to measure metabolic changes with treatment in patients with bone-tropic advanced prostate cancer.