Hyperpolarized carbon-13 MRI for early treatment response assessment in pancreatic ductal adenocarcinoma patients

Current methods for monitoring treatment response in pancreatic ductal adenocarcinoma (PDA), primarily relying tumor size measurement using response evaluation criteria in solid tumors (RECIST), are often delayed and limited by the infiltrative nature of the disease. Timely, non-invasive assessment is crucial for adapting therapies for non-responders. PDA tumor cells are characterized by significant metabolic reprogramming, driven by KRAS oncogene mutations, which enhance glycolysis and lactate production while downregulating alanine aminotransferase, which mediates pyruvate to alanine conversion. Hyperpolarized (HP) carbon-13 ( 13 C) magnetic resonance imaging (MRI) offers a non-invasive solution to interrogate these metabolic changes. Utilizing dynamic nuclear polarization, this technique provides unprecedented sensitivity(> 10,000-fold signal increase) and chemical specificity for rapid and pathway-specific investigation of dynamic metabolic processes that were previously inaccessible by 1 H MRI or CT. Pre-clinical studies have shown HP 13 C MRI using [1- 13 C]pyruvate as substrate can detect and monitor PDA precursor lesion progression, with an increase in the lactate-to-pyruvate ratio and decrease in the alanine-to-pyruvate ratio observed in the affected mice pancreas. Initial clinical studies have further demonstrated the feasibility and safety of HP 13 C MRI for quantifying metabolism in PDA patients. In this ongoing study, five PDA patients underwent multiparametric ¹H MRI and HP 13 C MRI both pre- and at 4&8 weeks post-treatment. 13 C pyruvate, lactate, alanine signal intensities and their respective ratios in the primary tumor and normal pancreas were assessed. All five patients exhibited elevated pre-treatment primary tumor lactate-to-pyruvate ratios. A significant decrease (approximately 25%) in the primary tumor lactate-to-pyruvate ratio post-treatment correlated with partial response by RECIST in four patients, while one patient with stable disease showed minimal change (<5%). Reduced alanine-to-pyruvate ratios were observed in pre-treatment tumors for two patients, though their relationship to treatment response could not be fully quantified. No significant changes in tumor ADC from diffusion-weighted ¹H MRI were observed pre- and post-treatment, suggesting that metabolic alterations detectable by HP 13 C MRI precede significant changes in cellularity at this early time point. These initial findings indicate that HP 13 C MRI can detect early metabolic changes in PDA tumors in response to therapy, holding significant potential for providing timely treatment response information, facilitating adaptive treatment strategies, and improving patient outcomes in PDA.