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

项目总结/摘要 前列腺癌是美国主要的健康问题，每年有超过160，000例新发病例和30，000例死亡。更 超过90%的晚期疾病患者有骨转移，中位生存期为一年。患者 患有转移性骨疾病的患者遭受骨痛、骨折、高钙血症、血细胞减少，并最终死亡。 这项早期“可行性”成像“生物标记驱动”试验的目标是研究新型3D超极化 (HP)13 C-丙酮酸MRI技术定量测量乳酸脱氢酶（LDH）催化的丙酮酸- 前列腺癌骨转移中的乳酸（kPL）转化率，以实现早期和快速的代谢 监测治疗反应和治疗耐药性的发展，以及评估达标情况 新靶向药物开发的治疗效果，从而解决当前未满足的临床需求。本临床 需要进行试验，因为目前骨转移的成像方式不足以量化缓解 到治疗干预。这可能导致在确定治疗有效性方面的显著延迟，并且 使患者长期遭受无效治疗的副作用， 没有好处的疾病。 超极化（HP）13 C-丙酮酸盐MRI是一种安全、非放射性、定量MR稳定同位素成像 这种方法可以提供前列腺癌骨转移的早期、实时代谢反应监测。 在常规mpMRI检查的基础上，使用快速2分钟HP MRI测量乳酸盐/乳酸盐比值， 转化率，kPL，一个潜在的有价值的“生物标志物”，反映了代谢重编程和早期代谢的变化。 对靶向治疗（例如AR、MYC抑制剂）的反应。虽然PSMA-PET改善了转移性乳腺癌的检测， PSMA表达不直接受靶向治疗（包括雄激素途径抑制剂）的影响 和新的MYC靶向疗法，因此不能可靠地捕获骨 在早期时间点的转移反应。HP 13 C-丙酮酸盐MR研究表明，MYC介导的 HP 13 C代谢转化率（kPL）增加与关键癌基因组相关， 随着进展到晚期前列腺癌而发生的改变，并在治疗后减少。 初步研究还表明，较高的kPL与雄激素途径的内在抵抗有关 抑制剂（例如恩杂鲁胺）。我们的多学科研究团队将这些发现转化为患者的可行性 研究并首次对前列腺癌骨患者进行HP 13 C-丙酮酸代谢MR成像 转移证明了可行性并支持这种方法的科学严谨性。新的生物标记物- 一项旨在应用新的HP 13 C-丙酮酸MRI技术监测雄激素受体和MYC的驱动试验 靶向药物治疗，目的是研究kPL作为定量体内标记物， 嗜骨性晚期前列腺癌患者治疗后的变化。

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.