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

项目摘要/摘要 前列腺癌是美国的一个主要健康问题，每年有超过16万新病例和3万人死亡。更多 超过90%的晚期疾病患者有骨转移，中位生存期为一年。病人 伴有转移性骨病的患者会出现骨痛、骨折、高钙血症、细胞减少症，最终导致死亡。 这项早期阶段的“可行性”成像“生物标记物驱动”试验的目标是研究新的三维超极化。 (HP)~(13)C-丙酮酸MRI技术定量测定丙酮酸催化的乳酸脱氢酶- 前列腺癌骨转移患者早期快速代谢的乳酸转化率 对治疗反应和治疗耐药性发展的反应监测，以及对目标的评估 新的靶向药物开发的治疗效果，从而解决目前未得到满足的临床需求。这个诊所 之所以需要进行试验，是因为目前骨转移瘤的成像方式不足以量化疗效。 到治疗性干预。这可能导致在确定治疗有效性方面出现重大延误，以及 使患者长期承受无效治疗的副作用，常常导致过度治疗 没有好处的发病率。 超极化(HP)13C-丙酮酸MRI是一种安全、无放射性、定量的MR稳定同位素成像 这种方法可以为前列腺癌骨转移提供早期、实时的代谢反应监测。 除了常规的mpMRI检查外，快速2分钟的HP MRI测量丙酮酸到乳酸 转化率，KPL，一个潜在的有价值的生物标记物，反映了代谢重新编程和早期的变化 对靶向治疗(如AR、MYC抑制剂)的反应。而PSMA-PET提高了对转移瘤的检测 疾病，PSMA的表达不会直接受到包括雄激素途径抑制剂在内的靶向治疗的影响 和新的MYC靶向治疗在临床试验评估中，因此不能可靠地捕获骨 早期时间点的转移反应。Hp~(13)C-丙酮酸核磁共振研究表明MYC介导的 幽门螺杆菌13C丙酮酸到乳酸代谢转化率KPL升高与关键癌基因组相关 随着前列腺癌的进展而发生的改变，并随着治疗的反应而减少。 初步研究还表明，较高的KPL与对雄激素途径的内在抵抗有关 抑制剂(如苯扎鲁胺)。我们的多学科研究团队将这些发现转化为患者的可行性 前列腺癌患者的首次Hp~(13)C-丙酮酸代谢磁共振成像研究 转移证明了这一方法的可行性并支持其科学严谨性。这个新的生物标记物- 驱动试验旨在应用新的HP 13C-丙酮酸磁共振技术监测雄激素受体和MYC 靶向药物治疗，目的是研究KPL作为体内代谢的定量标记物 嗜骨性晚期前列腺癌患者治疗的变化。

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.