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

使用超极化 13C 丙酮酸 MRI 测量前列腺癌骨转移的代谢活动，以改进靶向治疗监测

• 批准号: 10523532
• 负责人: Rahul Aggarwal
• 金额: $ 65.63万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10523532
• 关键词: 3-Dimensional; Address; Affect; Androgen Receptor; Androgens; Biological Markers; Biopsy; Bone Diseases; Bone Pain; Bromodomains and extra-terminal domain inhibitor; Cancer Model; Cancer Patient; Cessation of life; Clinical; Clinical Trials; Data; Detection; Development; Disease; Disseminated Malignant Neoplasm; Down-Regulation; Drug Targeting; Early treatment; Enrollment; Evaluable Disease; Evaluation; FOLH1 gene; Feasibility Studies; Fracture; Generations; Goals; Health; Hypercalcemia; Image; Interdisciplinary Study; Investigation; Lactate Dehydrogenase; Letters; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Measurement; Measures; Mediating; Medical; Metabolic; Metastatic Neoplasm to the Bone; Metastatic Prostate Cancer; Methods; Molecular; Monitor; Morbidity - disease rate; Neoplasm Metastasis; Noise; PIK3CG gene; Pathway interactions; Patient imaging; Patients; Pharmacotherapy; Phase; Positron-Emission Tomography; Prediction of Response to Therapy; Pyruvate; Renal carcinoma; Research; Resistance; Running; Serum; Serum Markers; Signal Transduction; Site; Techniques; Technology; Testing; Therapeutic Intervention; Time; Translating; Treatment Effectiveness; Tropical Disease; United States National Institutes of Health; Widespread Disease; advanced disease; advanced prostate cancer; antagonist; biomarker driven; bone; bone turnover; burden of illness; cancer genomics; castration resistant prostate cancer; cytopenia; design; detector; drug development; early phase trial; enzalutamide; feasibility trial; imaging approach; imaging biomarker; imaging modality; improved; in vivo; ineffective therapies; inhibitor; investigator-initiated trial; malignant breast neoplasm; metabolic imaging; molecular imaging; new therapeutic target; novel; novel strategies; novel therapeutics; patient population; pre-clinical; response; serum PSA; side effect; stable isotope; targeted treatment; therapy development; therapy resistant; tool development; treatment effect; treatment response

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.

项目概要/摘要 前列腺癌是美国的一个主要健康问题，每年有超过 160,000 例新发病例和 30,000 例死亡。 超过 90% 的晚期疾病患者出现骨转移，中位生存期为一年。 患有转移性骨病的人会遭受骨痛、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“生物标志物驱动”试验的目标是研究新型 3D 超极化 (HP) 13C-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，以实现早期和快速代谢 对治疗反应和治疗耐药性发展的反应监测，以及目标评估 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。 需要进行试验，因为当前骨转移的成像方式不足以量化反应 这可能会导致确定治疗效果的严重延迟，以及 使患者长期遭受无效治疗的副作用，常常导致过度治疗 发病而无益。 超极化 (HP) 13C-丙酮酸 MRI 是一种安全、非放射性、定量 MR 稳定同位素成像 该方法可以提供前列腺癌骨转移的早期、实时代谢反应监测。 除了传统的 mpMRI 检查之外，还可以快速 2 分钟 HP MRI 测量丙酮酸至乳酸 转化率、kPL（一种潜在有价值的“生物标志物”）、代谢重编程的变化以及早期 对靶向治疗（例如 AR、MYC 抑制剂）的反应，而 PSMA-PET 则改善了转移性的检测。 疾病中，PSMA 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 以及临床试验评估中的新型 MYC 靶向疗法，因此无法可靠地捕获骨 HP 13C-丙酮酸 MR 研究表明 MYC 介导的早期转移反应。 HP 13C 丙酮酸到乳酸的代谢转化率 (kPL) 增加与关键的肿瘤基因组相关 随着进展为晚期前列腺癌而发生的改变，并随着治疗的反应而减少。 初步研究还表明，较高的 kPL 与雄激素途径的内在抗性相关 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 13C-丙酮酸代谢 MR 成像 转移证明了这种方法的可行性并支持了这种新的生物标志物的科学严谨性。 驱动试验旨在应用新的 HP 13C-丙酮酸 MRI 技术来监测雄激素受体和 MYC 靶向药物治疗，目的是研究 kPL 作为测量代谢的定量体内标记物 骨向性晚期前列腺癌患者治疗的变化。