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.

项目摘要/摘要 前列腺癌是美国的主要健康问题，每年有16万例新病例和30,000例死亡。更多的 超过90％的晚期疾病患者的骨转移患者中位生存期为一年。患者 转移性骨骼疾病患有骨痛，骨折，高钙血症，细胞质减少和最终死亡。 这个早期“可行性”成像“生物标记驱动”试验的目标是研究新型的3D超极化 （HP）13C-丙酮酸MRI技术，以定量测量脱氢酶（LDH）催化丙酮酸 - 前列腺癌骨转移的乳酸（KPL）转化率，使早期和快速代谢 对治疗响应和热阻力的反应的响应监测以及靶向的评估 新靶向药物开发的治疗效果，从而满足当前未满足的临床需求。这个临床 需要试验，因为目前的骨转移的成像方式不足以量化响应 进行治疗干预措施。这可能会导致确定治疗效果的重大延迟，并 使患者长时间的无效疗法副作用，经常导致过多 发病率没有利益。 超极化（HP）13C-丙酮酸MRI是一种安全的，非放射性的，定量的MR稳定 - 同位素成像 可以提供早期实时代谢反应监测前列腺癌骨转移的方法。 在常规MPMRI检查中添加，丙酮酸到乳酸的快速2分钟HP MRI测量 转换率，KPL，一种潜在有价值的“生物标志物”，反映了代谢重编程和早期的变化 对靶向疗法的反应（例如AR，MYC抑制剂）。 PSMA-PET改善转移性的检测 疾病，PSMA表达不受靶向疗法（包括雄激素途径抑制剂）的直接影响 以及新型的MYC靶向疗法在临床试验评估中，因此无法可靠的捕获骨 转移在早期的响应。 HP 13C - 丙酮酸MR研究表明MYC介导 HP 13C丙酮酸到肽的代谢转化率KPL与关键致癌基因组有关 随着晚期前列腺癌的发展而发生的变化，并响应治疗而增加。 初步研究还表明，较高的KPL与雄激素途径的内在抗性有关 抑制剂（例如enzalutamide）。我们的多学科研究团队将这些发现转化为患者的可行性 研究并进行了有史以来首先的HP 13C-丙酮酸代谢MR成像的前列腺癌骨患者 转移表明可行性并支持这种方法的科学严谨性。这个新的生物标志物 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 靶向药物疗法的目的是研究KPL作为定量体内标记以测量代谢 骨 - 热带晚期前列腺癌患者的治疗变化。