Targeting Neuroendocrine Prostate Cancer Using Multi-Probe Hyperpolarized 13C MRI for Improved Treatment and Therapeutic Monitoring

使用多探头超极化 13C MRI 靶向神经内分泌前列腺癌以改善治疗和治疗监测

• 批准号: 10163810
• 负责人: Rahul Aggarwal
• 金额: $ 65.59万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10163810
• 关键词: Acetates; Adenocarcinoma; Aftercare; Alanine; Androgens; Basic Science; Biological; Biological Markers; Biology; Biopsy; Blood Tests; Cancer Patient; Clinical; Clinical Data; Clinical Investigator; Clinical Management; Clinical Trials; Detection; Development; Disease; Dreams; Drug Delivery Systems; Drug Monitoring; Drug Targeting; Generations; Genetic Transcription; Genomics; Glutamates; Glutaminase; Glutamine; Glycolysis; Goals; Histologic; Histology; Image; Imaging Techniques; Investigation; Label; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of prostate; Measurement; Measures; Mediating; Metabolic; Metabolic Pathway; Metabolism; Metastatic Neoplasm to Lymph Nodes; Metastatic Neoplasm to the Liver; Modality; Molecular; Monitor; Neoplasm Metastasis; Neuroendocrine Prostate Cancer; Neurosecretory Systems; Nodal; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phase I Clinical Trials; Platinum; Prediction of Response to Therapy; Primary Neoplasm; Process; Protocols documentation; Pyruvate; Research; Research Personnel; Resistance; Serum; Signal Transduction; Therapeutic; Therapeutic Clinical Trial; Time; Treatment Protocols; Up-Regulation; X-Ray Computed Tomography; abiraterone; advanced prostate cancer; aerobic glycolysis; androgen deprivation therapy; anticancer research; base; cancer genomics; castration resistant prostate cancer; chemotherapy; clinical development; clinical imaging; clinical translation; cohort; design; disorder subtype; fluorodeoxyglucose positron emission tomography; genomic signature; image guided; image-guided drug delivery; imaging approach; imaging modality; improved; improved outcome; individual patient; inhibitor/antagonist; lipid metabolism; mRNA Expression; men; metabolic imaging; metabolic profile; metabolomics; neuroendocrine differentiation; new therapeutic target; non-invasive imaging; novel; novel strategies; personalized care; pre-clinical; quantitative imaging; real time monitoring; response; response biomarker; small molecule; standard of care; success; time use; transgenic adenocarcinoma of mouse prostate; treatment response; tumor; tumor heterogeneity

PROJECT SUMMARY / ABSTRACT The goal of this image-guided drug delivery (IGDD) proposal is to overcome the translational barrier, as stated in PAR-16-044, to create a new quantitative imaging approach providing improved characterization of the cancer target for better drug selection and delivery, as well as improving real-time monitoring of whether the drug target was effectively treated. This will be accomplished by using a novel dual-probe (13C pyruvate and 13C glutamine) hyperpolarized (HP) 13C metabolic imaging technique to discriminate biologically divergent treatment-emergent neuroendocrine prostate cancer (NEPC) from advanced adenocarcinoma based on the metabolic profile of NEPC tumors and to use real-time changes in metabolism to monitor the drug's delivery and efficacy. NEPC is an increasingly prevalent, lethal subtype of prostate cancer that arises as an adaptive response to the application of androgen deprivation therapy and second-generation potent androgen pathway inhibitors. Neither blood tests (such as PSA or serum neuroendocrine markers) nor standard imaging metrics (like FDG PET) reliably distinguish NEPC from adenocarcinoma, nor quantify the degree of neuroendocrine differentiation. The scientific premise for this proposal is based on: (i) the success of our phase 1 clinical trial of HP 13C-pyruvate MRI in prostate cancer patients (7), (ii) the proliferation of commercially available clinical polarizers, (iii) the technical capability to image metastatic tumors, and (iv) the strong pre-clinical data demonstrating the value of HP 13C metabolic MRI in quantifying the MYC-mediated metabolic deregulation associated with neuroendocrine differentiation and in measuring its response to therapy. The clinical translation of this paradigm-shifting IGDD approach to improve the treatment of men with advanced prostate cancer is timely and meets a new important unmet clinical need. To accomplish this important project, we have assembled an exceptional team of basic science and clinical investigators with complimentary expertise in pre-clinical and clinical cancer research, HP 13C MRI, and in leading imaging and therapeutic clinical trials to: define the molecular and metabolic signature of NEPC tumors and develop new HP 13C labeled probes to identify neuroendocrine differentiation and treatment response (Aim 1); define the molecular and metabolic signature of metastatic NEPC tumors in patients and correlate with HP 13C pyruvate-to-lactate flux (kPL) measurements (Aim 2); perform first-ever serial combined HP 13C-pyruvate and HP 13C-glutamine MRI to investigate clinical value for distinguishing NEPC from adenocarcinoma and monitoring response to treatment (Aim 3). New research on the biology of NEPC has inspired novel investigational approaches to treating this disease, and although this proposal will focus on current standard of care treatment, the novel quantitative HP 13C metabolic MRI approaches developed in this proposal will have general applicability for a variety of new targeted therapeutic approaches being developed for NEPC including inhibitors of MYC transcriptional activity and glutamine metabolism.

项目概要/摘要 如前所述，该图像引导药物输送（IGDD）提案的目标是克服平移障碍 在 PAR-16-044 中，创建一种新的定量成像方法，提供改进的表征 癌症靶标，以便更好地选择和输送药物，并改善实时监测 药物靶点得到有效治疗。这将通过使用新型双探针（13C丙酮酸和 13C 谷氨酰胺）超极化 (HP) 13C 代谢成像技术可区分生物差异 基于晚期腺癌的治疗中出现的神经内分泌前列腺癌（NEPC） NEPC 肿瘤的代谢概况，并利用代谢的实时变化来监测药物的输送 和功效。 NEPC 是一种日益流行的致命性前列腺癌亚型，作为一种适应性的前列腺癌而出现。 对雄激素剥夺疗法和第二代强效雄激素途径应用的反应 抑制剂。既没有血液检查（例如 PSA 或血清神经内分泌标记物）也没有标准成像指标 （如 FDG PET）可靠区分 NEPC 和腺癌，也不能量化神经内分泌的程度 差异化。该提案的科学前提基于：(i) 我们的 1 期临床试验取得成功 HP 13C-丙酮酸 MRI 在前列腺癌患者中的应用 (7), (ii) 市售临床增殖 偏光镜，(iii) 转移性肿瘤成像的技术能力，以及 (iv) 强大的临床前数据 证明 HP 13C 代谢 MRI 在量化 MYC 介导的代谢失调方面的价值 与神经内分泌分化相关并测量其对治疗的反应。临床上 将这种范式转变的 IGDD 方法转化为改善晚期前列腺男性的治疗 癌症是及时的，满足了新的重要的未满足的临床需求。 为了完成这个重要的项目，我们组建了一支由基础科学和临床组成的杰出团队 研究人员在临床前和临床癌症研究、HP 13C MRI 和 领先的影像和治疗临床试验：定义 NEPC 的分子和代谢特征 肿瘤并开发新的 HP 13C 标记探针来识别神经内分泌分化和治疗 响应（目标 1）；定义患者转移性 NEPC 肿瘤的分子和代谢特征， 与 HP 13C 丙酮酸至乳酸通量 (kPL) 测量相关（目标 2）；执行有史以来第一次连续组合 HP 13C-丙酮酸和 HP 13C-谷氨酰胺 MRI 研究区分 NEPC 和 NEPC 的临床价值 腺癌和监测治疗反应（目标 3）。 NEPC 生物学的新研究 激发了治疗这种疾病的新研究方法，尽管该提案将重点关注 目前的护理治疗标准，本研究开发的新型定量 HP 13C 代谢 MRI 方法 该提案将普遍适用于正在开发的各种新的靶向治疗方法 对于 NEPC，包括 MYC 转录活性和谷氨酰胺代谢的抑制剂。