Characterization of PDX SCNC prostate cancer metastatic murine models and development of associated research resources

PDX SCNC 前列腺癌转移小鼠模型的表征和相关研究资源的开发

• 批准号: 10533469
• 负责人: John Kurhanewicz
• 金额: $ 7.59万
• 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: 2020-09-07 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10533469
• 关键词: 2,4-Dinitrophenol; Address; Androgen Receptor; Androgens; Basic Science; Biological Markers; Biology; Biopsy; Blood Tests; Bone Diseases; Cancer Detection; Carboplatin; Clinical; Clinical Investigator; Clinical Management; Clinical Protocols; Clinical Research; Clinical Trials; Communities; Consensus; Data; Data Analyses; Disease; Echo-Planar Imaging; Elements; Event; Funding; Generations; Genetic; Goals; Grant; Heterogeneity; Image; Imaging Device; Imaging Techniques; Information Resources; Institutes; Liver; Liver diseases; Magnetic Resonance; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of prostate; Measurement; Metabolic; Metastatic Neoplasm to the Bone; Metastatic Neoplasm to the Liver; Metastatic Prostate Cancer; Methods; Modeling; Molecular; Mus; Neoplasm Metastasis; Neuroendocrine Cell; Neuroendocrine Prostate Cancer; Neurosecretory Systems; Noise; Oncology; Outcome; Pathologic; Pathway interactions; Patients; Physiologic pulse; Platinum; Positron-Emission Tomography; Postdoctoral Fellow; Prediction of Response to Therapy; Process; Protocols documentation; Pyruvate; Receptor Signaling; Reproducibility; Research; Research Design; Research Project Grants; Resistance; Resources; Serum; Signal Transduction; Site; Small Cell Carcinoma; Somatostatin Receptor; Technology; Testing; Therapeutic Clinical Trial; Time; Treatment Efficacy; United States National Institutes of Health; Validation; advanced prostate cancer; analytical tool; androgen deprivation therapy; anticancer research; base; bone; cancer clinical trial; castration resistant prostate cancer; chemotherapy; clinical imaging; co-clinical trial; conventional therapy; data acquisition; data analysis pipeline; data modeling; data repository; data standards; fluorodeoxyglucose; imaging approach; imaging informatics; imaging modality; imaging study; improved; improved outcome; in vivo; informatics infrastructure; inhibitor; men; metabolic imaging; metabolic profile; model development; mouse model; new therapeutic target; next generation; novel; online repository; online resource; patient derived xenograft model; patient response; pre-clinical; preclinical development; predictive marker; programs; prostate cancer metastasis; quantitative imaging; radio frequency; real time monitoring; response; response biomarker; stable isotope; standard of care; temporal measurement; therapy resistant; tool; transcriptomics; transdifferentiation; translational barrier; treatment response; tumor; tumor xenograft; web portal

PROJECT SUMMARY / ABSTRACT The goal of this Oncology Co-Clinical Imaging Research Program (CIRP) proposal is to overcome the translational barrier, as stated in PAR-18-184, to develop co-clinical imaging research resources that will encourage a consensus on how quantitative imaging methods are optimized to improve the quality of imaging results for co-clinical trials. This will be accomplished by using novel quantitative metabolic preclinical hyperpolarized (HP) 13C magnetic resonance imaging (MRI) to assess therapeutic response of small cell neuroendocrine (SCNC) prostate cancer (PCa). The murine imaging study will be conducted in parallel to a clinical trial (NCI R01 CA215694), aiming to assess response of SCNC to carboplatin in men with metastatic PCa, led by Drs. John Kurhanewicz and Rahul Aggarwal at UCSF. SCNC is an increasingly prevalent, lethal subtype of PCa that arises as an adaptive response to the application of androgen deprivation therapy and second-generation potent androgen pathway inhibitors. The selection of the most appropriate treatment of patients with metastatic SCNC is hindered by the fact that neither blood tests or current imaging modalities can reliably identify therapeutic efficacy in these metastatic tumors which are also often not amenable to biopsy. The study design of this U24 project incorporates the four key elements of CIRP: 1) The preclinical development and optimization of quantitative HP 13C MRI acquisition and data analysis methods that address the lack in rigor and reproducibility of existing preclinical and clinical approaches (aim 1); 2) The use of appropriate patient-derived xenograft (PDX) models that reflect the genetic, metabolic and micro-environmental heterogeneity of SCNC metastases in patients; 3) The application of the optimized preclinical dynamic HP 13C MRI protocols and data modeling approaches to study the response of metastatic bone and liver disease in the PDX models to chemotherapy, paralleling the funded study in patients (aim 2); and 4) The establishment of an online resource of quantitative HP 13C MRI imaging protocols, data analyses, modeling tools, correlative biology data for wider dissemination, validation and establishment of consensus by the scientific community (aim 3). To accomplish this important translational quantitative imaging project, we have assembled an exceptional team of basic science and clinical investigators with complimentary expertise in preclinical and clinical cancer research, realistic PDX models, HP 13C MRI, informatics, and in leading imaging and therapeutic clinical trials. This research project will also capitalize on the extensive resources provided by the NIH funded P41 Hyperpolarized Magnetic Resonance Technology Resource Center, the large number of preclinical and clinical DNP polarizers and 13C-enabled MRI scanners, and imaging informatics infrastructure which exist at UCSF. Although this proposal will focus on current standard of care treatment, the new 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 SCNC as well as for the study of other diseases.

项目总结/摘要 本肿瘤学联合临床成像研究计划（CIRP）提案的目标是克服 翻译障碍，如PAR-18-184中所述，开发共同临床成像研究资源， 鼓励就如何优化定量成像方法以提高成像质量达成共识 共同临床试验的结果。这将通过使用新的定量代谢临床前 超极化（HP）13 C磁共振成像（MRI）评估小细胞治疗反应 神经内分泌（SCNC）前列腺癌（PCa）。鼠成像研究将与一项研究平行进行。 一项临床试验（NCI R 01 CA 215694），旨在评估SCNC在转移性乳腺癌男性中对卡铂的反应。 PCa，由加州大学旧金山分校的John Kurhanewicz和Rahul Aggarwal博士领导。SCNC是一种日益流行的致命的 作为对雄激素剥夺治疗的应用的适应性反应而产生的PCa亚型， 第二代强效雄激素途径抑制剂选择最合适的治疗方法 转移性SCNC患者的血液检查或当前的成像方式都不能 可靠地确定这些转移性肿瘤的治疗效果，这些转移性肿瘤通常也不适合活检。的 本U24项目的研究设计纳入了CIRP的四个关键要素：1）临床前开发和 优化定量HP 13 C MRI采集和数据分析方法，解决缺乏严谨性和 现有临床前和临床方法的再现性（目的1）; 2）使用适当的患者来源的 反映SCNC遗传、代谢和微环境异质性的异种移植（PDX）模型 3）优化的临床前动态HP 13 C MRI方案和数据的应用 在PDX模型中研究转移性骨和肝脏疾病对 化疗，与患者的资助研究平行（目的2）;和4）建立在线资源 定量HP 13 C MRI成像协议，数据分析，建模工具，相关生物学数据， 科学界的传播、验证和建立共识（目标3）。 为了完成这一重要的翻译定量成像项目，我们组建了一支出色的团队， 基础科学和临床研究人员，在临床前和临床癌症方面具有丰富的专业知识 我们的产品广泛应用于临床研究、逼真的PDX模型、HP 13 C MRI、信息学以及领先的成像和治疗临床试验。 该研究项目还将利用NIH资助的P41提供的广泛资源。 超极化磁共振技术资源中心，大量的临床前和临床 DNP偏振器和13 C使能的MRI扫描仪，以及存在于UCSF的成像信息学基础设施。 尽管该提案将集中于当前的护理治疗标准，但新的定量HP 13 C代谢 本提案中开发的MRI方法将对各种新的靶向治疗具有普遍适用性。 治疗方法正在开发的SCNC以及其他疾病的研究。