Translating HP 13C MRI as a Novel Paradigm for Assessing Drug Target Inhibition

将 HP 13C MRI 转化为评估药物靶点抑制的新范例

基本信息

批准号：
8731649
负责人：
Ralph Eugene Hurd
金额：
$ 65万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-12 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8731649
关键词：
1-Phosphatidylinositol 3-Kinase Address Advanced Malignant Neoplasm Biological Biological Markers Biopsy Cancer Center Cancer Patient Cell Proliferation Clinical Clinical Management Clinical Research Clinical Trials Collaborations Decision Making Development Diagnostic Neoplasm Staging Disease Down-Regulation Drug Targeting Future Goals Grant Hormone Receptor Human Image Imaging Device Imaging Techniques Imaging technology Industry Label Learning Liquid substance Liver Magnetic Resonance Imaging Magnetic Resonance Spectroscopy Malignant Neoplasms Malignant neoplasm of prostate Measures Metabolic Metastatic Neoplasm to the Liver Methods Metric Monitor Motivation Neoplasm Metastasis Outcome Pathway interactions Patients Performance Pharmaceutical Preparations Pharmacists Physiologic pulse Process Production Pyruvate Research Research Personnel Research Project Grants Resistance Resolution SDZ RAD Safety Sampling Scientist Signal Transduction Skin Neoplasms Solutions Sterility System Technology Testing Therapeutic Time Tissues Translating Translations Uncertainty United States National Institutes of Health anti-cancer therapeutic base cancer therapy design detector experience hormone therapy human FRAP1 protein improved industry partner inhibitor/antagonist instrument instrumentation interdisciplinary approach mTOR Inhibitor mTOR inhibition mTOR protein malignant breast neoplasm meetings molecular imaging multidisciplinary next generation non-invasive imaging novel pre-clinical preclinical study public health relevance response therapy resistant tumor tumor growth uptake

项目摘要

Project Summary/Abstract There is a clear unmet clinical need for a non-invasive real time imaging platform to assess drug target inhibition in order to enhance the therapeutic decision-making process and development of novel anti-cancer therapies. Many of the emerging anti-targeted agents induce arrest of cellular proliferation and tumor growth stabilization rather than tumor shrinkage. This makes early assessment of benefit with conventional imaging challenging, and currently available imaging and tissue-based biomarkers do not provide reliable evidence of target inhibition. Hence, drug developers and clinicians are faced with uncertainty whether tumor growth is due to a pharmacologically ineffective drug or biological tumor resistance. To be able to discern this difference with a non-invasive imaging platform would greatly impact the way we approach patients and develop targeted anti-cancer therapeutics. This is particularly relevant to patients with advanced stage cancer who cannot afford to lose irretrievable time by being exposed to a potentially ineffective agent. The goal of this academic-industrial collaborative research project is to accomplish the clinical translation of the "next-generation imaging technology" hyperpolarized 13C MRI. Here we propose to address the unmet clinical need of accurately assessing metabolic response of drug target inhibition of the mTOR pathway non-invasively in hormone therapy resistant breast cancer patients with liver metastases in a first ever proof of principle study. In a multidisciplinary approach bringing together UCSF MRI scientists, pharmacists and drug developers, this academic-industrial partnership will translate preclinical findings in hyperpolarized 13C MR imaging into a radiologic imaging tool to accurately assess drug target inhibition by mTOR inhibitors in patients. The partnership with industry will enable the required development of a clinical polarizer with a sterile fluid path (GE Research Circle Technologies), the construction of 13C MRI coils (USA Instruments) and production of sterile 13C labeled agent (Isotec); and ultimately integrate imaging into the development of novel targeted anti- cancer therapeutics (Celgene Corporation and others).

项目概要/摘要对用于评估药物靶标的非侵入性实时成像平台的临床需求显然尚未得到满足抑制以增强治疗决策过程和新型抗癌药物的开发疗法。许多新兴的抗靶向药物可抑制细胞增殖和肿瘤生长稳定而不是肿瘤缩小。这使得对传统成像的益处进行早期评估具有挑战性，目前可用的成像和基于组织的生物标志物并不能提供可靠的证据目标抑制。因此，药物开发商和临床医生面临着肿瘤生长是否是由于其原因的不确定性。对药理学上无效的药物或生物肿瘤的抗性。能够通过非侵入性成像平台辨别这种差异将极大地影响方法我们接触患者并开发有针对性的抗癌疗法。这与患者尤其相关患有晚期癌症，无法承受因暴露于潜在的危险而损失不可挽回的时间无效的代理。该学术-工业合作研究项目的目标是完成 “下一代成像技术”超极化13C MRI的临床转化。在此我们建议解决准确评估药物靶标抑制代谢反应的未满足的临床需求 mTOR 通路对激素治疗耐药的乳腺癌肝转移患者进行非侵入性治疗有史以来第一个原理研究证明。采用多学科方法，将 UCSF MRI 科学家、药剂师和药物人员聚集在一起开发人员，这种学术-工业合作伙伴关系将转化超极化 13C MR 的临床前发现成像到放射成像工具中，以准确评估患者体内 mTOR 抑制剂的药物靶标抑制作用。与业界的合作将有助于开发具有无菌流体路径的临床偏振器（GE Research Circle Technologies），13C MRI 线圈的建造（USA Instruments）和生产无菌13C标记试剂(Isotec)；并最终将成像整合到新型靶向抗肿瘤药物的开发中癌症治疗（新基公司等）。