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：
9022450
负责人：
Ralph Eugene Hurd
金额：
$ 65.57万
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/9022450
关键词：
1-Phosphatidylinositol 3-Kinase Address Advanced Malignant Neoplasm Biological Biological Markers Biopsy Breast Cancer Patient Breast cancer metastasis 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 FRAP1 gene Future Goals Grant Health 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 Monitor Motivation 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 Sterility System Technology Testing Therapeutic Time Tissue imaging Tissues Translating Translations Uncertainty United States National Institutes of Health anti-cancer therapeutic base cancer therapy design detector experience hormone therapy imaging platform improved industry partner inhibitor/antagonist instrument instrumentation interdisciplinary approach mTOR Inhibitor mTOR inhibition malignant breast neoplasm meetings molecular imaging multidisciplinary next generation non-invasive imaging novel patient subsets pre-clinical preclinical study response targeted agent targeted treatment therapy resistant tumor tumor growth uptake

项目摘要

DESCRIPTION (provided by applicant): 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 o 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).

描述（由申请人提供）：对于用于评估药物靶点抑制的非侵入性实时成像平台以增强治疗决策过程和新型抗癌疗法的开发，临床需求显然尚未得到满足。许多新兴的抗靶向药物诱导细胞增殖停滞和肿瘤生长稳定，而不是肿瘤缩小。这使得传统成像的早期效益评估具有挑战性，并且目前可用的成像和基于组织的生物标志物不能提供靶点抑制的可靠证据。因此，药物开发商和临床医生面临着肿瘤生长是由于药理学无效的药物还是生物肿瘤耐药性所致的不确定性。能够通过非侵入性成像平台辨别这种差异将极大地影响我们接触患者和开发靶向抗癌疗法的方式。这对于晚期癌症患者尤其重要，他们不能因为接触可能无效的药物而损失无法挽回的时间。该产学研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。在这里，我们提出在第一项原理验证研究中，解决未满足的临床需求，即以无创方式准确评估激素治疗耐药性乳腺癌肝转移患者对 mTOR 通路药物靶标抑制的代谢反应。通过将 UCSF MRI 科学家、药剂师和药物研发人员聚集在一起的多学科方法，这一学术与工业合作伙伴关系将把超极化 13C MR 成像的临床前发现转化为放射成像工具，以准确评估患者体内 mTOR 抑制剂的药物靶标抑制作用。与工业界的合作将实现所需的具有无菌流体路径的临床偏振器的开发（GE Research Circle Technologies）、13C MRI 线圈的构建（USA Instruments）以及无菌 13C 标记试剂的生产（Isotec）；并最终将成像整合到新型靶向抗癌疗法的开发中（Celgene Corporation 等）。