Noninvasive measurement of oncogenic signaling pathways with 89Zr-transferrin

使用 89Zr-转铁蛋白无创测量致癌信号通路

基本信息

批准号：
8786620
负责人：
Michael John Evans
金额：
$ 24.13万
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：
2014-01-01 至 2016-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8786620
关键词：
Androgen Receptor Apoptosis Award Biological Markers Biology Cell Line Cell Surface Proteins Cell Survival Clinical Clinical Management Clinical Oncology Collaborations Communities Continuing Education Data Development Diagnostic Disease Environment Epigenetic Process Faculty Fostering Gene Expression Genetic Genetically Engineered Mouse Glioblastoma Goals Human Image Imaging technology In Vitro Institution Interdisciplinary Study Kinetics Knowledge Label Laboratory Research Lead Learning Lesion Malignant Neoplasms Malignant neoplasm of prostate Measurement Measures Memorial Sloan-Kettering Cancer Center Mentors Modeling Molecular Target Monitor Mutation Oncogenic Output PC3 cell line PTEN gene Pathogenesis Pathology Pathway interactions Pharmaceutical Preparations Pharmacology Positioning Attribute Positron-Emission Tomography Pre-Clinical Model Prostate Proteins Radiochemistry Radiopharmaceuticals Recycling Research Research Infrastructure Research Proposals Resources Role Scientist Signal Pathway Signal Transduction Technology Therapeutic Therapeutic Intervention Training Training Programs Transferrin Transferrin Receptor Translations Tumor Biology Ursidae Family Validation Zirconium abstracting cancer diagnosis cancer imaging cancer therapy career career development experience human FRAP1 protein improved in vivo in vivo imaging inhibitor/antagonist insight interest kinase inhibitor leukemia mTOR Inhibitor man molecular imaging mouse model novel oncology pre-clinical programs prostate cancer model radiotracer receptor expression response skills small molecule theories treatment response tumor uptake zirconium oxide

项目摘要

Project Summary/Abstract This proposal describes a training program to advance my academic career in biomarker development for oncology. The purpose of this award is to encourage my independent research program, and this period will be used to expand my scientific knowledge and mentoring skills. During the K99 award period, I will be mentored by Dr. Charles Sawyers and co-mentored by Dr. Jason Lewis. Dr. Sawyers is an internationally recognized expert in clinical oncology, in particular, the development and assessment of targeted molecular therapeutics for hematological and prostate cancers, and has a longstanding interest in technologies that define drug pharmacology in vivo. Dr. Lewis is an Inorganic Chemist and Radiochemist with substantial experience in the preclinical validation and clinical translation of novel radiopharmaceuticals for imaging and therapy. Drs. Sawyers and Lewis have mentored many scientists and clinical fellows, several of whom have transitioned to successful academic careers. Memorial Sloan Kettering Cancer Center (MSKCC) will provide institutional support to me, including the resources to conduct laboratory research, opportunities to foster career development and continuing education, and an open scientific environment to foster the interaction required for me to achieve my goals. The overall goal of this research proposal is for me to learn the theory and practice of Radiochemistry in the context of developing new applications for zirconium-89 labeled transferrin (89Zr-Tf), a novel radiotracer for PET I co-invented at MSKCC. The proposal extends directly from my previous experience, as 89Zr-Tf is one of three novel radiotracers for Positron Emission Tomography (PET) that I developed through collaborations to measure androgen receptor (AR) or MYC signaling in prostate cancer. This research has established that genetic or pharmacologically driven changes in oncogenic signaling pathways can be non-invasively measured with PET imaging, further underscoring a role for molecular imaging in oncology. The specific aim of this proposal during the 2-year K99 award period is to use 89Zr-Tf to study the role of MYC in tumor response to targeted therapies (Specific Aim 1). The specific aims for the 3-year R00 award period extend from this aim, and are (1) to demonstrate that 89Zr-Tf can measure pharmacologically triggered changes in PI3K pathway signaling in prostate cancer models (Specific Aim 2, and (2) to determine whether 89Zr-Tf uptake is reflective of aberrant PI3K pathway signaling in preclinical models of glioblastoma multiforme (Specific Aim 3), two pathologies for which novel imaging biomarkers are urgently needed.

项目概要/摘要该提案描述了一项培训计划，以促进我在生物标志物开发方面的学术生涯肿瘤学。这个奖项的目的是鼓励我的独立研究计划，这段时间将用于扩展我的科学知识和指导技能。在K99奖励期间，我将由 Charles Sawyers 博士指导，并由 Jason Lewis 博士共同指导。索耶斯博士是一位国际临床肿瘤学领域公认的专家，特别是靶向分子药物的开发和评估血液癌和前列腺癌的治疗方法，并且对以下技术有着长期的兴趣定义体内药物药理学。 Lewis 博士是一位无机化学家和放射化学家，拥有丰富的经验用于成像和成像的新型放射性药物的临床前验证和临床转化经验治疗。博士。索耶斯和刘易斯指导了许多科学家和临床研究员，其中一些人曾过渡到成功的学术生涯。纪念斯隆凯特琳癌症中心 (MSKCC) 将提供对我的机构支持，包括进行实验室研究的资源、培养职业发展和继续教育，以及促进互动的开放科学环境我需要实现我的目标。这项研究计划的总体目标是让我学习放射化学的理论和实践锆 89 标记的转铁蛋白 (89Zr-Tf) 是一种新型放射性示踪剂，开发新应用的背景 PET 我在 MSKCC 共同发明。该提案直接源自我之前的经验，因为 89Zr-Tf 是其中之一我通过合作开发了三种用于正电子发射断层扫描 (PET) 的新型放射性示踪剂测量前列腺癌中的雄激素受体 (AR) 或 MYC 信号传导。这项研究已经确定可以非侵入性地测量致癌信号通路中遗传或药理学驱动的变化 PET 成像进一步强调了分子成像在肿瘤学中的作用。此次活动的具体目的两年 K99 奖励期内的提案是使用 89Zr-Tf 研究 MYC 在肿瘤反应中的作用靶向治疗（具体目标 1）。 3年R00奖励期的具体目标延伸自此目标， (1) 证明 89Zr-Tf 可以测量 PI3K 通路中药理学触发的变化前列腺癌模型中的信号转导（具体目标 2 和 (2)）以确定 89Zr-Tf 摄取是否具有反射性多形性胶质母细胞瘤临床前模型中异常 PI3K 通路信号传导的研究（具体目标 3），两个迫切需要新型成像生物标志物的病理学。