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

• 批准号: 8990827
• 负责人: Michael John Evans
• 金额: $ 24.11万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 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/8990827
• 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; FRAP1 gene; 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; Monitor; Mutation; Oncogenic; Output; 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; TFRC gene; Technology; Therapeutic Intervention; Training; Training Programs; Transferrin; Translations; Tumor Biology; Ursidae Family; Validation; Zirconium; abstracting; antitumor effect; biomarker development; cancer biomarkers; cancer diagnosis; cancer imaging; cancer therapy; career; career development; experience; imaging biomarker; improved; in vivo; in vivo imaging; inhibitor/antagonist; insight; interest; kinase inhibitor; leukemia; mTOR Inhibitor; man; molecular imaging; molecular targeted therapies; mouse model; novel; novel marker; oncology; pre-clinical; programs; prostate cancer cell line; prostate cancer model; radiotracer; receptor expression; response; skills; small molecule; targeted treatment; tenure track; theories; treatment response; tumor; uptake; zirconium oxide; 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; FRAP1 gene; 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; Monitor; Mutation; Oncogenic; Output; 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; TFRC gene; Technology; Therapeutic Intervention; Training; Training Programs; Transferrin; Translations; Tumor Biology; Ursidae Family; Validation; Zirconium; abstracting; antitumor effect; biomarker development; cancer biomarkers; cancer diagnosis; cancer imaging; cancer therapy; career; career development; experience; imaging biomarker; improved; in vivo; in vivo imaging; inhibitor/antagonist; insight; interest; kinase inhibitor; leukemia; mTOR Inhibitor; man; molecular imaging; molecular targeted therapies; mouse model; novel; novel marker; oncology; pre-clinical; programs; prostate cancer cell line; prostate cancer model; radiotracer; receptor expression; response; skills; small molecule; targeted treatment; tenure track; theories; treatment response; tumor; uptake; zirconium oxide

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.

项目摘要/摘要 该建议描述了一项培训计划，以推进我在生物标志物开发方面的学术生涯 肿瘤学。该奖项的目的是鼓励我的独立研究计划，这一时期将 用于扩大我的科学知识和指导能力。在K99奖励期间，我将 由查尔斯·索耶斯（Charles Sawyers）博士指导，并由杰森·刘易斯（Jason Lewis）博士合作。索耶斯博士是国际 公认的临床肿瘤学专家，尤其是靶向分子的发展和评估 血液学和前列腺癌的治疗疗法，对技术的长期兴趣 定义体内药物学。刘易斯博士是一位无机化学家和放射药师， 具有成像和成像的新型放射性药物的临床前验证和临床翻译经验 治疗。博士。索耶人和刘易斯指导了许多科学家和临床研究员，其中一些 过渡到成功的学术职业。纪念Sloan Kettering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，培养机会 职业发展和继续教育，以及开放的科学环境，以促进互动 我需要实现目标。 这项研究建议的总体目标是让我学习放射化学的理论和实践 为锆89标记的转铁蛋白（89zr-tf）开发新应用的背景，这是一种新型的放射性示踪剂 宠物我在MSKCC共同发明。该提案直接从我以前的经验延伸，因为89zr-tf是 我通过合作与 在前列腺癌中测量雄激素受体（AR）或MYC信号传导。这项研究确定了 遗传或药理驱动的致癌信号通路的变化可以是无创测量的 通过PET成像，进一步强调了分子成像在肿瘤学中的作用。这个的具体目的 2年K99奖励期间的提案是使用89ZR-TF研究MYC在肿瘤反应中的作用 靶向疗法（特定目标1）。 3年R00奖励期的具体目的从这个目标延长， 并且（1）证明89ZR-TF可以测量PI3K途径的药理触发的变化 前列腺癌模型中的信号传导（特定的目标2和（2）确定89ZR-TF吸收是否反射 多形胶质母细胞瘤模型中异常PI3K途径信号传导（特定AIM 3），两个 迫切需要新型成像生物标志物的病理。