Noninvasive measurement of oncogenic signaling pathways with 89Zr-transferrin

项目总结/摘要 该提案描述了一个培训计划，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颁奖期间，我将 由Charles Sawyers博士和Jason刘易斯博士共同指导。索耶斯博士是国际上 公认的临床肿瘤学专家，特别是靶向分子药物的开发和评估， 血液和前列腺癌的治疗方法，并对 定义体内药物药理学。刘易斯博士是一位无机化学家和放射化学家， 在成像用新型放射性药物的临床前验证和临床转化方面的经验， 疗法Sawyers和刘易斯指导了许多科学家和临床研究员，其中一些人已经 成功的学术生涯。Memorial Sloan Kettering Cancer Center（MSKCC） 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，以及一个开放的科学环境，以促进互动 是我实现目标所必需的 这个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标记转铁蛋白（89 Zr-Tf）是一种新型的放射性示踪剂， 我在MSKCC共同发明了PET。这个建议直接从我以前的经验延伸而来，因为89 Zr-Tf是一种 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。这项研究表明， 可以非侵入性地测量致癌信号传导途径中的遗传或微生物学驱动的变化 进一步强调了分子成像在肿瘤学中的作用。其具体目的是 在为期2年的K99奖期间，一项提案是使用89 Zr-Tf研究MYC在肿瘤反应中的作用， 靶向治疗（具体目标1）。3年R 00奖励期的具体目标从这一目标延伸， 证明89 Zr-Tf可以测量PI 3 K通路中的信号转导触发的变化 前列腺癌模型中的89 Zr-Tf信号传导（具体目标2，和（2）确定89 Zr-Tf摄取是否是反映性的 在多形性胶质母细胞瘤临床前模型中异常PI 3 K通路信号传导（特异性目的3）， 因此，迫切需要新的成像生物标志物的病理学。

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.