Noninvasive measurement of oncogenic signaling pathways with 89Zr-transferrin

描述（由申请人提供）：本提案描述了一个培训计划，以促进我在肿瘤学生物标志物开发方面的学术生涯。这个奖项的目的是鼓励我的独立研究计划，这段时间将用于扩大我的科学知识和指导技能。在K99奖期间，我将由查尔斯·索耶博士指导，并由杰森·刘易斯博士共同指导。Sawyers博士是国际公认的临床肿瘤学专家，特别是血液和前列腺癌靶向分子治疗的开发和评估，并对定义体内药物药理学的技术长期感兴趣。刘易斯博士是一位无机化学家和放射化学家，在用于成像和治疗的新型放射性药物的临床前验证和临床转化方面具有丰富的经验。Sawyers和刘易斯指导了许多科学家和临床研究员，其中一些人已经过渡到成功的学术生涯。纪念斯隆凯特琳癌症中心（MSKCC）将为我提供机构支持，包括进行实验室研究的资源，促进职业发展和继续教育的机会，本研究计划的总体目标是让我在开发新应用的背景下学习放射化学的理论和实践锆-89标记的转铁蛋白（89 Zr-Tf），一种新的PET I放射性示踪剂，在MSKCC共同发明。该建议直接从我以前的经验中延伸出来，因为89 Zr-Tf是我通过合作开发的用于测量前列腺癌中雄激素受体（AR）或MYC信号的正电子发射断层扫描（PET）的三种新型放射性示踪剂之一。这项研究已经确定，致癌信号传导通路中的遗传或细胞因子驱动的变化可以用PET成像进行非侵入性测量，进一步强调了分子成像在肿瘤学中的作用。在为期2年的K99奖励期间，该提案的具体目标是使用89 Zr-Tf研究MYC在肿瘤对靶向治疗反应中的作用（具体目标1）。3年R 00奖励期的具体目标是从这一目标延伸，并且是（1）证明89 Zr-Tf可以测量前列腺癌模型中PI 3 K通路信号传导中的放射性触发的变化（具体目的2，和（2）确定89 Zr-Tf摄取是否反映多形性胶质母细胞瘤临床前模型中异常的PI 3 K途径信号传导（具体目标3），迫切需要新型成像生物标志物的两种病理。

DESCRIPTION (provided by applicant): 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.