Noninvasive measurement of oncogenic signaling pathways with 89Zr-transferrin

描述(由申请人提供)：本建议书描述了一个培训计划，以促进我在肿瘤学生物标记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，这段时间将用来扩大我的科学知识和指导技能。在K99颁奖期间，我将得到查尔斯·索耶斯博士的指导和杰森·刘易斯博士的共同指导。索耶斯博士是国际公认的临床肿瘤学专家，尤其是针对血液病和前列腺癌的靶向分子疗法的开发和评估，他对定义体内药物药理学的技术有着长期的兴趣。刘易斯博士是一名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拥有丰富的经验。索耶斯和刘易斯博士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，以及一个开放的科学环境，以促进我实现目标所需的互动。这项研究提案的总体目标是让我在开发新的应用背景下学习放射化学的理论和实践，这是我在MSKCC共同发明的一种新型PET放射性示踪剂-89标记转铁蛋白(89Zr-Tf)。这项建议直接源于我以前的经验，因为89Zr-Tf是我通过合作开发的三种用于正电子发射断层扫描(PET)的新型放射性示踪剂之一，用于测量前列腺癌的雄激素受体(AR)或MYC信号。这项研究已经证实，遗传或药物驱动的致癌信号通路的变化可以通过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K99的两年获奖期内，这项建议的具体目的是使用89Zr-Tf来研究MYC在肿瘤靶向治疗反应中的作用(具体目标1)。为期3年的R00获奖期的具体目标是：(1)证明89Zr-Tf可以在前列腺癌模型中测量药物触发的PI3K通路信号的变化(特殊目标2)，以及(2)确定89Zr-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PI3K通路信号(特殊目标3)，这两种病理迫切需要新的成像生物标记物。

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.