New generation of radiotracers for PET imaging of molecular signatures of tumors

用于肿瘤分子特征 PET 成像的新一代放射性示踪剂

基本信息

批准号：
8689727
负责人：
VICTOR KRASNYKH
金额：
$ 20.88万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
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：
2014-08-07 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8689727
关键词：
Affect Affinity Ankyrin Repeat Antibodies Biologic Characteristic Biological Biological Markers Biopsy Blood Blood Circulation Blood Vessels Cancer Model Cancer Patient Clinical Data Detection Development Diagnosis Diagnostic Disease Disease Progression Epidermal Growth Factor Receptor Generations Goals Human Image Imaging technology In Vitro Individual Isotopes Knowledge Life Literature Malignant Neoplasms Measurement Methodology Methods Micrometastasis Molecular Molecular Profiling Molecular Target Outcome Pathologist Patients Phenotype Positron-Emission Tomography Predictive Value Property Proteins Public Health Publishing Radioisotopes Research Sampling Errors Sensitivity and Specificity Signal Transduction Specificity Structure Technology Testing Therapeutic Time Tissues Tracer Translating Translations Treatment Cost Treatment Efficacy Work base cancer diagnosis cancer therapy cancer type clinical practice cost design evidence base improved molecular imaging novel programs prototype public health relevance radioligand radiotracer response treatment planning treatment strategy tumor

项目摘要

DESCRIPTION (provided by applicant): Because cancer is a heterogenous disease at the clinical, histological, and molecular levels and because tumor phenotype often changes as tumors develop, the efficacy of established treatments vary quite significantly among individual patients. This is particularly true for therapies that target specific tumor biomarkers. A useful strategy to guide the development of individualized, more efficient treatment strategies is molecular profiling of tumors. However, current tumor profiling methods are suboptimal: they require multiple biopsies, their results are often compromised by sampling errors and inconsistencies in pathologists' interpretations; also, current methods are not applicable to disseminated micrometastases. A more accurate method of profiling individual tumors is thus clearly needed, as it would help to improve the efficacy of targeted treatments in potentially responsive patients and avoid such treatments in patients unlikely to respond. Toward this end, the objective of this proposed research is to develop and test a new generation of targeted radiotracers for use in positron emission tomography (PET) imaging of tumors' molecular signatures. The proposed PET strategy will facilitate detection of target tumors and enable accurate, noninvasive quantitative measurement of intratumoral levels of an established tumor biomarker that predicts disease progression and responsiveness to targeted treatments. We propose using a novel molecular prototype for these radiotracers in combination with the short-lived radioisotopes to produce data quickly, thereby reducing the burden on patients and accelerating the diagnosis-treatment cycle. We hypothesize that Designed Ankyrin Repeat Proteins (DARPins), a novel class of rationally designed proteins, represent a desirable advanced molecular platform for tracer design. DARPins' unique biological properties make them an excellent alternative to antibodies (Ab) and Ab derivatives that are traditionally used for this purpose despite their known limitations. We will test our hypothesis and achieve our objective by pursuing two specific aims: Specific aim 1. Develop and characterize in vitro DARPin-based radiotracers for PET imaging of human epidermal growth factor receptor-2 (Her2). Specific aim 2. Demonstrate the specificity of DARPin-enabled PET imaging for Her2 and determine its detection limits in an orthotopic model of cancer. This work will facilitate the development of personalized treatment plans best suited for individual cancer patients and thus yield significant improvements in treatment efficacy and cost efficiency.

描述（由申请人提供）：因为癌症是一种在临床，组织学和分子水平上的异源性疾病，并且由于肿瘤表型通常随着肿瘤的发展而经常变化，因此既定治疗的功效在个别患者中的疗效差异很大。对于靶向特定肿瘤生物标志物的疗法尤其如此。指导个性化，更有效治疗策略发展的有用策略是肿瘤的分子分析。但是，当前的肿瘤分析方法是次优的：它们需要多个活检，其结果通常会因对病理学家解释的误差和不一致而损害；同样，当前方法不适用于传播微型转移。因此，显然需要一种更准确的分析个体肿瘤的方法，因为它将有助于提高靶向治疗的潜在反应敏感患者的疗效，并避免患者对患者的这种治疗不太可能做出反应。为此，这项拟议的研究的目的是开发和测试新一代的靶向放射性示例，以用于肿瘤分子特征的正电子发射断层扫描（PET）成像。提出的PET策略将促进靶肿瘤的检测，并能够准确，无创的定量测量已建立的肿瘤生物标志物的肿瘤内水平，以预测疾病进展和对靶向治疗的反应。我们建议将新型的分子原型与短寿命的放射性同位素结合使用，以迅速产生数据，从而减少患者的负担并加速诊断治疗周期。我们假设设计了一种新型的理性设计蛋白（DARPINS），这是一种理性设计的蛋白质，代表了示踪剂设计的理想的晚期分子平台。 Darpins独特的生物学特性使它们成为传统上用于的抗体（AB）和AB衍生物的绝佳替代品尽管有已知的局限性，但这个目的。我们将通过追求两个具体目标来检验我们的假设并实现我们的目标：特定目标1。开发和表征基于DARPIN的放射性示例，用于人类表皮生长因子受体-2的PET成像（HER2）。具体目的2。证明对HER2的启用DARPIN PET成像的特异性，并确定其在癌症的原位模型中的检测极限。这项工作将促进制定个性化治疗计划最适合单个癌症患者，从而在治疗效率和成本效率方面产生显着提高。