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

描述（由申请人提供）：由于癌症在临床、组织学和分子水平上是一种异质性疾病，并且由于肿瘤表型经常随着肿瘤的发展而变化，因此现有治疗方法的疗效在个体患者中差异很大。针对特定肿瘤生物标志物的治疗尤其如此。一个有用的策略来指导个体化的发展，更有效的治疗策略是肿瘤的分子谱。然而，目前的肿瘤分析方法并不理想：它们需要多次活检，其结果经常受到采样错误和病理学家解释不一致的影响；此外，目前的方法不适用于播散性微转移。因此，显然需要一种更准确的分析单个肿瘤的方法，因为它将有助于提高对可能有反应的患者进行靶向治疗的疗效，并避免对不太可能有反应的患者进行此类治疗。为此，本研究的目的是开发和测试新一代靶向放射性示踪剂，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、无创地定量测量肿瘤内已建立的肿瘤生物标志物水平，预测疾病进展和对靶向治疗的反应。我们建议将这些放射性示踪剂的新型分子原型与短寿命放射性同位素结合使用，以快速产生数据，从而减轻患者的负担并加快诊断-治疗周期。我们假设设计的锚蛋白重复蛋白（DARPins）是一类新型的合理设计的蛋白，代表了一个理想的示踪剂设计的先进分子平台。DARPins独特的生物学特性使其成为抗体（Ab）和Ab衍生物的极好替代品

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.