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

描述(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，而且肿瘤表型经常随着肿瘤的发展而变化，因此现有的治疗方法在不同患者之间的疗效差别很大。对于针对特定肿瘤生物标记物的治疗来说，情况尤其如此。指导发展个体化、更有效的治疗策略的一个有用的策略是肿瘤的分子图谱。然而，目前的肿瘤分析方法并不是最优的：它们需要多次活检，其结果经常受到抽样错误和病理学家解释不一致的影响；此外，当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方法来描述单个肿瘤，因为这将有助于提高潜在反应患者的靶向治疗效果，并避免对不太可能有反应的患者进行此类治疗。为此，这项拟议研究的目标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。拟议的PET战略将有助于检测目标肿瘤，并能够准确、非侵入性地定量测量肿瘤内的水平，该生物标志物可以预测疾病进展和对靶向治疗的反应。我们建议使用一种新的放射性示踪剂的分子原型，结合短寿命的放射性同位素来快速产生数据，从而减轻患者的负担，加快诊断-治疗周期。我们假设设计的Ankyrin重复蛋白(DARPins)是一类新型的合理设计的蛋白质，代表了示踪剂设计的一个理想的高级分子平台。DARPins独特的生物学特性使其成为抗体(Ab)及其衍生物的极佳替代品，这些抗体及其衍生物传统上用于 这一目的，尽管其已知的限制。我们将通过追求两个特定的目标来验证我们的假设并实现我们的目标：特定的目标1.开发和表征基于DARPin的体外放射性示踪剂，用于人表皮生长因子受体-2(Her2)的PET成像。具体目的2.证明启用DARPin的PET成像对Her2的特异性，并在原位癌症模型中确定其检测限。这项工作将有助于 开发最适合个别癌症患者的个性化治疗计划，从而在治疗效果和成本效益方面产生显著改善。

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.