A Suite of Tumor Targeting Peptides for Personalized Therapy of Lung Cancer

描述（由申请人提供）：在美国，每年诊断出213，000例肺癌新病例;这些患者中的60%在一年内死亡。由于肺癌的异质性，根据肿瘤分子特征定制的个性化治疗预计将提供更好的临床疗效。为了使个性化治疗的广泛使用成为现实，临床医生必须能够快速“分类”肿瘤特征，识别在该肿瘤亚型中有效的治疗，有效地将治疗剂递送到患者体内，并在患者体内进行治疗。 肿瘤，并在治疗过程中监测肿瘤特征。肿瘤靶向配体正在成为定制疗法开发中的重要组成部分。我实验室的长期目标是开发全面的肿瘤特异性配体，用于肺癌的功能诊断和靶向治疗，包括从不吸烟者的肺癌。为此，本实验室在一系列人非小细胞肺癌（NSCLC）细胞系上构建了噬菌体展示肽库。从这些选择中，分离出11种新的肽配体。所述肽选择性结合NSCLC细胞，同时避免非恶性支气管上皮细胞，并显示皮摩尔至低纳摩尔范围的细胞结合亲和力。在40种不同的人非小细胞肺癌细胞系上测定了肽结合; 80%的测试细胞系与至少一种肽结合，> 35%与2种或多种配体结合。因此，该组肽可以覆盖临床中遇到的大部分NSCLC病例。这些肽具有额外的益处，它们触发细胞摄取，允许治疗剂在细胞内递送。最后，在动物模型中，这些肽会回到肿瘤中。这些配体被引导转化为用于治疗NSCLC的有效递送系统。本项目的目标是充分优化这些分子靶向药物递送的递送试剂。目的1将确定肽与未培养的原代人NSCLC肿瘤样品结合的广度和特异性。在目标2中，将合成并优化独特的多价肽引导的隐形脂质体，以实现脂质体递送至肿瘤的最高水平，同时最小化在其他组织中的摄取和网状内皮系统（RES）的清除。将以系统的方式评估肽价、亲和力、肽电荷和肽密度的作用。最后在 目的3，将在NSCLC的动物异种移植模型中评估目的2中开发的载药脂质体的抗肿瘤功效。一种创新的“纳米脂质体”配方将被用来实现高负荷加载和调整药物释放动力学。将进行房室药代动力学（PK）和药效学（PD）研究。完成后，将生成一套经验证的NSCLC肿瘤靶向药物。开发的分子靶向递送系统将显著提高NSCLC治疗的疗效。

DESCRIPTION (provided by applicant): In the United States, 213,000 new cases of lung cancer are diagnosed yearly; 60% of these patients die within one year. Due to the heterogeneity of lung cancer, personalized therapies tailored to the molecular signatures of a tumor are anticipated to provide better clinical efficacy. To make widespread use of personalized therapies a reality, clinicians must have the ability to rapidly "classify" the tumor signature, identify treatments effective in that tumor subtype, deliver therapeutics effectively to the tumor, and monitor the tumor signature during the course of treatment. Tumor targeting ligands are becoming an important component in the development of customized therapies. The long-term objective of my laboratory is to develop comprehensive panels of tumor-specific ligands for functional diagnosis and targeted therapy for lung cancer, including lung cancer arising in never smokers. For this purpose, my laboratory has biopanned phage-displayed peptide libraries on a series of human non small cell lung cancer (NSCLC) cell lines. From these selections, 11 novel peptidic ligands were isolated. The peptides bind selectively to NSCLC cells while avoiding nonmalignant bronchial epithelial cells, and display cell binding affinities i the picomolar to low nanomolar range. Peptide binding was determined on 40 different human NSCLC cell lines; 80% of the cell lines tested bind to at least one peptide and > 35% bind 2 or more of the ligands. Thus, this panel of peptides may cover a large fraction of NSCLC cases encountered in the clinic. These peptides have the added benefit that they trigger cellular uptake allowing for therapeutics to be delivered intracellularly. Lastly, the peptides home to tumors in animal models. These ligands are primed to be translated into effective delivery systems for the treatment of NSCLC. The objective of this project is to fully optimize these delivery reagents for molecularly targeted drug delivery. Aim 1 will determine the breadth and specificity of peptide binding to uncultured primary human NSCLC tumor samples. In Aim 2, unique multivalent peptide-guided stealth liposomes will be synthesized and optimized to achieve the highest level of liposome delivery to the tumor while minimizing uptake in other tissues and clearance by the reticuloendothelial system (RES). The role of peptide valency, affinity, peptide charge, and peptide density will be assessed in a systematic fashion. Finally, in Aim 3, the anti-tumor efficacy of drug loaded liposomes developed in aim 2 will be assessed in animal xenograft models of NSCLC. An innovative "nanoliposome" formulation will be employed to achieve high load loading and tune the drug release kinetics. Compartmental pharmacokinetic (PK) and pharmacodynamic (PD) studies will be executed. Upon completion, a validated suite of NSCLC tumor targeting agents will have been generated. The molecularly-targeted delivery systems developed will dramatically improve efficacy of NSCLC treatment.