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

描述(申请人提供)：在美国，每年新确诊的肺癌病例有21.3万例，其中60%的患者在一年内死亡。由于肺癌的异质性，根据肿瘤的分子特征量身定做的个性化治疗有望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，临床医生必须有能力快速地对肿瘤信号进行分类，识别在该肿瘤亚型中有效的治疗方法，有效地将治疗方法提供给 并在治疗过程中监测肿瘤征象。肿瘤靶向配体正在成为个性化治疗发展的重要组成部分。我的实验室的长期目标是开发全面的肿瘤特异性配体小组，用于肺癌的功能诊断和靶向治疗，包括从不吸烟的肺癌。为此，我的实验室在一系列人类非小细胞肺癌(NSCLC)细胞系上进行了噬菌体展示肽库的生物扫描。从这些选择中分离出11个新的多肽配体。这些多肽选择性地与非小细胞肺癌细胞结合，同时避开非恶性支气管上皮细胞，并显示出从皮摩尔到低纳摩尔范围的细胞结合亲和力。在40个不同的人非小细胞肺癌细胞系上测定了多肽结合；80%的受测细胞系至少与一种多肽结合，35%的细胞结合两种或两种以上的配体。因此，这组多肽可能涵盖临床上遇到的大部分非小细胞肺癌病例。这些多肽还有一个额外的好处，那就是它们可以触发细胞摄取，允许治疗药物在细胞内输送。最后，在动物模型中，这些多肽是肿瘤的归宿。这些配体已准备好转化为治疗非小细胞肺癌的有效递送系统。本项目的目标是充分优化这些给药试剂，以实现分子靶向药物给药。目的1将确定与未培养的原代人非小细胞肺癌肿瘤标本结合的多肽的广度和特异性。在目标2中，将合成和优化独特的多价多肽引导的隐形脂质体，以实现最高水平的脂质体输送到肿瘤，同时将其他组织的摄取和网状内皮系统(RES)的清除降至最低。将以系统的方式评估多肽的价态、亲和力、多肽电荷和多肽密度的作用。最后，在 目的3，在非小细胞肺癌动物移植模型上评价AIM 2中开发的载药脂质体的抗肿瘤效果。一种创新的“纳米脂质体”配方将被用来实现高负载和调整药物释放动力学。将进行隔室药代动力学(PK)和药效学(PD)研究。完成后，将产生一套经过验证的非小细胞肺癌肿瘤靶向药物。开发的分子靶向递送系统将极大地提高非小细胞肺癌的治疗效果。

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.