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

一套用于肺癌个体化治疗的肿瘤靶向肽

基本信息

批准号：
8508211
负责人：
Kathlynn C Brown
金额：
$ 31.01万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-10 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8508211
关键词：
Affect Affinity Animal Model Animals Binding Biological Markers Cancer cell line Cell Line Cell surface Cells Cessation of life Charge Chronic Myeloid Leukemia Clinic Clinical Coupled Data Development Diagnosis Drug Carriers Drug Delivery Systems Drug Formulations Drug Kinetics Epithelial Cells FDA approved Goals Heterogeneity Home environment Human In Vitro Incidence Individual Kinetics Laboratories Ligand Binding Ligands Liposomes Lung Neoplasms Malignant Neoplasms Malignant neoplasm of lung Molecular Profiling Monitor Monoclonal Antibodies Newly Diagnosed Non-Malignant Non-Small-Cell Lung Carcinoma Normal tissue morphology Oncologist Organ Patients Peptide Phage Display Library Peptides Pharmaceutical Preparations Pharmacodynamics Pharmacologic Substance Phenotype Reagent Research Reticuloendothelial System Role Sampling Series Smoking Societies Specificity Survival Rate System Testing Therapeutic Therapeutic Agents Tissues Translating Tumor Subtype United States Vinorelbine Xenograft Model cancer cell cancer diagnosis cancer therapy clinical efficacy cost density drug efficacy effective therapy improved in vivo innovation molecular imaging nanoliposome neoplastic cell never smoker non-smoker novel success targeted delivery tumor uptake

项目摘要

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.

描述（由申请人提供）：在美国，每年新诊断出 213,000 例肺癌病例；其中 60% 的患者在一年内死亡。由于肺癌的异质性，针对肿瘤分子特征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，临床医生必须有能力快速“分类”肿瘤特征，识别对该肿瘤亚型有效的治疗方法，有效地向患者提供治疗方法。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组合，用于肺癌（包括从不吸烟者中发生的肺癌）的功能诊断和靶向治疗。为此，我的实验室对一系列人类非小细胞肺癌 (NSCLC) 细胞系进行了生物淘选噬菌体展示肽库。从这些选择中，分离出了 11 种新型肽配体。这些肽选择性地结合 NSCLC 细胞，同时避开非恶性支气管上皮细胞，并在皮摩尔至低纳摩尔范围内表现出细胞结合亲和力。在 40 种不同的人类 NSCLC 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 种或更多种配体结合。因此，这组肽可能涵盖临床中遇到的大部分非小细胞肺癌病例。这些肽还有一个额外的好处，即它们可以触发细胞摄取，从而使治疗药物能够在细胞内传递。最后，这些肽是动物模型中肿瘤的归宿。这些配体有望转化为治疗非小细胞肺癌的有效递送系统。该项目的目标是充分优化这些递送试剂以实现分子靶向药物递送。目标 1 将确定肽与未培养的原代人 NSCLC 肿瘤样本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，以实现最高水平的脂质体递送至肿瘤，同时最大限度地减少其他组织的吸收和网状内皮系统 (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，在目标 3，目标 2 中开发的载药脂质体的抗肿瘤功效将在 NSCLC 动物异种移植模型中进行评估。将采用创新的“纳米脂质体”配方来实现高负载并调整药物释放动力学。将进行药代动力学（PK）和药效学（PD）研究。完成后，将生成一套经过验证的 NSCLC 肿瘤靶向药物。开发的分子靶向递送系统将显着提高 NSCLC 治疗的疗效。