Optimization of aminolevulinic acid-protoporphyrin IX for fluorescence-guided tumor resection and treatment

荧光引导肿瘤切除和治疗中氨基乙酰丙酸-原卟啉 IX 的优化

• 批准号: 10705406
• 负责人: BIN CHEN
• 金额: $ 42.2万
• 依托单位: SAINT JOSEPH'S UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10705406
• 关键词: ABCG2 gene; Address; Aftercare; Aminolevulinic Acid; Area; Award; Biological; Brain Neoplasms; Cancer Patient; Cell Death; Cell Line; Characteristics; Clinical; Conventional Surgery; Excision; Exhibits; FDA approved; Flow Cytometry; Fluorescence; Fluorescence Microscopy; Fluorescence Spectrometry; Fluorescent Probes; Funding; Future; Genetic Engineering; Genotype; Glioma; Goals; Heterogeneity; Human; Image; In Vitro; Isocitrate Dehydrogenase; Light; Malignant Neoplasms; Measurement; Measures; Metabolic; Modeling; Molecular Probes; Mutation; Normal tissue morphology; Operative Surgical Procedures; PUVA Photochemotherapy; Pathway interactions; Pharmaceutical Preparations; Phenotype; Phototherapy; Recurrence; Research; Resolution; Skin Cancer; Solid Neoplasm; Structure; Students; Surgeon; Surgical Oncology; Surgical margins; Testing; Time; Training; Tumor Tissue; U118; base; brain tissue; cancer surgery; common treatment; cytotoxicity; design; enzyme biosynthesis; experience; ferrochelatase; fluorescence imaging; fluorescence microscope; glioma cell line; graduate student; hands on research; heme biosynthesis; imager; improved; in vivo; kinase inhibitor; lapatinib; neoplastic cell; overexpression; preservation; protoporphyrin IX; response; subcutaneous; surgery outcome; treatment choice; treatment response; tumor; tumor growth; undergraduate student

The long-term goal of our research is to determine tumor phenotypic and genotypic characteristics that reduce tumor protoporphyrin IX fluorescence and design mechanism-based approaches to overcome these limiting factors – this first renewal builds on progress made in our initial funding period. Surgery is the most common treatment for all types of solid tumors. A successful cancer surgery is to completely remove tumor tissues and maximally preserve normal structures. To improve cancer surgery accuracy and precision, fluorescent molecular probes have been developed and are being increasingly used in the oncological surgery. Fluorescence from intraoperative molecular probes enables surgeons to visualize tumor tissues in real time and perform fluorescence-guided resection (FGR). It has been well demonstrated that FGR leads to more complete tumor resection and better surgical outcomes than conventional surgery under white light. Aminolevulinic acid (ALA) is one of a few FDA-approved intraoperative fluorescent probes and the only molecular probe based on the metabolic alterations in tumor cells. ALA has no fluorescence on its own and needs to be metabolized in the heme biosynthesis pathway in tumor cells to produce a fluorescent and photosensitizing metabolite protoporphyrin IX (PpIX), which enables tumor fluorescence imaging and photodynamic therapy (PDT). Although ALA-PpIX has been clinically used for tumor FGR, its applications are limited by low tumor PpIX fluorescence, high tumor fluorescence heterogeneity, and low tumor-to-normal tissue fluorescence contrast. Studies in the initial funding period of this award have led to the identification of ABCG2 transporter activity as a critical factor in reducing tumor PpIX fluorescence. Importantly, we have identified clinically used agents to suppress ABCG2 activity to enhance tumor PpIX fluorescence. In this renewal, we will use an FDA-approved drug lapatinib (Lap), the most potent one we have identified for the enhancement of tumor PpIX fluorescence, and hypothesize that lapatinib improves the use of ALA for FGR and PDT of gliomas. We chose to study this enhancement strategy in gliomas because ALA is now primarily used for guiding the resection of gliomas and, more importantly, ABCG2 expression elevation is a common feature in human gliomas. To this end, we will evaluate Lap in combination with ALA for the enhancement of PpIX fluorescence and PDT response in human glioma cell lines with different genotype and phenotype (Aim 1) and glioma tumor models (Aim 2). Through this research, we hope to demonstrate that Lap in combination with ALA enhances tumor PpIX fluorescence and PDT response. The successful completion of this research will lead to an optimized use of ALA for FGR and PDT treatment of gliomas.

我们研究的长期目标是确定肿瘤的表型和基因特征 肿瘤原卟啉IX荧光和设计基于机制的方法来克服这些限制 因素-第一次续签是在我们最初的资助期取得进展的基础上进行的。手术是最常见的 治疗所有类型的实体肿瘤。一个成功的癌症手术是完全切除肿瘤组织和 最大限度地保护正常结构。为了提高癌症手术的精确度和精确度，荧光分子 探头已经被开发出来，并越来越多地应用于肿瘤外科。来自以下的荧光 术中分子探针使外科医生能够实时观察肿瘤组织并进行 荧光引导切除(FGR)。已有很好的证据表明，FGR导致更完全的肿瘤 手术切除效果优于白光下常规手术。氨基乙酰丙酸(ALA)是 FDA批准的为数不多的术中荧光探针之一，也是唯一基于 肿瘤细胞的代谢改变。ALA本身没有荧光，需要在体内代谢 肿瘤细胞中产生荧光光敏代谢物的血红素生物合成途径 原卟啉IX(PpIX)，使肿瘤荧光成像和光动力疗法(PDT)成为可能。虽然 ALA-PPIX已在临床上用于肿瘤FGR，但其应用受到肿瘤PPIX低荧光的限制， 肿瘤荧光异质性高，肿瘤与正常组织荧光对比度低。在美国的研究 这项奖励的初始资助期导致将ABCG2转运体活动确定为关键因素 在降低肿瘤PPIX荧光方面。重要的是，我们已经确定了临床上使用的抑制ABCG2的药物 增强肿瘤PPIX荧光活性。在这次更新中，我们将使用FDA批准的药物拉帕替尼(Lap)， 我们已经确定的对增强肿瘤PpIX荧光最有效的一种，并假设 拉帕替尼改善了ALA对胶质瘤FGR和PDT的使用。我们选择研究这一增强策略 因为ALA现在主要用于指导胶质瘤的切除，更重要的是，ABCG2 表达上调是人脑胶质瘤的常见特征。为此，我们将结合LAP进行评估 ALA增强人胶质瘤细胞系PPIX荧光和光动力反应的研究 基因和表型(AIM 1)和胶质瘤肿瘤模型(AIM 2)。通过这项研究，我们希望 证明LAP与ALA联合使用可增强肿瘤的PpIX荧光和光动力反应。这个 这项研究的成功完成将导致对ALA用于FGR和PDT治疗的优化使用 神经胶质瘤。