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

基本信息

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
项目类别：
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

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

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项目摘要

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减少肿瘤表型和基因型特征肿瘤原核IX荧光和基于设计机制的方法来克服这些限制因素 - 第一个续约是基于我们最初的资助期间取得的进展。手术是最常见的所有类型的实体瘤的治疗。成功的癌症手术是完全去除肿瘤组织和最大地保留正常结构。为了提高癌症手术的精度和精度，荧光分子问题已经出现，并越来越多地用于肿瘤手术中。荧光来自术中分子问题使外科医生能够实时可视化肿瘤时间并进行荧光引导切除（FGR）。已经很好地证明了FGR会导致更完整的肿瘤在白光下，切除和更好的手术结局。氨基乙烯酸（ALA）为基于FDA批准的几个术中荧光探针之一，是唯一基于的分子探针之一肿瘤细胞的代谢改变。 ALA本身没有荧光，需要在肿瘤细胞中的血红素生物合成途径，产生荧光和光敏代谢产物原源性IX（PPIX），可实现肿瘤荧光成像和光动力疗法（PDT）。虽然 ALA-PPIX已用于临床用于肿瘤FGR，其应用受到低肿瘤PPIX荧光的限制，高肿瘤荧光异质性和低肿瘤至正常的组织荧光对比度。研究该奖项的初始资金期限导致将ABCG2转运蛋白活动识别为关键因素在还原肿瘤荧光时。重要的是，我们已经确定了临床使用的药物来抑制ABCG2 活性以增强肿瘤PPIX荧光。在此续约中，我们将使用FDA批准的药物Lapatinib（LAP），我们确定的最有潜力的是增强肿瘤PPIX荧光的能力，并假设是拉帕替尼改善了ALA用于FGR和胶质瘤的PDT的使用。我们选择研究这种增强策略在神经胶质瘤中，因为ALA现在主要用于指导神经胶质瘤的切除，更重要的是ABCG2 表达升高是人神经胶质瘤中的常见特征。为此，我们将评估结合圈使用ALA在人神经胶质瘤细胞系中增强PPIX荧光和PDT反应的增强基因型和表型（AIM 1）和神经胶质瘤模型（AIM 2）。通过这项研究，我们希望证明与ALA结合使用的膝盖会增强肿瘤PPIX荧光和PDT响应。这这项研究的成功完成将导致对ALA的优化使用，用于FGR和PDT处理神经胶质瘤。