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：
10360122
负责人：
BIN CHEN
金额：
$ 1.29万
依托单位：
UNIVERSITY OF THE SCIENCES PHILADELPHIA
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：
2022-01-01 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10360122
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

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肿瘤表型和基因型特征，以减少肿瘤原卟啉 IX 荧光和基于设计机制的方法来克服这些限制因素——第一次续约建立在我们最初资助期间取得的进展的基础上，手术是最常见的。成功的癌症手术是彻底切除肿瘤组织并治疗所有类型的实体瘤。为了最大限度地保留正常结构，提高癌症手术的准确性和精确性，荧光分子。探针已被开发出来并越来越多地用于肿瘤手术中。术中分子探针使外科医生能够实时观察肿瘤组织并进行手术荧光引导切除术（FGR）已被充分证明，FGR 可以使肿瘤更加完整。与白光下的传统手术相比，氨基乙酰丙酸（ALA）具有更好的切除效果。 FDA 批准的少数术中荧光探针之一，也是唯一基于 ALA 本身没有荧光，需要在肿瘤细胞中代谢。肿瘤细胞中血红素生物合成途径产生荧光和光敏代谢物原卟啉 IX (PpIX)，可实现肿瘤荧光成像和光动力治疗 (PDT)。 ALA-PpIX已在临床上用于肿瘤FGR，其应用受到低肿瘤PpIX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的研究。该奖项的初始资助期已确定 ABCG2 转运蛋白活性是一个关键因素重要的是，我们已经确定了临床上使用的抑制 ABCG2 的药物。增强肿瘤 PpIX 荧光的活性在本次更新中，我们将使用 FDA 批准的药物拉帕替尼 (Lap)，我们已经确定了最有效的增强肿瘤 PpIX 荧光的方法，并捕获了这一点拉帕替尼改善了 ALA 在神经胶质瘤 FGR 和 PDT 中的使用，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 表达升高是人类胶质瘤的一个共同特征，为此，我们将结合评估Lap。与 ALA 一起增强人胶质瘤细胞系的 PpIX 荧光和 PDT 反应通过这项研究，我们希望能够了解基因型和表型（目标 1）以及神经胶质瘤肿瘤模型（目标 2）。证明 Lap 与 ALA 结合可增强肿瘤 PpIX 荧光和 PDT 反应。这项研究的成功完成将导致 ALA 在 FGR 和 PDT 治疗中的优化使用神经胶质瘤。