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：
9516530
负责人：
BIN CHEN
金额：
$ 35.63万
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：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9516530
关键词：
ABCG2 gene Address Affect Amino Acids Aminolevulinic Acid Breast Cancer Cell Breast Cancer Model Breast Cancer cell line Cancer Patient Cancer cell line Cells Characteristics Clinical Contrast Media Detection Dose Enzymes Excision Exhibits FDA approved Fluorescence Fluorescent Probes Future Gene Deletion Genotype Goals Heme Heterogeneity Human Malignant Neoplasms Malignant neoplasm of pancreas Metabolic Modality Modeling Molecular Probes Mutation Noise Normal tissue morphology Operative Surgical Procedures PUVA Photochemotherapy Pathway interactions Phenotype Photosensitization Primary Neoplasm Production Protocols documentation Recurrence Research Resistance Signal Transduction Solid Neoplasm Structure Surgeon Surgical Oncology Surgical margins Testing Time Treatment outcome Tumor Tissue base cancer cell cancer surgery clinical application common treatment enzyme biosynthesis ferrochelatase heme biosynthesis improved improved outcome inhibitor/antagonist kinase inhibitor lapatinib orthotopic breast cancer pancreatic cancer cells pancreatic neoplasm protoporphyrin IX screening small molecule surgery outcome transport inhibitor triple-negative invasive breast carcinoma tumor

项目摘要

Surgery is the most common treatment for all types of solid tumors. A successful cancer surgery is to completely remove cancer cells and maximally preserve normal structures. To improve cancer surgery outcomes, fluorescent molecular probes have been developed and increasingly used for guiding tumor removal during surgery. Fluorescence emitted from these intraoperative molecular probes enables surgeons to visualize tumor tissues in real time and perform fluorescence-guided tumor resection. It has been well demonstrated that fluorescence-guided tumor resection enables more complete tumor resection and enhances treatment outcomes. Aminolevulinic acid (ALA) is one of a few FDA-approved intraoperative fluorescent probes. Although ALA itself is not fluorescent, it is metabolized in the heme biosynthesis pathway to a fluorescent and photosensitizing metabolite protoporphyrin IX (PpIX), enabling fluorescence detection and photodynamic therapy (PDT). ALA-PpIX has been clinically used for guiding the resection of various types of tumors. However, clinical applications of ALA are limited by issues such as low PpIX tumor production, PpIX fluorescence heterogeneity, and low tumor/normal fluorescence contrast. Our goal is to optimize ALA-based modalities by addressing tumor phenotypic and genotypic characteristics that affect tumor PpIX fluorescence. Two optimization strategies are proposed in this research. Specific Aim 1 is to optimize ALA-PpIX fluorescence-guided tumor resection and treatment by suppressing PpIX efflux. We have found that triple negative breast cancer (TNBC) cell lines show reduced ALA-PpIX fluorescence and are resistant to ALA-PDT due to elevated ABCG2 transporter activity. We have searched for clinical ABCG2 transporter inhibitors and will use them to improve ALA-PpIX fluorescence-guided resection and treatment of TNBC tumors with increased ABCG2 transporter activity. Specific Aim 2 is to optimize the dose of ALA for PpIX fluorescence-guided resection and treatment of tumors with genetic alterations in heme biosynthesis enzymes. We have found that pancreatic cancers exhibit genetic alterations in heme biosynthesis enzymes, which change ALA-PpIX production profile. We will optimize ALA dose to increase PpIX fluorescence contrast between tumor and normal tissues to improve fluorescence-guided resection of pancreatic cancers. Through this research, we hope to demonstrate that ALA protocols optimized to fit tumor phenotype and genotype offer better surgical outcomes than applying it based on one-size-fits-all approach.

手术是所有类型实体瘤最常见的治疗方法。成功的癌症手术是彻底清除癌细胞并最大限度地保留正常结构。改善癌症手术结果，荧光分子探针已被开发并越来越多地用于引导肿瘤手术期间去除。这些术中分子探针发出的荧光使得外科医生实时观察肿瘤组织并进行荧光引导肿瘤切除。它有已充分证明荧光引导肿瘤切除术可以实现更完整的肿瘤切除并提高治疗效果。氨基乙酰丙酸 (ALA) 是 FDA 批准的少数几种术中药物之一荧光探针。虽然ALA本身不发出荧光，但它在血红素生物合成中被代谢通往荧光和光敏代谢物原卟啉 IX (PpIX) 的途径，使荧光成为可能检测和光动力治疗（PDT）。 ALA-PpIX已在临床上用于指导切除各种类型的肿瘤。然而，ALA的临床应用受到肿瘤PpIX低等问题的限制。产量、PpIX 荧光异质性和低肿瘤/正常荧光对比度。我们的目标是通过解决影响肿瘤表型和基因型特征来优化基于 ALA 的模式肿瘤 PpIX 荧光。本研究提出了两种优化策略。具体目标 1 是通过抑制 PpIX 外流来优化 ALA-PpIX 荧光引导的肿瘤切除和治疗。我们发现三阴性乳腺癌 (TNBC) 细胞系显示 ALA-PpIX 荧光减弱，并且由于 ABCG2 转运蛋白活性升高，对 ALA-PDT 具有抵抗力。我们已经搜索了临床 ABCG2 转运蛋白抑制剂，并将使用它们来改善 ALA-PpIX 荧光引导的切除和治疗 ABCG2 转运蛋白活性增加的 TNBC 肿瘤。具体目标 2 是优化 ALA 剂量用于 PpIX 荧光引导切除和治疗血红素基因改变的肿瘤生物合成酶。我们发现胰腺癌表现出血红素的遗传改变生物合成酶，改变 ALA-PpIX 的生产概况。我们将优化 ALA 剂量以增加肿瘤和正常组织之间的 PpIX 荧光对比可改善荧光引导切除胰腺癌。通过这项研究，我们希望证明 ALA 协议经过优化以适应肿瘤表型和基因型比一刀切提供更好的手术结果方法。