Acidic Phospholipid-Selective Treatment for Neuroblastoma

酸性磷脂选择性治疗神经母细胞瘤

• 批准号: 8087347
• 负责人: XIAOYANG QI
• 金额: $ 33.46万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-27 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8087347
• 关键词: Adverse effects; Affinity; Age; American Cancer Society; Animal Model; Animals; Apoptosis; Apoptotic; Biological Products; Blood Vessels; Body part; Cell Death; Cell membrane; Cell surface; Cells; Cellular Structures; Ceramides; Child; Childhood; Clinical; Clinical Research; Combined Modality Therapy; Complex; Data; Diagnosis; Diagnostic; Disease; Disease remission; Drug Delivery Systems; Exhibits; Glioma; Glycoproteins; Goals; High Dose Chemotherapy; Histology; Human; In Vitro; Injection of therapeutic agent; Isotretinoin; Lipids; MYCN gene; Malignant Neoplasms; Mediating; Methods; Mitochondria; Modeling; Molecular; Monoclonal Antibodies; Multi-Drug Resistance; Mus; Neoplasm Metastasis; Neuroblastoma; Normal Cell; Normal tissue morphology; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phosphatidylserines; Phospholipids; Preparation; Proteins; Radiation therapy; Radiosurgery; Recurrence; Refractory; Research; Research Personnel; Risk Factors; Signal Pathway; Solid; Solid Neoplasm; Staging; Stem cell transplant; Surface; Survival Rate; Technology; Testing; Therapeutic Agents; Time; Toxic effect; Work; acid sphingomyelinase; base; beta-Glucosidase Stimulating Protein; cancer cell; cancer therapy; cancer type; chemotherapy; cytotoxic; design; drug development; high risk; improved; infancy; innovation; killings; lysosomal proteins; neoplastic cell; neuroblastoma cell; novel; novel strategies; novel therapeutics; outcome forecast; pancreatic neoplasm; pre-clinical; research study; response; success; tumor; tumor growth

DESCRIPTION (provided by applicant): Our research goal is to develop a new, robust therapeutic agent that seeks and destroys human neuroblastoma. Neuroblastoma is the most common cancer in infancy and children. High-risk neuroblastomas are difficult to cure even with the most aggressive of combination or multi-modal therapies. Our preliminary studies suggest the feasibility of using new protelipid nanovesicles to target and treat neuroblastomas with minimal side effects. The nanovesicle is consisted of the small fusogenic lysosomal protein saposin C (SapC) and the phospholipid dioleoylphosphatidylserine (DOPS). This stably formed SapC-DOPS nanovesicle has preferential affinity for phosphatidylserine (PS) exposed on the surface of cancer cells and neovessels. We have shown that the nanovesicles have high propensity to accumulate in neuroblastoma tumors, and induces apoptosis in the cancer cells. Upon repeated SapC-DOPS injection in neuroblastoma-bearing animals, we observed a significantly inhibitory effect on tumor growth by inducing apoptotic cancer cell death via acid sphingomyelinase-derived ceramide-mediated signaling pathways. The objective in this proposal is to determine SapC-DOPS nanovesicles for their application in treating neuroblastomas. The specific aims are to (1) determine the relationship of cell surface PS levels of human neuroblastoma cells and the targeting and cytotoxic responses to SapC-DOPS nanovesicles, (2) develop a SapC-DOPS sensitization agent that specifically promotes the PS exposure on the surface of human neuroblastoma, and (3) delineate the molecular mechanism underlying SapC-DOPS induced apoptotic cell death of human neuroblastoma via the ceramide-mediated mitochondria-centric signaling pathway. This research is innovative because SapC-DOPS nanovesicles offer a unique approach for seeking and treating neuroblastomas, as well as other tumors with cell surface exposed PS. The successfully completion of the proposed research will have a major impact on the field of cancer clinical research, since it provides a safe and broad clinical approach for cancer therapy. PUBLIC HEALTH RELEVANCE: Neuroblastoma is an extracranial solid cancer that most commonly occurs in infancy and childhood. Current treatment methods for high risk neuroblastomas, consisting of surgery, radiation, and multi-modal chemotherapy, have not been effective in significantly improve survival rate. There is an urgent need for efficacious treatments. We are creating a new therapeutic agent for treating neuroblastomas. Our novel approach is to use protein-lipid nanovesicles that can preferentially seek cancer and selectively destroy tumor cells without damaging normal cells. We are investigating the cancer-selective targeting and killing mechanism of the nanovesicles using human neuroblastoma cells and animal models. Success in the proposed research studies will enable us to test the product in humans.

描述（由申请人提供）：我们的研究目标是开发一种新的，强大的治疗药物，用于寻找和破坏人类神经母细胞瘤。神经母细胞瘤是婴幼儿最常见的癌症。高风险神经母细胞瘤即使采用最积极的联合或多模式治疗也难以治愈。我们的初步研究表明，使用新的蛋白纳米囊泡靶向治疗神经母细胞瘤的可行性，且副作用最小。纳米囊泡由小的促聚变溶酶体蛋白皂苷C （SapC）和磷脂二油基磷脂酰丝氨酸（DOPS）组成。这种稳定形成的SapC-DOPS纳米囊泡对暴露在癌细胞和新生血管表面的磷脂酰丝氨酸（PS）具有优先亲和力。我们已经证明纳米囊泡在神经母细胞瘤肿瘤中具有高蓄积倾向，并诱导癌细胞凋亡。反复注射SapC-DOPS后，我们观察到SapC-DOPS通过酸性鞘磷脂酶衍生的神经酰胺介导的信号通路诱导凋亡癌细胞死亡，对肿瘤生长有明显的抑制作用。本研究的目的是确定SapC-DOPS纳米囊泡在神经母细胞瘤治疗中的应用。具体目的是：(1)确定人神经母细胞瘤细胞表面PS水平与SapC-DOPS纳米囊泡靶向和细胞毒性反应的关系；(2)开发特异性促进人神经母细胞瘤表面PS暴露的SapC-DOPS增敏剂；(3)阐明SapC-DOPS通过神经酰胺介导的线粒体中心信号通路诱导人神经母细胞瘤凋亡细胞死亡的分子机制。这项研究具有创新性，因为SapC-DOPS纳米囊泡为寻找和治疗神经母细胞瘤以及其他细胞表面暴露于PS的肿瘤提供了一种独特的方法。该研究的成功完成将对癌症临床研究领域产生重大影响，因为它为癌症治疗提供了一种安全而广泛的临床方法。