Combination therapy to inhibit neuroblastoma growth

抑制神经母细胞瘤生长的联合疗法

基本信息

批准号：
8132231
负责人：
JASTI S. RAO
金额：
$ 35.55万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8132231
关键词：
1 year old Accounting Adhesions Adolescent Adverse effects Animals Apoptosis Apoptotic Basic Science Behavior Benign Biologic Characteristic Biological Biological Factors Biological Process Blood Vessels Brain Cell Communication Cell Death Cell Line Cell Proliferation Cells Child Childhood Solid Neoplasm Clinical Clinical Trials Combined Modality Therapy Complementary DNA Cysteine Data Deposition Development Diploidy Disease DsRed Exhibits Extracellular Matrix Extracellular Protein Family Genetic Glioma Glycoproteins Goals Growth Heterogeneity Histologic Histology Image Immune response Implant In Vitro Invaded Length Long-Term Survivors MYCN gene Malignant - descriptor Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of ovary Malignant neoplasm of pancreas Mediating Metastatic Neoplasm to the Bone Modality Molecular Neoplasm Metastasis Neural Crest Cell Neuroblastoma Normal Cell Osteonectin Pathway interactions Patients Plasmids Proteins Radiation Radiation therapy Radiosurgery Refractory Relative (related person)Residual state Resistance Role Signal Transduction Staging Stromal Cells Sympathetic Nervous System Therapeutic Therapeutic Effect Treatment Protocols Tumor Angiogenesis Xenograft procedure angiogenesis base bone bone cell cancer cell cancer therapy cell growth cell motility high risk in vivo in vivo Model irradiation migration neoplastic cell neuroblastoma cell novel therapeutic intervention outcome forecast overexpression pancreatic cancer cells public health relevance radiation effect research study treatment effect tumor tumor growth tumor progression tumor xenograft tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Combination therapy to inhibit neuroblastoma growth Neuroblastoma is the most common pediatric solid tumor that arises from the sympathetic nervous system. Neuroblastoma tumors exhibit clinical and biological heterogeneity associated with certain genetic aberrations. Advanced state IV neuroblastoma is refractory to all conventional therapeutic modalities and is associated with a dismal prognosis. The cure rate of children with high-risk stage IV neuroblastoma remains at <20%, providing a compelling reasons to better understand the molecular mechanisms that can be targeted to treat this disease. Radiotherapy remains a major component of treatment modalities for controlling both malignant and benign tumors. In patients with residual or recurring benign tumors, there is increasing concern about radiation-related side effects that may occur even with highly accurate therapies such as radiosurgery. Despite some therapeutic effect, recent evidence has shown that irradiation may promote malignant behaviors of cancer cells both in vitro and in vivo by activating several pathways involved in tumor invasiveness, angiogenesis and metastasis. Another consequence of radiation is that tumors often become resistant to radiation. An increasing number of long-term survivors with late sequelae highlight the need for novel therapeutic approaches. Tumor growth and angiogenesis occur in the context of the extracellular matrix (ECM), the levels and deposition of which are controlled in part by secreted protein, acidic and rich in cysteine (SPARC), a matricellular glycoprotein. SPARC modulates cellular interaction with the ECM and has diverse roles in normal cells, many of which have been shown to contribute to tumorigenesis. The relative levels of SPARC expression in normal brain decreased with malignant transformation, as indicated by our group and others. Our preliminary studies demonstrated that over-expression of SPARC inhibited neuroblastoma cell proliferation, migration, angiogenesis and tumor growth in vivo compared to parental and EV- transfected cells. We also provided that SPARC may act as a sensitizer to radiotherapy. We hypothesize that modulation of SPARC combined with radiation and the anticancer effects of these treatments will be determined. The specific aims of this proposal are as follows: In Specific Aim 1, we will evaluate the effects of the p-SPARC and radiation, alone and in combination, on neuroblastoma cell migration and invasion in both in vitro and in vivo models. In Specific Aim 2, we will determine the effects of p-SPARC and radiation, alone and in combination, on neuroblastoma cell growth, proliferation, adhesion and apoptosis. In Specific Aim 3, we will determine the effect of p-SPARC and radiation, alone and in combination, on neuroblastoma cell interactions with the microenvironment of both in vitro and in vivo and the effect of p-SPARC and radiation, alone and in combination, on angiogenesis both in vitro and in vivo. This combination of in vitro basic science experiments and translational in vivo studies will provide the basis for development of a new therapeutic approach to neuroblastoma tumors which are resistant to conventional radiotherapy. PUBLIC HEALTH RELEVANCE: Neuroblastoma accounts for 10% of all juvenile cancers. Advanced stage neuroblastoma in children over one-year old is largely incurable using current treatment protocols. However, an increasing number of long-term survivals with secondary effects from this treatment highlighted the need for development of novel therapeutic approaches. This proposal represents a comprehensive analysis to determine the therapeutic benefit of SPARC expression in combination with radiation for the treatment of neuroblastoma.

描述（由申请人提供）：抑制神经母细胞瘤生长的联合疗法神经母细胞瘤是最常见的儿科实体瘤，起源于交感神经系统。神经母细胞瘤表现出与某些遗传畸变相关的临床和生物学异质性。晚期 IV 期神经母细胞瘤对所有常规治疗方式均无效，并且预后不佳。高危 IV 期神经母细胞瘤儿童的治愈率保持在 <20%，这为更好地了解可靶向治疗该疾病的分子机制提供了令人信服的理由。放射治疗仍然是控制恶性和良性肿瘤的治疗方式的主要组成部分。对于残留或复发良性肿瘤的患者，人们越来越担心即使采用放射外科等高精度治疗也可能发生与放射相关的副作用。尽管有一定的治疗效果，但最近的证据表明，辐射可能通过激活涉及肿瘤侵袭、血管生成和转移的多种途径，在体外和体内促进癌细胞的恶性行为。辐射的另一个后果是肿瘤常常对辐射产生抵抗力。越来越多的长期幸存者出现晚期后遗症，凸显了对新治疗方法的需求。肿瘤生长和血管生成发生在细胞外基质 (ECM) 的背景下，其水平和沉积部分受到富含半胱氨酸的酸性分泌蛋白 (SPARC)（一种基质细胞糖蛋白）的控制。 SPARC 调节细胞与 ECM 的相互作用，并在正常细胞中发挥多种作用，其中许多已被证明有助于肿瘤发生。正如我们小组和其他人所指出的，正常大脑中 SPARC 表达的相对水平随着恶性转化而降低。我们的初步研究表明，与亲代细胞和 EV 转染细胞相比，SPARC 的过表达抑制了体内神经母细胞瘤细胞的增殖、迁移、血管生成和肿瘤生长。我们还提出 SPARC 可能充当放射治疗的增敏剂。我们假设 SPARC 的调节与放射结合以及这些治疗的抗癌作用将被确定。该提案的具体目标如下：在具体目标 1 中，我们将在体外和体内模型中评估 p-SPARC 和辐射单独或联合使用对神经母细胞瘤细胞迁移和侵袭的影响。在具体目标 2 中，我们将确定 p-SPARC 和辐射单独或联合使用对神经母细胞瘤细胞生长、增殖、粘附和凋亡的影响。在具体目标 3 中，我们将确定 p-SPARC 和辐射单独和组合对神经母细胞瘤细胞与体外和体内微环境相互作用的影响，以及 p-SPARC 和辐射单独和组合的影响，关于体外和体内血管生成。这种体外基础科学实验和体内转化研究的结合将为开发一种新的治疗方法奠定基础，以治疗对传统放射治疗有抵抗力的神经母细胞瘤肿瘤。公共卫生相关性：神经母细胞瘤占所有青少年癌症的 10%。使用目前的治疗方案，一岁以上儿童的晚期神经母细胞瘤基本上无法治愈。然而，越来越多的长期存活者因这种治疗而产生副作用，这凸显了开发新治疗方法的必要性。该提案代表了一项综合分析，以确定 SPARC 表达与放射治疗联合治疗神经母细胞瘤的治疗效果。