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：
8616351
负责人：
Christopher Sumeet Babu Gondi
金额：
$ 34.48万
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 2016-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8616351
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.

描述（由申请人提供）：抑制神经母细胞瘤生长神经母细胞瘤的联合疗法是源自交感神经系统最常见的儿科实体瘤。神经母细胞瘤肿瘤表现出与某些遗传畸变相关的临床和生物异质性。晚期静脉注射神经母细胞瘤对所有常规的治疗方式难治性，并且与沮丧的预后有关。具有高风险期IV期神经母细胞瘤儿童的治愈率<20％，这提供了一种令人信服的理由，可以更好地了解可以针对治疗该疾病的分子机制。放疗仍然是控制恶性肿瘤和良性肿瘤的治疗方式的主要组成部分。在残留或经常性良性肿瘤的患者中，即使使用诸如放射外科手术之类的高度精确疗法，也可能会出现与辐射相关的副作用的关注。尽管有一些治疗作用，但最近的证据表明，通过激活参与肿瘤侵袭性，血管生成和转移的几种途径，可以在体外和体内促进癌细胞的恶性行为。辐射的另一个结果是，肿瘤通常对辐射具有抵抗力。越来越多的长期幸存者和后遗症晚期强调了对新型治疗方法的需求。肿瘤生长和血管生成发生在细胞外基质（ECM）的背景下，其水平和沉积部分由分泌的蛋白质，酸性且富含半胱氨酸（SPARC）（一种术语细胞糖蛋白）控制。 SPARC调节与ECM的细胞相互作用，并在正常细胞中具有不同的作用，其中许多细胞已证明有助于肿瘤发生。正常大脑中SPARC表达的相对水平随恶性转化而降低，如我们的小组和其他人所示。我们的初步研究表明，与父母和ev染的细胞相比，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。我们还规定，SPARC可以充当放射疗法的敏化剂。我们假设调节SPARC与辐射结合，并确定这些治疗方法的抗癌作用。该提案的具体目的如下：在特定的目标1中，我们将单独和组合在体外和体内模型中评估P-SPARC和辐射对神经母细胞瘤细胞迁移和侵袭的影响。在特定的目标2中，我们将单独和组合，对神经母细胞瘤细胞生长，增殖，粘附和凋亡的影响确定P-SPARC和辐射的影响。在特定的目标3中，我们将单独和组合p-SPARC和辐射的影响对神经母细胞瘤细胞与体外和体内的微环境的相互作用以及p-SPARC和辐射的影响，单独和辐射的影响，在体外和体内均可进行血管生成。体外基础科学实验和体内转化研究的这种组合将为开发一种新的治疗方法来开发一种对传统放疗的神经母细胞瘤肿瘤的基础。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Chronic radiation exposure of neuroblastoma cells reduces nMYC copy number.

DOI：
10.3892/ol.2017.6652
发表时间：
2017-09
期刊：
Oncology letters
影响因子：
2.9
作者：
Gnanamony M;Antony R;Fernández KS;Jaime L;Lin J;Joseph PA;Gondi CS
通讯作者：
Gondi CS

SPARC overexpression inhibits cell proliferation in neuroblastoma and is partly mediated by tumor suppressor protein PTEN and AKT.

DOI：
10.1371/journal.pone.0036093
发表时间：
2012
期刊：
PloS one
影响因子：
3.7
作者：
Bhoopathi P;Gorantla B;Sailaja GS;Gondi CS;Gujrati M;Klopfenstein JD;Rao JS
通讯作者：
Rao JS

The secreted protein acidic and rich in cysteine (SPARC) induces endoplasmic reticulum stress leading to autophagy-mediated apoptosis in neuroblastoma.

DOI：
10.3892/ijo.2012.1678
发表时间：
2013-01
期刊：
International journal of oncology
影响因子：
5.2
作者：
Sailaja GS;Bhoopathi P;Gorantla B;Chetty C;Gogineni VR;Velpula KK;Gondi CS;Rao JS
通讯作者：
Rao JS

Notch signaling regulates tumor-induced angiogenesis in SPARC-overexpressed neuroblastoma.

DOI：
10.1007/s10456-012-9301-1
发表时间：
2013-01
期刊：
ANGIOGENESIS
影响因子：
9.8
作者：
Gorantla, Bharathi;Bhoopathi, Praveen;Chetty, Chandramu;Gogineni, Venkateswara Rao;Sailaja, G. S.;Gondi, Christopher S.;Rao, Jasti S.
通讯作者：
Rao, Jasti S.

SPARC overexpression suppresses radiation-induced HSP27 and induces the collapse of mitochondrial Δψ in neuroblastoma cells.

DOI：
10.3892/ol.2017.6075
发表时间：
2017-06
期刊：
Oncology letters
影响因子：
2.9
作者：
Tanpure S;Boyineini J;Gnanamony M;Antony R;Fernández KS;Libes J;Lin J;Pinson D;Joseph PA;Gondi CS
通讯作者：
Gondi CS