Therapeutic Targets in Alveolar Rhabdomyosarcoma

腺泡状横纹肌肉瘤的治疗靶点

基本信息

批准号：
7913742
负责人：
CHARLES KELLER
金额：
$ 7.86万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2010-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7913742
关键词：
1-Phosphatidylinositol 3-Kinase Ablation Activities of Daily Living Address Adult Alleles Alveolar Rhabdomyosarcoma Anchorage-Independent Growth Biological Biological Assay Breeding Cancer Patient Cause of Death Cell Culture Techniques Cell Proliferation Cells Child Childhood Childhood Alveolar Rhabdomyosarcoma Classification Clinic Clinical Clinical Trials Complex Data Diagnosis Disease Disease Progression Distant Drug Delivery Systems Drug resistance Enrollment Foundations Frequencies Future Gene Expression Generations Genetic Goals Human Imatinib In Vitro Knock-out Ligands Lymphatic MAP Kinase Gene Malignant Neoplasms Measures Mediating Mediator of activation protein Membrane Messenger RNA Modeling Molecular Mus Mutation Neoplasm Metastasis Oncogenes Outcome PDGFRB gene Pathogenesis Pathway interactions Patients Phenotype Phosphorylation Pilot Projects Platelet-Derived Growth Factor Platelet-Derived Growth Factor Receptor Play Primary Neoplasm Protein Isoforms Protein Tyrosine Kinase Protein p53 Proteins Refractory Research Rhabdomyosarcoma Role Signal Pathway Signal Transduction Site Skeletal Muscle Small Interfering RNA Solid Neoplasm Specificity Staging System TP53 gene Testing Therapeutic Therapeutic Effect Transcriptional Activation Translating Treatment Failure Tyrosine Kinase Inhibitor autocrine base fusion gene human disease improved in vitro testing in vivo inhibitor/antagonist insight lymph nodes malignant muscle neoplasm migration mouse model paracrine platelet-derived growth factor A platelet-derived growth factor C public health relevance receptor research study response therapeutic target tumor tumor growth tumor progression

项目摘要

DESCRIPTION (provided by applicant): Progression and metastasis of solid tumors is a principal cause of death for cancer patients. The childhood muscle cancer alveolar rhabdomyosarcoma is a classic example. A gap in understanding the disease-specific mechanisms of progression underlies the dismal outcome for patients with advanced alveolar rhabdomyosarcoma. Our initial studies of rhabdomyosarcoma gene expression amongst patients enrolled in a national clinical trial suggest that the platelet-derived growth factor receptor A (PDGFR-A) may be a mediator of disease progression and metastasis. In our studies PDGFR-A has been found to be a transcriptional target of Pax3:Fkhr, the translocation-mediated fusion gene found in the majority of alveolar rhabdomyosarcomas. We hypothesize that ligand-dependent or constitutive PDGFR-A signaling pathways play a prominent role in progression and metastasis of alveolar rhabdomyosarcoma. To test this hypothesis, we have generated conditional mouse tumor models that authentically recapitulate the primary mutations and the metastatic progression of alveolar rhabdomyosarcomas in humans. Tumors in this model have dramatic responses to the receptor tyrosine kinase inhibitor, Imatinib, which significantly inhibits PDGFR-A signaling. Our first aim is to delineate the PDGFR-A signaling pathway in rhabdomyosarcoma by functional testing in vitro. For these experiments, mouse and human alveolar rhabdomyosarcoma cell cultures will be examined for alterations of the Akt, MAPK, and PKC signaling pathways in the presence or absence of PDGFR-A inhibitors or siRNA. The functional ability to metastasize under PDGFR-A inhibitory conditions will be assayed in ovo. Our second aim is to determine the pathophysiological impact of PDGFR-A blockade for rhabdomyosarcoma in vivo. To achieve this aim, we will use a conditional allele of PDGFR-A to abrogate PDGFR-A signaling in our mouse model of alveolar rhabdomyosarcoma, and we will measure the differences in onset, frequency, and progression with and without PDGFR-A signaling. This study establishes proof-of-principal for a systematic, rational genetic approach to molecular therapeutics in childhood alveolar rhabdomyosarcomas and other tumors. PUBLIC HEALTH RELEVANCE: Progression and metastasis of solid tumors is a principal cause of death for cancer patients. The childhood muscle cancer alveolar rhabdomyosarcoma is a classic example. A gap in understanding the disease-specific mechanisms of progression underlies the dismal outcome for patients with advanced alveolar rhabdomyosarcoma. This study of platelet-derived growth factors in cancer progression establishes proof-of- principal for a systematic, rational genetic approach to molecular therapeutics in childhood alveolar rhabdomyosarcomas and other tumors.

描述（由申请人提供）：实体瘤的进展和转移是癌症患者死亡的主要原因。儿童肌肉癌肺泡横纹肌肉瘤是一个典型的例子。对疾病特异性进展机制的理解存在差距，这是晚期肺泡横纹肌肉瘤患者惨淡结局的根源。我们对参加国家临床试验的患者中横纹肌肉瘤基因表达的初步研究表明，血小板衍生生长因子受体 A (PDGFR-A) 可能是疾病进展和转移的介质。在我们的研究中，PDGFR-A 被发现是 Pax3:Fkhr 的转录靶标，Pax3:Fkhr 是在大多数肺泡横纹肌肉瘤中发现的易位介导的融合基因。我们假设配体依赖性或组成型 PDGFR-A 信号通路在肺泡横纹肌肉瘤的进展和转移中发挥着重要作用。为了检验这一假设，我们建立了条件小鼠肿瘤模型，真实地再现了人类肺泡横纹肌肉瘤的原发突变和转移进展。该模型中的肿瘤对受体酪氨酸激酶抑制剂伊马替尼有显着的反应，伊马替尼显着抑制 PDGFR-A 信号传导。我们的首要目标是通过体外功能测试来描述横纹肌肉瘤中的 PDGFR-A 信号通路。对于这些实验，将检查小鼠和人肺泡横纹肌肉瘤细胞培养物在存在或不存在 PDGFR-A 抑制剂或 siRNA 的情况下 Akt、MAPK 和 PKC 信号通路的变化。将在卵内测定在PDGFR-A抑制条件下转移的功能能力。我们的第二个目标是确定 PDGFR-A 阻断对体内横纹肌肉瘤的病理生理学影响。为了实现这一目标，我们将使用 PDGFR-A 的条件等位基因来消除肺泡横纹肌肉瘤小鼠模型中的 PDGFR-A 信号传导，并且我们将测量有或没有 PDGFR-A 信号传导的发病、频率和进展的差异。这项研究为儿童腺泡横纹肌肉瘤和其他肿瘤的分子治疗的系统、合理的遗传方法建立了原理证明。公共卫生相关性：实体瘤的进展和转移是癌症患者死亡的主要原因。儿童肌肉癌肺泡横纹肌肉瘤是一个典型的例子。对疾病特异性进展机制的理解存在差距，这是晚期肺泡横纹肌肉瘤患者惨淡结局的根源。这项关于血小板衍生生长因子在癌症进展中的研究为儿童肺泡横纹肌肉瘤和其他肿瘤的分子治疗的系统、合理的遗传方法建立了原理证明。