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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：
8250430
负责人：
CHARLES KELLER
金额：
$ 30.94万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-22 至 2014-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8250430
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 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 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（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。儿童肌癌肺泡横纹肌肉瘤是一个典型的例子。了解疾病特异性进展机制的差距是晚期肺泡横纹肌肉瘤患者预后不佳的原因。我们在一项全国性临床试验中对横纹肌肉瘤患者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中介。在我们的研究中，PDGFR-A被发现是Pax3:Fkhr的转录靶点，Pax3:Fkhr是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性PDGFR-A信号通路在肺泡横纹肌肉瘤的进展和转移中起重要作用。为了验证这一假设，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性突变和转移进展。该模型中的肿瘤对受体酪氨酸激酶抑制剂伊马替尼有显著反应，伊马替尼可显著抑制PDGFR-A信号传导。我们的第一个目标是通过体外功能测试来描绘横纹肌肉瘤中的PDGFR-A信号通路。在这些实验中，将检测小鼠和人肺泡横纹肌肉瘤细胞培养在PDGFR-A抑制剂或siRNA存在或不存在时Akt、MAPK和PKC信号通路的变化。PDGFR-A抑制条件下的功能转移能力将在卵中进行检测。我们的第二个目标是确定PDGFR-A阻断对横纹肌肉瘤体内的病理生理影响。为了实现这一目标，我们将在肺泡横纹肌肉瘤小鼠模型中使用PDGFR-A的条件等位基因来消除PDGFR-A信号，我们将测量PDGFR-A信号和不PDGFR-A信号的发病、频率和进展的差异。本研究为儿童肺泡横纹肌肉瘤和其他肿瘤的分子治疗提供了系统、合理的遗传方法。

项目成果

期刊论文数量（21）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A new approach for prediction of tumor sensitivity to targeted drugs based on functional data.

一种基于功能数据预测靶向药物敏感性的新方法。

DOI：
10.1186/1471-2105-14-239
发表时间：
2013-07-29
期刊：
BMC bioinformatics
影响因子：
3
作者：
Berlow N;Davis LE;Cantor EL;Séguin B;Keller C;Pal R
通讯作者：
Pal R

18F-FDG microPET imaging detects early transient response to an IGF1R inhibitor in genetically engineered rhabdomyosarcoma models.

18F-FDG microPET 成像可检测基因工程横纹肌肉瘤模型中对 IGF1R 抑制剂的早期瞬时反应。

DOI：
10.1002/pbc.24075
发表时间：
2012
期刊：
Pediatric blood & cancer
影响因子：
3.2
作者：
Soundararajan,Anuradha;Abraham,Jinu;Nelon,LauraD;Prajapati,SureshI;Zarzabal,LeeAnn;Michalek,JoelE;McHardy,StantonF;Hawkins,DouglasS;Malempati,Suman;Keller,Charles
通讯作者：
Keller,Charles

IL-4R drives dedifferentiation, mitogenesis, and metastasis in rhabdomyosarcoma.

DOI：
10.1158/1078-0432.ccr-10-3445
发表时间：
2011-05-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
0
作者：
Hosoyama T;Aslam MI;Abraham J;Prajapati SI;Nishijo K;Michalek JE;Zarzabal LA;Nelon LD;Guttridge DC;Rubin BP;Keller C
通讯作者：
Keller C

The long road to immunotherapy for childhood rhabdomyosarcoma.

儿童横纹肌肉瘤免疫治疗的漫长道路。

DOI：
10.1002/pbc.23136
发表时间：
2011
期刊：
Pediatric blood & cancer
影响因子：
3.2
作者：
Huang,Elaine;Rubin,BrianP;Keller,Charles
通讯作者：
Keller,Charles

PDGFR-A is a therapeutic target in alveolar rhabdomyosarcoma.

DOI：
10.1038/onc.2008.255
发表时间：
2008-11-20
期刊：
ONCOGENE
影响因子：
8
作者：
Taniguchi, E.;Nishijo, K.;McCleish, A. T.;Michalek, J. E.;Grayson, M. H.;Infante, A. J.;Abboud, H. E.;Legallo, R. D.;Qualman, S. J.;Rubin, B. P.;Keller, C.
通讯作者：
Keller, C.