Molecular Biology of Pediatric Tumors

小儿肿瘤的分子生物学

• 批准号: 6756772
• 负责人: LEE J. HELMAN
• 金额: --
• 依托单位: DIVISION OF CLINICAL SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6756772
• 关键词: Ewing's tumor; apoptosis; child (0-11); complementary DNA; data collection methodology /evaluation; dogs; fibroblasts; gene expression; human tissue; insulin receptor; insulinlike growth factor; laboratory mouse; ligands; microarray technology; molecular oncology; molecular pathology; neoplasm /cancer genetics; oncogenes; osteosarcoma; pediatric neoplasm /cancer; rhabdomyosarcoma; sarcoma; sirolimus; somatostatin

We have continued to focus on the role of insulin-like growth factors (IGF's) and tumor specific translocations in the pathogenesis of pediatric sarcomas, specifically rhabdomyosarcomas (RMS), Ewing's sarcomas/PNET (Ewing's family of tumors EFT), and osteogenic sarcomas (OS). We have recently published the results of a randomized study of GH-IGF-I inhibition using a somatostatin analog in dogs with osteosarcomas. We hypothesized that lowering IGF-I levels would lead to increased apoptosis in tumor cells treated with standard chemotherapy. However, data from the 46 dogs randomized on this study failed to demonstrate either an increase in survival, or an increase in necrosis/apoptosis in doges randomized to the somatostatin analogue in spite of demonstrating a 50% decrease in circulating IGF-I in that cohort. We have therefore elected to not pursue this line of investigation further at this time. We have continued to utilize C2 mouse myoblasts overexpressing IGF2 to determine specific consequences of IGF2 overexpression in a muscle background. We have recently published our findings that IGF-II induced resistance to apoptosis is mediated in part through p70S6K signaling. This is reversed by rapamycin, and we are currently conducting preclinical studies in a mouse model of rhabdomyosarcoma and osteosarcoma to determine whether an analog of rapamycin, CCI-779, will improve survival in combination with standard cytotoxic therapy. We intend to measure inhibition of p70S6kinase activity and 4E-BP1 as molecular targets of this treatment. We are continuing to study the role of FKHR in mediating IGF related anti-apoptotic events as well, since this gene is altered in the t(2;13) translocation in alveolar rhabdomyosarcoma and appears to be an important signal in this pathway. We have found that FKHR phosphorylation appears to be uniquely regulated in these tumors compared to normal myoblasts. We are continuing to collaborate on a genetic model of rhabdomyosarcoma in mice, and have found that this model predicts abnormalities in the p16-CDK-4-cylcin D-Rb pathway in these tumors and have confirmed such abnormalities in human tumor specimens. These data have recently been published. We have used cDNA microarray analysis to identify genetic determinants of metastasis in an established mouse orthotopic model of osteosarcoma with spontaneous metastases. . One gene identified that appears to be highly correlated with metastatic behavior is ezrin, a member of the ezrin-radixin-moesin family of proteinst that function as plasma membrane-cytoskeletal linkers. We have demonstrated in our animal model that blockade of ezrin leads to significantly decreased metastatic potential. We are now attempting to determine whether ezrin expression in human osteosarcoma may also correlate with metastatic potential.

我们继续关注类似胰岛素样生长因子（IGF）和肿瘤特异性易位在小儿肉瘤发病机理中的作用，特别是横纹肌肉瘤（RMS），Ewing的肉瘤/PNET（Ewing的肿瘤家族）和骨基肉瘤（OSEgenic Sarcomas（OS）。我们最近在患有骨肉瘤的狗中使用生长抑素类似物对GH-IGF-I抑制作用进行了随机研究的结果。我们假设降低IGF-I水平会导致用标准化疗治疗的肿瘤细胞凋亡增加。然而，这项研究随机进行的46只狗的数据未能证明生存率的增加，或者在该队列中循环IGF-I的循环IGF-I下降了50％，但在随机与生长抑素类似物的Dode的坏死/凋亡增加。因此，我们当选目前不进一步进行这一调查。 我们继续利用过表达IGF2的C2小鼠成肌细胞来确定在肌肉背景下IGF2过表达的特定后果。我们最近发表了我们的发现，即IGF-II诱导对凋亡的抗性是通过P70S6K信号的部分介导的。雷帕霉素将其逆转，目前我们正在横纹肌肉瘤和骨肉瘤的小鼠模型中进行临床前研究，以确定雷帕霉素的类似物CCI-779是否会改善与标准细胞毒性治疗结合的生存率。我们打算测量对P70S6-激酶活性和4E-BP1的抑制作用，作为该处理的分子靶标。 我们正在继续研究FKHR在介导IGF相关的抗凋亡事件中的作用，因为该基因在肺泡横纹肌肉瘤中的t（2; 13）易位中发生了改变，并且似乎是该途径中的重要信号。我们发现，与正常的成肌细胞相比，在这些肿瘤中，FKHR磷酸化似乎受到了独特的调节。 我们正在继续在小鼠中进行横纹肌肉瘤的遗传模型，并发现该模型预测这些肿瘤中P16-CDK-4-甲苯蛋白D-RB途径的异常，并证实了人类肿瘤标本中的这种异常。这些数据最近已发布。 我们已经使用了cDNA微阵列分析来鉴定骨肉瘤的骨质骨肉瘤的遗传决定因素，并自发转移。 。一个似乎与转移性行为高度相关的基因是Ezrin，Ezrin是Ezrin-radixin-Moesin of Protinst的成员，它们充当质膜 - 膜 - 环骨骨骼接头。我们在动物模型中证明了埃兹林的阻断导致转移性潜力显着降低。现在，我们正在尝试确定人骨肉瘤中的Ezrin表达是否也可能与转移潜力相关。