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.

我们继续关注胰岛素样生长因子 (IGF) 和肿瘤特异性易位在儿科肉瘤发病机制中的作用，特别是横纹肌肉瘤 (RMS)、尤文氏肉瘤/PNET（尤文氏肿瘤家族 EFT）和成骨肉瘤（操作系统）。我们最近发表了一项使用生长抑素类似物对骨肉瘤犬进行 GH-IGF-I 抑制的随机研究结果。我们假设降低 IGF-I 水平会导致标准化疗治疗的肿瘤细胞凋亡增加。然而，来自本研究中随机分配的 46 只狗的数据未能证明随机接受生长抑素类似物的狗的存活率增加或坏死/凋亡增加，尽管该队列中循环 IGF-I 减少了 50% 。因此，我们选择目前不进一步进行这一调查。 我们继续利用过度表达 IGF2 的 C2 小鼠成肌细胞来确定 IGF2 过度表达在肌肉背景中的具体后果。我们最近发表了我们的研究结果，即 IGF-II 诱导的细胞凋亡抵抗部分是通过 p70S6K 信号传导介导的。雷帕霉素可以逆转这一情况，我们目前正在横纹肌肉瘤和骨肉瘤小鼠模型中进行临床前研究，以确定雷帕霉素类似物 CCI-779 与标准细胞毒疗法相结合是否会提高生存率。我们打算测量 p70S6 激酶活性和 4E-BP1 的抑制作为该治疗的分子靶标。 我们正在继续研究 FKHR 在介导 IGF 相关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) 易位中发生改变，并且似乎是该途径中的重要信号。我们发现，与正常成肌细胞相比，FKHR 磷酸化似乎在这些肿瘤中受到独特的调节。 我们正在继续合作开发小鼠横纹肌肉瘤的遗传模型，并发现该模型可以预测这些肿瘤中 p16-CDK-4-cylcin D-Rb 通路的异常，并在人类肿瘤标本中证实了这种异常。这些数据最近已公布。 我们使用 cDNA 微阵列分析来鉴定已建立的自发性骨肉瘤小鼠原位模型中转移的遗传决定因素。 。发现的一个似乎与转移行为高度相关的基因是埃兹蛋白（ezrin），它是埃兹蛋白-根蛋白-莫斯蛋白（ezrin-radixin-moesin）家族的成员，具有质膜-细胞骨架连接子的功能。我们在动物模型中证明，埃兹蛋白的阻断会导致转移潜力显着降低。我们现在正试图确定人骨肉瘤中的埃兹蛋白表达是否也与转移潜力相关。