PTEN-C0X2-mT0R SIGNALING IN ENDOMETRIAL CANCER

子宫内膜癌中的 PTEN-C0X2-mT0R 信号传导

• 批准号: 8248359
• 负责人: Sudhansu K Dey
• 金额: $ 23.78万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-12-01 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8248359
• 关键词: Address; Age; American; Animal Model; Attenuated; Biological Models; Carcinoma in Situ; Chemopreventive Agent; Colon Carcinoma; Complex; Coxibs; Development; Diagnosis; Dinoprostone; Disease; Dose; Endometrial Carcinoma; Etiology; Female; Frequencies; Genes; Genital system; Homologous Gene; Human; Hyperplasia; Immunosuppressive Agents; Incidence; Inflammation; Instruction; Investigation; Knowledge; Lipids; Malignant Neoplasms; Malignant neoplasm of lung; Mus; Mutate; Mutation; PTEN gene; Pathway interactions; Phosphoric Monoester Hydrolases; Play; Prevention; Progesterone Receptors; Prostaglandins; Research; Risk; Role; Signal Pathway; Signal Transduction; Sirolimus; Solid Neoplasm; Study models; Testing; Therapeutic Index; Toxic effect; Uterus; Virulence; Woman; cancer cell; cancer initiation; carcinogenesis; cardiovascular risk factor; celecoxib; combat; cyclooxygenase 2; human WFDC2 protein; improved; inhibitor/antagonist; mTOR protein; malignant breast neoplasm; mouse model; myometrium; overexpression; prostaglandin EP2 receptor; tool; treatment strategy; tumor growth; tumor initiation; tumor progression

PROJECT SUMMARY (See instructions): Endometrial cancer (EMC) is the most common malignancy of the female genital tract and the fourth most common cancer among American women following breast, lung and colon cancers. Each year, about 40,000 women in the US alone become victims of EMC and about 20% of them die from the disease. The etiology of EMC is not fully understood. Several common genetic alterations are associated with human EMC. The gene with the highest frequency of alteration in EMC is Phosphatase and tensin homolog (Pten). The loss of Pten results in enhanced PISK activity and Akt activation. Increased levels of activated Akt (pAkt) stimulate both cyclooxygenase-2 (Cox2) and mammalian targets of rapamycin complex 1 (mTORCI) activity which are associated with EMC. Cox2 is overexpressed in many solid tumors and Cox2-derived prostaglandins (PGs), especially PGE2 via its receptors EP2/EP4, significantly contribute to carcinogenesis. We have recenfiy shown that levels of pAKT are elevated in Pten-deleted mouse uteri carrying EMC. Our preliminary results also show that mTORCI activity is remarkably upregulated in mouse models of EMC. These observations suggest that Cox2-derived PGs and the mTORCI pathway play significant roles in the development and progression of EMC and inhibiting these pathways may attenuate the incidence and/or virulence of EMC. However, the fact that long-term use of Cox2 inhibitors is associated with increased cardiovascular risks underscores the need for further investigation to circumvent those risks. There is an urgent need to build upon the current knowledge to develop new strategies in which the therapeutic index is improved. Rational combinafions of low doses of these inhibitors offer the potential for improved efficacy with reduced toxicity. Our central theme is to test the hypotheses that Pten deficiency activates PI3K-pAkt-Cox2 and PI3K-pAkt-mT0RC1 pathways that together initiate and promote EMC and targeting both Cox2 and mTORC1 will be synergistic and more effective than either alone in combating EMC. We will test this hypothesis using our newly established mouse model of EMC.

项目总结（见说明）： 子宫内膜癌（EMC）是女性生殖道最常见的恶性肿瘤，也是美国女性中仅次于乳腺癌、肺癌和结肠癌的第四大常见癌症。每年，仅在美国就有大约40，000名女性成为EMC的受害者，其中约20%死于这种疾病。EMC的病因尚未完全了解。几种常见的遗传变异与人类 EMC。在EMC中改变频率最高的基因是磷酸酶和张力蛋白同源物（Pten）。 Pten的缺失导致PISK活性和Akt活化增强。激活的Akt（pAkt）水平的增加刺激与EMC相关的环氧化酶-2（Cox2）和雷帕霉素复合物1（mTORCI）活性的哺乳动物靶标。Cox2在许多实体瘤中过表达，并且Cox2衍生的前列腺素（PGs），特别是通过其受体EP2/EP4的PGE2，显著促进癌发生。 我们最近发现，在携带EMC的Pten缺失小鼠子宫中，pAKT水平升高。我们的初步结果还表明，mTORCI活性在EMC小鼠模型中显著上调。 这些观察结果表明，Cox2衍生的PG和mTORCI通路在EMC的发生和进展中发挥重要作用，抑制这些通路可能会减弱EMC的发病率和/或毒力。然而，长期使用Cox2抑制剂与心血管风险增加相关的事实强调了需要进一步研究以规避这些风险。有一个 迫切需要在现有知识的基础上开发新的策略，以提高治疗指数。这些抑制剂的低剂量的合理组合提供了改善疗效和降低毒性的潜力。我们的中心主题是测试Pten缺乏激活PI3K-pAkt-Cox2和PI3K-pAkt-mT0RC1通路的假设，这些通路共同启动和促进EMC，并且靶向Cox2和mT0RC1将是协同的，并且在对抗EMC方面比单独使用更有效。我们将使用我们新建立的EMC小鼠模型来验证这一假设。