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.

项目摘要（参见说明）： 子宫内膜癌（EMC）是女性生殖道最常见的恶性肿瘤，也是美国女性中继乳腺癌、肺癌和结肠癌之后第四大常见癌症。每年，仅美国就有约 40,000 名女性成为 EMC 的受害者，其中约 20% 死于该病。 EMC 的病因尚不完全清楚。几种常见的基因改变与人类有关 电磁兼容。 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 的缺失会导致 PISK 活性和 Akt 激活增强。激活的 Akt (pAkt) 水平升高会刺激环氧合酶 2 (Cox2) 和哺乳动物靶标雷帕霉素复合物 1 (mTORCI) 活性，这些活性与 EMC 相关。 Cox2 在许多实体瘤中过度表达，Cox2 衍生的前列腺素 (PG)，尤其是通过其受体 EP2/EP4 产生的 PGE2，对致癌作用有显着促进作用。 我们最近发现，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 小鼠模型中显着上调。 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着重要作用，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制定提高治疗指数的新策略。低剂量这些抑制剂的合理组合有可能提高疗效并降低毒性。我们的中心主题是测试以下假设：Pten 缺陷会激活 PI3K-pAkt-Cox2 和 PI3K-pAkt-mT0RC1 通路，这些通路共同启动和促进 EMC，并且针对 Cox2 和 mTORC1 将在对抗 EMC 方面发挥协同作用，并且比单独使用任一通路更有效。我们将使用我们新建立的 EMC 小鼠模型来测试这一假设。