Mouse Models and Translational Studies of Endometrial Cancer

描述(申请人提供)：子宫内膜癌(子宫内膜癌)是最常见的女性生殖道癌症，美国每年约有4万新病例。一些常见的推动子宫内膜癌进展的初始步骤的基因改变已经被记录在案，例如肿瘤抑制基因PTEN的失活突变。然而，PTEN突变和大多数其他有充分证据的子宫内膜癌基因损害是推动良性增生性疾病形成的早期步骤，这些增生性疾病仍然局限于子宫。相比之下，人们对促进增生性疾病发展为真正侵袭性、致命性癌症的分子步骤知之甚少，这种癌症可以扩散到全身。在这里，我们建议建立在我们实验室进行的先前研究的基础上。具体地说，我们已经证明了LKB1肿瘤抑制基因的失活推动了小鼠和人类高侵袭性癌症的形成。LKB1的功能尚不完全清楚，但已知它通过其直接靶标AMPK抑制细胞生长的主要调节因子mTOR。因此，LKB1失活会导致mTOR活性增加，进而促进细胞增殖和癌症。我们的目标是1)更详细地了解LKB1缺失对子宫内膜细胞和侵袭性生长的生物学影响；2)进一步确定LKB1在子宫内膜癌中失活的分子机制；3)通过使用体内遗传模型系统来研究LKB1与其他子宫内膜癌基因的合作，从而也开发更精细的子宫内膜癌遗传模型；以及4)探索使用这些遗传模型系统来验证mTOR抑制剂作为针对子宫内膜癌的通路特异性治疗的作用。这些相互关联的目标将利用独特的试剂和方法，包括验证的子宫内膜Cre缺失株，使基因靶向特定于子宫内膜上皮细胞。这些研究还将利用之前开发的人类子宫内膜肿瘤标本库。这些研究将深入了解子宫内膜癌的生物学和遗传学基础，为开发基于DNA或免疫组织化学的预后预测测试创造重要机会，并可能有朝一日导致改进的、有针对性的治疗方法的开发，以治疗或防止子宫内膜癌的形成和扩散。 公共卫生相关性：子宫内膜癌(子宫内层)是女性生殖道最常见的癌症。然而，人们对促进良性癌前病变进展为完全恶性和致命性子宫内膜癌的步骤知之甚少。在这个项目中，我们建议开发和利用新的遗传模型系统来发现和理解这些关键步骤。我们还将利用这些模型作为平台来测试和验证治疗子宫内膜癌的新疗法。这些研究将深入了解子宫癌的生物学和遗传学基础，为开发基于DNA或免疫组织化学的预后预测测试创造重要机会，并可能有朝一日导致改进的、有针对性的治疗方法的开发，以治疗或防止子宫癌的形成和扩散。

DESCRIPTION (provided by applicant): Endometrial cancer (cancer of the lining of the uterus) is the most common cancer of the female reproductive tract, with about forty thousand new cases in the United States each year. A number of common genetic alterations driving the initial steps of endometrial cancer progression have been documented, such as inactivating mutations of the tumor suppressor gene PTEN. However, PTEN mutations and most other well- documented genetic lesions in endometrial cancers represent early steps driving the formation of benign hyperplasias that remain confined to the uterus. In contrast, little is known about the molecular steps promoting the progression of hyperplasias to truly invasive, lethal cancers that can spread throughout the body. Here we propose to build upon a foundation of prior research carried out in our laboratory. Specifically, we have demonstrated that inactivation of the LKB1 tumor suppressor drives the formation of highly invasive cancers in both mice and humans. The functions of LKB1 are not entirely understood, but it is known to act via its direct target AMPK to inhibit mTOR, a master regulator of cell growth. LKB1 inactivation thus leads to increased mTOR activity, which in turn promotes increased cell proliferation and cancer. Our goals are to 1) gain a more detailed view of the biological impact of LKB1 loss upon endometrial cells and invasive growth; 2) further define the molecular mechanisms by which LKB1 is inactivated in endometrial cancer; 3) study the cooperation of LKB1 with other endometrial cancer genes through the use of an in vivo genetic model system, and thereby also develop more refined genetic models of endometrial cancer; and 4) explore the use of these genetic model systems to validate an mTOR inhibitor as a pathway-specific therapy against endometrial cancer. These interrelated goals will take advantage of unique reagents and approaches including a validated endometrial Cre deletor line that enable gene targeting specifically within endometrial epithelial cells. These studies will also take advantage of a previously developed bank of human endometrial tumor specimens. These studies will lead to insights into the biological and genetic basis of endometrial cancer, create significant opportunities to develop predictive DNA-based or immunohistochemical tests for prognosis, and may someday lead to the development of improved, targeted therapies to treat or prevent endometrial cancer formation and spread. PUBLIC HEALTH RELEVANCE: Cancer of the endometrium (the inner lining of the uterus) is the most common cancer of the female reproductive tract. However, relatively little is known about the steps that promote the progression of benign precancers to fully malignant and lethal endometrial cancers. In this project we propose to develop and utilize new genetic model systems to discover and understand these critical steps. We will also use these models as platforms to test and validate new therapies to treat endometrial cancer. These studies will lead to insights into the biological and genetic basis of uterine cancer, create significant opportunities to develop predictive DNA-based or immunohistochemical tests for prognosis, and may someday lead to the development of improved, targeted therapies to treat or prevent uterine cancer formation and spread.