Mouse Models and Translational Studies of Endometrial Cancer

描述（由申请人提供）：子宫内膜癌（子宫内膜癌）是女性生殖道最常见的癌症，美国每年约有4万例新发病例。一些常见的基因改变驱动子宫内膜癌进展的初始步骤已被记录，如肿瘤抑制基因PTEN的失活突变。然而，子宫内膜癌中的PTEN突变和大多数其他有据可查的遗传病变代表了驱动良性增生形成的早期步骤，这些增生仍然局限于子宫。相比之下，人们对促进增生发展为真正的侵袭性、致命性癌症的分子步骤知之甚少，这些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。具体来说，我们已经证明，LKB 1肿瘤抑制因子的失活驱动了小鼠和人类高度侵袭性癌症的形成。LKB 1的功能尚未完全了解，但已知其通过其直接靶向AMPK抑制mTOR（细胞生长的主要调节因子）发挥作用。因此，LKB 1失活导致mTOR活性增加，这反过来又促进细胞增殖和癌症增加。我们的目标是：1）获得LKB 1丢失对子宫内膜细胞和侵袭性生长的生物学影响的更详细的视图; 2）进一步确定LKB 1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研究LKB 1与其他子宫内膜癌基因的协作，从而也开发更精细的子宫内膜癌遗传模型;和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途径特异性疗法。这些相互关联的目标将利用独特的试剂和方法，包括经过验证的子宫内膜Cre删除线，使基因靶向特异性子宫内膜上皮细胞。这些研究还将利用先前开发的人类子宫内膜肿瘤标本库。 这些研究将有助于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的预测性或免疫组化检测的预后创造重要机会，并可能有一天导致开发改进的靶向治疗方法来治疗或预防子宫内膜癌的形成和扩散。 子宫内膜癌（子宫内膜）是女性生殖道最常见的癌症。然而，对于良性癌前病变发展为完全恶性和致命的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。我们还将使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。这些研究将有助于深入了解子宫癌的生物学和遗传学基础，为开发基于DNA的预测性或免疫组化检测的预后创造重要机会，并可能有一天导致开发改进的靶向治疗方法来治疗或预防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.