LKB1 tumor suppressor and human cancer

我们实验室和其他实验室最近的工作表明，LKB1(STKII)肿瘤抑制基因在各种人类癌症中经常失活(通过缺失或点突变)。虽然Lkb1失活通过增强侵袭和转移促进肿瘤进展，因此似乎是一个不利的预后特征，但在分子水平上对Lkb1缺乏促进肿瘤发生的机制知之甚少。我们目前对Lkb1的理解表明，Lkb1部分通过AMPK和mTOR途径发挥作用，但有强有力的证据表明，Lkb1也通过其他平行途径发挥作用，这些途径仍有待阐明。因此，我们利用Lkb1缺乏来开发新的靶向治疗的能力相当有限。这项建议代表了四名研究人员的共同努力，他们拥有互补的专业领域，并在Lkb1生物学、老鼠癌症模型和转化性癌症研究领域建立了富有成效的合作记录。我们将完善我们已经开发的胰腺癌、非小细胞肺癌、子宫癌和黑色素瘤的基于Lkb1的忠实小鼠遗传模型。这些小鼠模型将用于1)研究Lkb1调节肿瘤进展的机制；2)识别Lkb1缺陷癌症表达的生物标记物，并利用我们现有的上述肿瘤数据库，探索它们作为人类不良结果和治疗反应预测因子的有效性；以及3)开发和测试针对Lkb1缺陷癌症的新型治疗药物和策略。这些模型将采用最先进的条件和躯体失活策略，并将Lkb1缺乏与其他已建立的致癌驱动事件结合起来，这四个实验室对此进行了充分研究。这些努力将利用四个参与机构在分子生物学、小动物成像、比较病理学、药理学和实验治疗学方面的独特优势。这项研究将加强对Lkb1失活在各种肿瘤中的作用的理解，并将这一新的理解转化为新的预测生物标记物和治疗方法。

Recent work from our laboratories and others has shown that the LKB1 (STKII) tumor suppressor gene is frequently inactivated (through deletions or point mutations) in a wide variety of human cancers. Although Lkb1 inactivation facilitates tumor progression by enhanced invasion and metastasis and therefore appears to be an adverse prognostic feature, the mechanisms whereby Lkb1 deficiency promotes tumorigenesis are poorly understood at the molecular level. Our current understanding of Lkb1 suggests that it acts in part through the AMPK and mTOR pathway, but there is strong evidence that Lkb1 also acts through alternative parallel pathways that remain to be elucidated. Consequently, our ability to exploit Lkb1 deficiency to develop new targeted therapies is rather limited. This proposal represents a joint effort by four investigators with complementary areas of expertise and an established track record of productive collaborations in the areas of Lkb1 biology, mouse cancer models, and translational cancer research. We will refine faithful murine Lkb1-based genetic models we have already developed of pancreatic adenocarcinoma, non-small cell lung cancer, uterine cancer, and melanoma. These murine models will be used to 1) study the mechanisms whereby Lkb1 regulates tumor progression; 2) identify biomarkers expressed by Lkb1-deficient cancers and explore their utility as predictors of adverse outcomes and therapeutic responses in humans, taking advantage of our existing banks for the above tumors; and 3) develop and test novel therapeutic agents and strategies against Lkb1-deficient cancers. These models will employ state-of-the-art conditional and somatic inactivation strategies, and combine Lkb1 deficiency with other established oncogenic driver events well-studied in the four laboratories. These efforts will leverage the unique strengths of the four participating institutions in molecular biology, small animal imaging, comparative pathology, pharmacology, and experimental therapeutics. This research will lead to an enhanced understanding of the role of Lkb1 inactivation in a variety of neoplasms, and translate this new understanding into novel predictive biomarkers and therapeutic approaches.