LKB1 tumor suppressor and human cancer

我们实验室和其他人的最新工作表明，LKB 1（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）。尽管Lkb 1失活通过增强侵袭和转移促进肿瘤进展，因此似乎是一种不良预后特征，但Lkb 1缺乏促进肿瘤发生的机制在分子水平上知之甚少。我们目前对Lkb 1的理解表明，它部分通过AMPK和mTOR途径起作用，但有强有力的证据表明，Lkb 1还通过其他平行途径起作用，这些途径仍有待阐明。因此，我们利用Lkb 1缺陷开发新靶向治疗的能力相当有限。该提案代表了四名研究人员的共同努力，他们具有互补的专业知识领域，并在Lkb 1生物学，小鼠癌症模型和转化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可靠的基于小鼠Lkb 1的遗传模型。这些小鼠模型将用于1）研究Lkb 1调节肿瘤进展的机制; 2）鉴定Lkb 1缺陷型癌症表达的生物标志物，并利用我们现有的上述肿瘤库，探索其作为人类不良结局和治疗反应预测因子的效用; 3）开发和测试针对Lkb 1缺陷型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体细胞失活策略，并将联合收割机Lkb 1缺陷与四个实验室充分研究的其他已建立的致癌驱动事件相结合。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。这项研究将导致对Lkb 1失活在各种肿瘤中的作用的进一步理解，并将这种新的理解转化为新的预测生物标志物和治疗方法。

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.