Novel strategies to target lung cancer metastasis to bone

项目摘要/摘要： 转移是癌症死亡的主要原因。骨转移是一种特别糟糕的表现 预后。不幸的是，骨骼是癌症最常见的转移部位之一，例如 乳房、前列腺和肺。此外，骨转移会导致严重的疼痛、活动能力丧失和增加。 骨折，以及其他合并症。其潜在的发病机制尚不完全清楚和治疗。 选择大多局限于试图减少诊断后的疼痛和骨折风险。因此，一个 增强对潜在病因和/或预防或减少骨骼的新策略的理解 转移将代表着对一个迫切需要新选择的领域的重大进步。一大障碍 了解和开发骨转移的治疗方案是临床前缺乏的 这些模型忠实地概括了这一多阶段的复杂过程。我们已经从基因上鉴定出一种新的 研究肺癌进展和骨转移的工程化小鼠模型。此外，我们 相信我们已经确定了一种新的癌细胞生长和存活的危险因素，以及一种强烈 无机磷(PI)对骨微环境的影响。本文提出的研究将探讨 骨转移的潜在机制结合最先进的小鼠转移模型 一种新的、高度翻译的营养学背景下的显微镜和微型计算机断层扫描 预防方法。具体地说，我们将检验如下假设：KrasG12D；Lkb1fl/fl；ROSA-荧光素酶 小鼠是一种自发性肺癌骨转移的模型。此外，这种模式可以是 用于研究治疗和预防模式，并提供对这一复合体的机械洞察 疾病。为了验证这一假设，我们将：1)治疗靶向自发性骨转移，使用 KLLlenti小鼠模型，以及2)确定PI转运的差异是否驱动骨寻求表型。影响： 目前提案的结果有可能通过以下方式提供有关机制的新信息 一种常见的营养成分可能被操纵来改变与癌症病因相关的细胞行为，如 以及更好地了解促进肿瘤细胞建立的骨骼环境。

Project Summary/Abstract: Metastasis is the leading cause of death from cancer. Metastasis to bone represents a particularly poor prognosis. Unfortunately, the skeleton is one of the most common sites of metastasis for cancers such as breast, prostate and lung. Further, metastasis to bone results in significant pain, loss of mobility and increased fractures, among other comorbidities. The underlying mechanisms are incompletely understood and treatment options are mostly limited to attempting to reduce pain and fracture risk after diagnosis. Therefore, an enhanced understanding of the underlying etiology and/or a novel strategy to prevent or reduce bone metastasis would represent a significant advance to a field sorely in need of new options. One major obstacle to understanding, as well as developing therapeutic options for bone metastases is the paucity of pre-clinical models that faithfully recapitulate this multi-stage complex process. We have identified a novel genetically engineered mouse model in which to study lung cancer progression and metastasis to bone. Further, we believe we have identified a novel risk factor for cancer cell growth and survival as well as a factor that strongly influences the bone microenvironment in inorganic phosphate (Pi). Studies proposed herein will probe at the underlying mechanisms of bone metastasis combining a state-of-the-art mouse metastasis model, advanced microscopy and micro-computed tomography in the context of a novel and highly translational nutrition based prevention approach. Specifically, we will test the hypothesis that: The KrasG12D; Lkb1fl/fl; Rosa-luciferase mouse represents a model of spontaneous lung cancer metastasis to bone. Further, that this model can be used to study therapeutic and prevention modalities as well as provide mechanistic insight into this complex disease. To test this hypothesis we will: 1) therapeutically target spontaneous metastasis to bone using the KLLlenti mouse model, and 2) determine if differences in Pi transport drive a bone seeking phenotype. Impact: Results from the current proposal have the potential to provide new information about the mechanisms by which a common nutritional element might be manipulated to alter cell behavior related to cancer etiology as well as a better understanding of the skeletal environment which promotes tumor cell establishment.