Novel strategies to target lung cancer metastasis to bone

项目概要/摘要： 转移是癌症死亡的主要原因。骨转移是一种特别差的 预后不幸的是，骨骼是癌症最常见的转移部位之一， 乳腺前列腺和肺此外，转移到骨导致显著的疼痛、移动性丧失和增加的疼痛。 骨折和其他合并症。其潜在机制尚未完全了解， 选择大多局限于试图减少诊断后的疼痛和骨折风险。所以一间 增强对潜在病因学的理解和/或预防或减少骨质疏松的新策略 转移将代表着一个迫切需要新选择的领域的重大进展。一个主要障碍 了解，以及开发骨转移的治疗选择是缺乏临床前 模型忠实地概括了这个多阶段的复杂过程。我们从基因上鉴定出一种新的 研究肺癌进展和骨转移的工程小鼠模型。我们还 我相信我们已经确定了一个新的癌细胞生长和存活的风险因素，以及一个强烈影响癌细胞生长和存活的因素。 无机磷（Pi）影响骨微环境。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， 显微镜和微型计算机断层扫描的背景下，一种新的和高度翻译的营养为基础的 预防方法。具体而言，我们将检验以下假设：KrasG 12 D; Lkb 1fl/fl; Rosa-荧光素酶 小鼠代表自发性肺癌转移到骨的模型。此外，该模型可以 用于研究治疗和预防模式，并提供对这种复杂的机制的见解， 疾病为了验证这一假设，我们将：1）使用免疫组织化学方法治疗性靶向自发转移至骨。 KLLlenti小鼠模型，和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提供有关机制的新信息， 其中一种常见的营养元素可能被操纵以改变与癌症病因学相关的细胞行为， 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.