Novel strategies to target lung cancer metastasis to bone

针对肺癌骨转移的新策略

基本信息

批准号：
10646351
负责人：
GEORGE R. BECK
金额：
$ 17.93万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-15 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10646351
关键词：
A549 Adenocarcinoma Adenocarcinoma In Situ Alleles Antibodies Behavior Breast Calcium Cancer Cell Growth Cancer Control Cancer Etiology Cancer Patient Cause of Death Cell Line Cell Survival Cells Clinical Complex Consumption Data Diagnosis Diet Dietary Intervention Disease Disseminated Malignant Neoplasm Elements Environment Etiology Event Failure Femoral Fractures Fracture Frequencies Genetically Engineered Mouse Growth Homing Hyperplasia Image Immune system Incidence Intake KRASG12D Knowledge Link LoxP-flanked allele Luciferases Lung Lung Adenocarcinoma Malignant Neoplasms Malignant neoplasm of lung Metastatic Neoplasm to the Bone Methodology Microscopy Minerals Modality Modeling Monitor Mus Neoplasm Metastasis Nutritional Osteoporosis Pain Pharmaceutical Preparations Phenotype Phosphotransferases Physiological Pre-Clinical Model Prevalence Prevention Prevention approach Process Prognosis Prostate Recovery Regulation Resolution Risk Factors Serum Site Skeleton Soil TNFSF11 gene Testing Therapeutic Therapeutic Studies Transgenic Mice Tropism Tumor Promotion Tumor Suppressor Proteins Xenograft Model bisphosphonate bone bone imaging bone loss bone metabolism bone turnover cancer cell cancer diagnosis cancer prevention cell behavior cellular imaging comorbidity draining lymph node drug repurposing fracture risk human migration imaging modality in vivo innovation inorganic phosphate insight lanthanum carbonate lifestyle factors metastatic process microCT mouse model neoplastic cell novel novel anticancer drug novel strategies novel therapeutic intervention nutrition osteopontin pain reduction pharmacologic pre-clinical prevent release factor sensor side effect skeletal therapeutic target three dimensional cell culture tumor tumor progression

项目摘要

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.

项目摘要/摘要：转移是癌症死亡的主要原因。转移到骨头代表一个特别差的预后。不幸的是，骨骼是癌症的最常见转移部位之一乳房，前列腺和肺。此外，转移到骨骼会导致明显的疼痛，流动性丧失和增加裂缝等合并症。基本机制未完全理解和治疗诊断后的选择大多仅限于尝试减少疼痛和骨折风险。因此，一个增强对潜在病因和/或预防或减少骨骼的新型策略的理解转移将代表着需要新选择的巨大进步。一个主要障碍理解，以及为骨转移开发治疗选择是临床前的缺乏忠实地概括这个多阶段复杂过程的模型。我们已经从遗传上确定了一个新颖工程小鼠模型，研究肺癌进展并转移到骨骼的模型。此外，我们相信我们已经确定了癌细胞生长和生存的新风险因素，以及强烈的因素影响无机磷酸盐（PI）的骨微环境。本文提出的研究将在骨转移的基本机制结合了最先进的小鼠转移模型，高级在新颖且高度转化的营养的背景下，显微镜和微型层析成像预防方法。具体而言，我们将检验以下假设：Krasg12d； lkb1fl/fl;罗莎 - 卢西酶小鼠代表自发性肺癌转移对骨的模型。此外，这个模型可以是用于研究治疗和预防方式，并提供对这一复合物的机械洞察力疾病。为了检验该假设，我们将：1）使用治疗方法将自发转移靶向骨 Klllenti小鼠模型，以及2）确定PI转运的差异是否驱动了寻求骨骼的表型。影响：当前提案的结果有可能提供有关机制的新信息可能会操纵哪种常见的营养元素，以改变与癌症病因相关的细胞行为以及对促进肿瘤细胞建立的骨骼环境的更好理解。