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。骨转移代表了一种特别差的情况预后。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，骨转移会导致严重疼痛、活动能力丧失和增加骨折等合并症。根本机制尚不完全了解，治疗方法也不完全清楚选择大多局限于诊断后尝试减少疼痛和骨折风险。因此，一个增强对潜在病因的了解和/或预防或减少骨质疏松的新策略转移将代表着一个急需新选择的领域的重大进步。一大障碍缺乏临床前研究是理解骨转移以及开发骨转移治疗方案的关键。模型忠实地概括了这个多阶段的复杂过程。我们已经鉴定出一种新的基因工程小鼠模型用于研究肺癌进展和骨转移。此外，我们相信我们已经发现了癌细胞生长和存活的一个新的危险因素，以及一个强烈影响癌细胞生长和存活的因素。影响无机磷酸盐（Pi）的骨微环境。本文提出的研究将探讨结合最先进的小鼠转移模型、先进的骨转移的潜在机制显微镜和微型计算机断层扫描在一种新颖且高度转化的营养学背景下预防方法。具体来说，我们将测试以下假设： KrasG12D； Lkb1fl/fl；蔷薇荧光素酶小鼠代表了自发性肺癌骨转移的模型。此外，该模型可以用于研究治疗和预防方式，并提供对该复合体的机制洞察疾病。为了检验这一假设，我们将：1）使用以下方法治疗自发性骨转移： KLLlenti 小鼠模型，2) 确定 Pi 运输的差异是否驱动寻骨表型。影响：当前提案的结果有可能通过以下方式提供有关该机制的新信息：可以操纵一种常见的营养元素来改变与癌症病因学相关的细胞行为，例如以及更好地了解促进肿瘤细胞建立的骨骼环境。