Osteogenic Niche Biology in Progression and Endocrine Resistance of Bone Metastases

骨转移进展和内分泌抵抗中的成骨生态位生物学

基本信息

批准号：
10474332
负责人：
DAVID R ROWLEY
金额：
$ 47.91万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-05 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10474332
关键词：
3-Dimensional Address Affect Androgen Receptor Androgens Area Biological Models Biology Bone Growth Breast Breast Cancer Cell Calvaria Cancer Biology Cancer Cell Growth Cell Communication Cells Data Development Dissection Endocrine Endosteum Estradiol Estrogen Receptor alpha Estrogen Receptor beta Estrogen receptor positive Estrogens Evolution Female Fracture Gender Genetically Engineered Mouse Goals Gonadal Steroid Hormones Hematopoietic Homeostasis Human Individual Injections Laboratories Lead Maintenance Malignant Bone Neoplasm Malignant Neoplasms Malignant neoplasm of prostate Mediating Mediator of activation protein Metastatic Neoplasm to the Bone Metastatic breast cancer Modeling Molecular Mus Neoplasm Metastasis Neoplasm Transplantation Organoids Osteoblasts Osteogenesis Osteolytic Pathologic Pathway interactions Phenotype Play Prostate Publications Research Personnel Resistance Role Steroid therapy Steroidal Estrogen Steroids Techniques Testosterone Therapeutic Tissues Translating Treatment Efficacy Uncertainty Work aged bone bone loss bone mass bone strength breast cancer progression cancer cell high risk iliac artery improved in vivo in vivo Model intravital imaging intravital microscopy male malignant breast neoplasm new therapeutic target novel novel therapeutic intervention osteogenic osteoprogenitor cell prostate cancer cell prostate cancer metastasis prostate cancer progression receptor refractory cancer repaired response standard of care steroid hormone substantia spongiosa targeted treatment therapy resistant treatment response tumor microenvironment tumor progression wound healing

项目摘要

Project Summary: Anti-steroid therapy is standard of care therapy for both ER+ breast cancer and for prostate cancer. Both cancers metastasize predominantly to bone. Estrogens and androgens are also key mediators of normal bone growth, homeostasis, and maintenance of the osteogenic niche in both females and males. Both cancers metastasize to the osteogenic/hematopoietic niche in trabecular bone. Accordingly, the early stage bone colonization of prostate and ER+ breast cancer may involve similar osteogenic cell-dependent mechanisms. The osteoprogenitor and osteoblasts in the osteogenic niche are regulated primarily by ERα and AR actions in both genders. Deficiencies these receptors often translate into severe pathological bone conditions. Thus, any anti-steroid therapies targeting prostate and ER+ breast cancers will also inevitably affect the microenvironment, i.e., the osteogenic niche cells. However, there is a lack of understanding of how anti- steroid therapies affect the biology of osteogenic niche cells, and how this affects cancer progression and evolution to therapeutic resistance. The Zhang and Rowley laboratories have both developed novel 3D osteogenic heterotypical organoid models that addresses human breast and prostate cancer cells interaction with human osteogenic cells respectively. Moreover, novel intra-iliac artery injection and mouse calvaria intravital imaging models have permitted the study of direct interactions with the osteogenic niche in trabecular bone in vivo. Preliminary data suggests anti-steroid therapy may result in a repair phenotype in the osteogenic niche that may promote cancer progression and therapeutic resistance. Hence, it is our hypothesis that anti- steroid therapy affects the osteogenic niche to a more homeostasis-repair phenotype that is cancer-promoting. To address this, we propose two Specific Aims. Specific Aim 1. To address bone osteogenic niche - cancer interactions in differential steroid and anti-steroid action conditions using novel 3D osteogenic organoid approaches. This Aim will address the relative importance of ERα, ERβ, and AR in mediating estrogen, androgen, and anti-steroid actions in the genesis of a reactive osteogenic niche, how it affects breast and prostate cancer biology, and how it alters anti-steroid therapeutic efficacies. Specific Aim 2. To address mechanisms of anti-steroid (estrogen and androgen) biology in the osteogenic niche and how this affects colony initiation and progression of breast and prostate cancer in vivo. Using genetically engineered mouse models, novel tumor transplantation approaches and cutting-edge intravital microscopy, we will examine the impact of anti-steroid treatments on the osteogenic niche in vivo and how it leads to endocrine resistance. The overall goal of this multi-PI proposal is to identify common mechanisms of osteogenic niche biology that affects the evolution of breast and prostate metastatic progression during anti-steroid therapy. These pathways may represent targets for novel therapeutic approaches.

项目摘要：抗类固醇治疗是ER+乳腺癌和前列腺癌的护理疗法标准。两个都癌症主要转移到骨头。雌激素和雄激素也是正常骨的关键介体妇女和男性的成生众生殖位的生长，体内稳态和维持。两种癌症转移到小梁骨中的成骨/造血生态位。根据早期的骨头前列腺和ER+乳腺癌的定殖可能涉及类似的成骨细胞依赖机制。成骨小裂中的骨基因生成剂和成骨细胞由ERα和AR作用正规化。两个性别。缺乏这些受体通常转化为严重的病理骨条件。那，任何靶向前列腺和ER+乳腺癌的抗类动物疗法也将不可避免地影响微环境，即成骨细胞。但是，对反对的理解很少类固醇疗法会影响成骨细胞的生物学，这如何影响癌症的进展和抗治疗性的演变。张和罗利实验室都开发了小说3D 成骨的异型器官模型，以解决人类乳腺癌和前列腺癌细胞相互作用与人的成骨细胞相关。此外，新型的易丝脉动脉注射和小鼠瓦尔瓦里亚插入成像模型已允许研究与小梁中的成骨壁ni的直接相互作用骨体内。初步数据表明抗甾体疗法可能导致成骨的修复表型可能促进癌症和治疗性抗性的利基市场。因此，我们的假设是类固醇疗法影响成骨的生态位，对促进癌症的更稳态治疗表型。为了解决这个问题，我们提出了两个具体目标。特定目的1。解决骨骼成骨菌群癌使用新型的3D成骨类器官在差异类固醇和抗染色体作用条件下的相互作用方法。该目标将解决ERα，ERβ和AR在中介雌激素中的相对重要性，雄激素和抗类动物作用在反应性成骨的生态莱基的起源中，它如何影响乳房和前列腺癌的生物学及其如何改变抗类固醇治疗能量特定目的2。成骨生物学中的抗类动物（雌激素和雄激素）生物学的机制，这如何影响体内乳腺癌和前列腺癌的菌落开始和进展。使用一般设计的鼠标模型，新型的肿瘤移植方法和尖端的插入式显微镜，我们将检查抗类固醇治疗对体内成骨菌群的影响及其如何导致内分泌耐药性。这该多PI提案的总体目标是确定影响影响影响的成裂生物学的常见机制抗肌动物治疗期间乳腺和前列腺转移性进展的演变。这些途径可能代表新型治疗方法的靶标。