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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：
10231044
负责人：
DAVID R ROWLEY
金额：
$ 48.89万
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 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10231044
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：报告抗类固醇激素治疗是治疗ER+乳腺癌和前列腺癌的标准护理和治疗方案。癌症的转移主要与骨骼有关。雌激素和雄激素也是正常骨骼的关键调节因子。无论是男性还是女性，其主要的成骨细胞--利基细胞的生长、动态平衡、维持和维持都是癌症。肿瘤转移导致小梁骨中最早的成骨/造血细胞分化为骨小梁，从而导致早期骨质疏松症。前列腺癌和ER+乳腺癌的定植过程可能也涉及类似的成骨细胞依赖的免疫机制。成骨细胞中的成骨祖细胞和成骨细胞在成骨的利基市场中主要受ERα和AR的调节。男性和女性。这些激素受体的缺陷往往会转化为严重的病理性骨骼疾病。因此，任何疾病都不会发生。针对前列腺癌和ER+乳腺癌的抗类固醇药物治疗也将不可避免地影响患者的健康。微环境，即最主要的成骨细胞和利基细胞。然而，对于它如何抗肿瘤仍然缺乏足够的理解。类固醇疗法可能会影响成骨细胞和利基细胞的生物学行为，以及这一过程如何影响癌症的进展和预后。进化归因于治疗药物的耐药性。张教授和罗利教授的实验室都开发出了一种新颖的3D技术。成骨和异型有机体细胞模型解决了人类乳腺癌和前列腺癌细胞之间的相互作用。分别与人和成骨细胞移植。此外，一种新颖的髂内动脉注射技术和小鼠颅骨移植。生命中的神经成像模型已经允许在小梁中与主要的成骨细胞和利基细胞进行直接的生物相互作用的最新研究。体内的骨修复。初步的研究数据表明，抗类固醇激素治疗可能不会导致新的成骨细胞的修复和表型改变。利基市场认为，它可能会促进癌症的进展和治疗上的耐药性。因此，它是我们的最新假说之一。类固醇激素治疗会影响更多的动态平衡-修复表型的成骨和利基类型，这是一种促进癌症的表型。为了解决这个问题，我们提出了两个具体的治疗目标。一个具体的治疗目标：1.解决骨、成骨和小生境癌症。通过使用一种新型的3D成骨有机化合物，在不同的类固醇药物和抗类固醇药物的作用条件下，相互作用。方法。这一目标将解决ERα、ERβ、和ARα在调节雌激素方面的相对重要性。雄激素、激素和抗类固醇激素的作用在探讨一种高度反应性和成骨的利基的发生机制，以及它是如何影响乳房和乳房的。前列腺癌和生物学，以及它是如何改变抗类固醇和治疗效果的。具体的目标是2。需要解决的问题。抗类固醇激素(雌激素和雄激素)和生物学的作用机制在促进成骨的利基环境中发挥作用，以及这种影响是如何影响的。克隆人乳腺癌和前列腺癌在体内的启动和进展过程。使用的是转基因小鼠。新型的肿瘤移植方法和尖端的活体显微技术，我们将继续研究这些技术。抗类固醇药物治疗对体内成骨细胞和利基细胞的影响，以及它如何导致内分泌耐药。总体而言，这项多PI生物提案的目标是确定其影响的成骨细胞、利基生物和生物学的共同作用机制。乳腺癌和前列腺癌在抗类固醇药物治疗过程中的转移性进展。这些途径可能会导致癌症的发生。代表了新的治疗方法的目标。