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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：
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.

项目总结: