Macrophage and osteoclast specific targeting for the prevention and treatment of breast cancer bone metastasis

巨噬细胞和破骨细胞特异性靶向预防和治疗乳腺癌骨转移

• 批准号: 10457824
• 负责人: Blake Eason Hildreth
• 金额: $ 12.67万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-07 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10457824
• 关键词: 4T1; Antibodies; Award; Binding; Biology; Bioluminescence; Bone Resorption; Bone neoplasms; Brain; Breast Cancer Cell; Breast Cancer Treatment; Breast cancer metastasis; Cancer Biology; Cell Surface Receptors; Cells; Cessation of life; Clinical Research; Collaborations; Combined Modality Therapy; Communication; Cytolysis; Data; Development; Disease; Doctor of Philosophy; Encapsulated; Enhancers; Evaluation; FVB/N Mouse; Fracture; Genes; Genetic; Goals; Growth; Growth and Development function; Hematopoietic; Histology; Human; Image; Inbred BALB C Mice; Incidence; Injections; Knowledge; Laboratories; Liposomes; Liver; Lung; Macrophage Colony-Stimulating Factor Receptor; Malignant Bone Neoplasm; Malignant Neoplasms; Mentored Research Scientist Development Award; Mentors; Metastatic Neoplasm to the Bone; Methods; Modeling; Molecular Analysis; Mus; Myelogenous; Neoplasm Metastasis; Operative Surgical Procedures; Osteoclasts; Outcome; Pain; Patients; Pattern; Pharmacology; Play; Positioning Attribute; Postdoctoral Fellow; Preparation; Prevention; Primary Neoplasm; Protein Family; Proteins; Quality of life; Radiology Specialty; Receptor Inhibition; Receptor Signaling; Research; Research Personnel; Research Training; Residencies; Role; Scientist; Site; Specificity; TNFSF11 gene; Techniques; Testing; Therapeutic; Training; Transcriptional Regulation; Treatment Efficacy; Tumor Burden; Tumor-associated macrophages; Work; Writing; base; bisphosphonate; bone; bone loss; cancer cell; cancer genetics; career; comparative; efficacy validation; inhibitor; lymph nodes; macrophage; malignant breast neoplasm; mouse model; neoplastic; neoplastic cell; novel strategies; novel therapeutics; prevent; primary bone cancer; responsible research conduct; side effect; skills; standard of care; tenure track; transcription factor; transcriptome sequencing; tumor; tumor growth; tumor microenvironment

Project Summary/Abstract: I have completed DVM, MS, and PhD degrees, a surgical residency, and am now a Post-Doctoral Research Fellow in cancer and bone genetics and biology. This K01 award will facilitate my transition into an independent position as a tenure-track clinician-scientist studying bone metastasis and primary bone tumors. My clinical and research training will benefit both human and veterinary clinicians and researchers and promote the development of essential translational and comparative collaborations. Advancement towards independence will occur by many mechanisms during this K01 award. I will obtain knowledge and skills central to this award’s research strategy and my career goals. I will continue to hone previously learned techniques but also receive training in new methods to study cancer biology and genetics, the tumor microenvironment, bone biology, and metastasis. I will receive training in essential non-laboratory research skills such as grantsmanship, scientific writing, responsible conduct of research, and mentoring. Metastatic disease is the leading cause of breast cancer-related deaths and bone metastases occur in ~75% of patients with metastasis. In bone, cancer cells secrete factors that 1) stimulate macrophages (MPs) to differentiate into osteoclasts (OCs) and 2) increase osteoclastic bone resorption (lysis), leading to bone loss, pain, and fracture. Therefore, preventing the establishment of and treating existing bone metastasis is the goal of therapy. Colony stimulating factor 1 receptor (CSF1R) regulates the expression of the transcription factor (TF) PU.1. Our preliminary data demonstrate that the CSF1R/PU.1 axis is a key regulator of 1) tumor-associated MP (TAM) function and 2) normal MP and OC differentiation and function. In addition, several TFs and genes essential for OC differentiation and function have a strong enhancer binding pattern by PU.1 resembling “superenhancers”. These enhancers are enriched for BET proteins which bind to PU.1 to regulate key osteoclastogenic TFs. The objective of this award is to 1) investigate the role of the CSF1R/PU.1 axis and 2) determine if superenhancers play a role, in breast cancer bone metastasis. Our hypothesis is that the CSF1R/PU.1 axis is essential for bone metastasis and this occurs in the context of superenhancers. We will initially assess the effects of MP-specific deletion of PU.1 on breast cancer bone metastasis and determine genes regulated by PU.1 in both primary tumor MPs and bone metastasis MPs and OCs (Aim 1). We will then evaluate if BET inhibition can reduce the development of, and growth of established, bone metastasis and determine if increasing its specificity to specifically target MPs and OCs will increase its therapeutic efficacy (Aim 2). Lastly, we will evaluate if combination therapy with the most efficacious BET inhibitor preparation from Aim 2 and a CSF1R inhibitor targeting the CSF1R/PU.1 axis is more efficacious against the development and growth of bone metastasis when compared to either agent alone (Aims 3 and 4A- B). Findings could have a major impact on treatment, quality of life, and survival of bone metastasis patients.

项目概况/摘要：我已经完成了DVM， MS和PhD学位，现在是外科住院医师

项目成果

Modeling Primary Bone Tumors and Bone Metastasis with Solid Tumor Graft Implantation into Bone.

• DOI: 10.3791/61313
• 发表时间: 2020-09-09
• 期刊: Journal of visualized experiments : JoVE
• 作者: Hildreth BE 3rd;Palmer C;Allen MJ
• 通讯作者: Allen MJ

Effects of Dickkopf-1 (DKK-1) on Prostate Cancer Growth and Bone Metastasis.

• DOI: 10.3390/cells12232695
• 发表时间: 2023-11-24
• 期刊: CELLS
• 影响因子: 6
• 作者: Yuan, Shiyu;Hoggard, Nathan K.;Kantake, Noriko;Hildreth, Blake E.;Rosol, Thomas J.
• 通讯作者: Rosol, Thomas J.