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: 10217282
• 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/10217282
• 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/antagonist; 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.

项目摘要/摘要：我已经完成了DVM，MS和PhD学位，外科住宅，现在 癌症，骨骼遗传学和生物学的博士后研究员。这个K01奖将有助于我 过渡到独立的位置，作为研究骨转移和原发性的终身轨道临床科学家 骨肿瘤。我的临床和研究培训将使人类和兽医临床医生和研究人员受益 并促进基本翻译和比较合作的发展。向上的进步 在此K01奖中，将通过许多机制实现独立性。我将获得知识和技能中心 该奖项的研究策略和我的职业目标。我将继续磨练以前学到的技术，但是 还接受了研究癌症生物学和遗传学的新方法的培训，肿瘤微环境，骨头 生物学和转移。我将获得基本非实验室研究技能的培训，例如授予技巧， 科学写作，负责任的研究和心理行为。转移性疾病是 约75％的转移患者发生了与乳腺癌相关的死亡和骨转移。在骨骼中，癌症 细胞的秘密因素1）刺激巨噬细胞（MP）分化为破骨细胞（OCS）和2）增加 整骨骨骼分辨率（裂解），导致骨质流失，疼痛和骨折。因此，防止 建立和治疗现有的骨转移是治疗的目标。菌落刺激因子1接收器 （CSF1R）调节转录因子（TF）PU.1的表达。我们的初步数据表明 CSF1R/PU.1轴是1）肿瘤相关MP（TAM）功能的关键调节剂和2）正常MP和OC 分化和功能。此外，几种对OC分化和功能必不可少的TF和基因具有 PU.1类似于“超级女人”的强大增强子结合模式。这些增强剂丰富了下注 与PU.1结合以调节关键破骨细胞生成TF的蛋白质。该奖项的目的是1）调查 CSF1R/PU.1轴的作用和2）确定超女性在乳腺癌骨中是否起作用 转移。我们的假设是CSF1R/PU.1轴对骨转移至关重要，这发生在 超级女人的背景。我们最初将评估PU.1的MP特异性缺失对乳腺癌的影响 原发性肿瘤MPS和骨转移MPS中由PU.1调节的骨转移和确定的基因 和OCS（AIM 1）。然后，我们将评估BET抑制是否可以减少的发展和增长 已建立的骨转移，并确定其对特定靶向MP和OC的特异性是否会增加 提高其治疗效率（AIM 2）。最后，我们将评估组合疗法是否具有最有效的效率 AIM 2和针对CSF1R/PU的CSF1R抑制剂的BET抑制剂制备。1轴更有效 与单独的任何一种药物相比，反对骨转移的发展和生长（目标3和4a- b）。发现可能会对骨转移患者的治疗，生活质量和存活产生重大影响。