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

项目摘要/摘要：我已经完成了DVM、硕士和博士学位，外科住院医生，现在是 癌症、骨遗传学和生物学的博士后研究员。这一K01奖项将促进我的 转变为研究骨转移和原发肿瘤的终身制临床医生和科学家的独立职位 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 并促进必要的翻译和比较合作的发展。迈向 在这次K01颁奖期间，许多机制将实现独立。我将获得集中的知识和技能 这个奖项的研究策略和我的职业目标。我会继续磨练以前学到的技巧，但 还接受了研究癌症生物学和遗传学、肿瘤微环境、骨骼等新方法的培训 生物学和转移。我将接受基本的非实验室研究技能的培训，如资助人精神， 科学写作、负责任的研究和指导。转移性疾病是导致 乳腺癌相关死亡和骨转移发生在大约75%的转移患者中。在骨骼方面，癌症 细胞分泌的因子1)刺激巨噬细胞(MPS)分化为破骨细胞(OCs)，2)增加 破骨细胞性骨吸收(溶解)，导致骨丢失、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。集落刺激因子1受体 (CSF1R)调节转录因子(Tf)PU.1的表达。我们的初步数据表明 Csf1R/PU1轴是1)肿瘤相关MP()功能和2)正常MP和OC的关键调节因子 分化和功能。此外，一些对OC分化和功能至关重要的转录因子和基因 由PU1形成的类似“超级增强子”的强增强子结合模式。这些增强剂对BET有丰富的作用 与PU1结合的蛋白质，调节关键的破骨细胞生成因子。该奖项的目的是：1)调查 CSF1R/PU.1轴的作用和2)确定超级增强子是否在乳腺癌骨中发挥作用 转移。我们的假设是CSF1R/PU.1轴在骨转移中是必不可少的，这发生在 超级增强剂的背景。我们将初步评估MP特异性PU1缺失对乳腺癌的影响 原发肿瘤MPS和骨转移MPS中PU1调控基因与骨转移的关系 和OCS(目标1)。然后我们将评估抑制BET是否可以减少BET的发展和生长 已建立的骨转移，并确定增加其特异性是否特异地靶向MPS和OCS 提高其疗效(目标2)。最后，我们将评估联合治疗是否与最有效 从AIM 2和靶向CSF1R/PU.1轴的CSF1R抑制剂制备BET抑制剂更有效 与单独使用任何一种药物相比，抗骨转移的发展和生长(目标3和4A- b)。研究结果可能会对骨转移患者的治疗、生活质量和生存产生重大影响。

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.