Modulation of Epigenetic Target in the Bone to Treat Breast Cancer Metastasis

调节骨中的表观遗传靶标来治疗乳腺癌转移

基本信息

批准号：
10736034
负责人：
Han Xiao
金额：
$ 66.62万
依托单位：
RICE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-03 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10736034
关键词：
Adverse effects Affinity Antitumor Response Binding Biology Bone Diseases Bone Metastases Prevention Bone neoplasms Brain Breast Cancer survivor Breast Cancer therapy Breast cancer metastasis Cancer Cell Growth Cell physiology Cells Cessation of life Clinic Collaborations Communities Data Destinations Diagnosis Disseminated Malignant Neoplasm Distant Engineering Enhancers Enzymes Epigenetic Process Estrogen receptor positive Exhibits Genomics Goals Histones Homing Homologous Gene Human Immune Immunosuppression Impairment In Vitro Injections Lesion Liver Lung Malignant Bone Neoplasm Malignant Neoplasms Mammary Neoplasms Medicine Metastatic Neoplasm to the Bone Micrometastasis Modeling Modification Molecular Myeloid-derived suppressor cells Neoplasm Metastasis Normal tissue morphology Nude Mice Operative Surgical Procedures Organ Osteolytic Patients Phenotype Primary Neoplasm Prodrugs Prognosis Reporting Research Rice Series Shapes Site Skeletal system Skeleton Solid T cell response T-Lymphocyte Therapeutic Time Tissues Toxic effect Transferase Treatment Efficacy Tumor Immunity Universities Visceral Xenograft procedure bisphosphonate bone breast cancer progression cancer cell cancer therapy college design epigenetic therapy hormone therapy iliac artery improved in vivo inhibitor knock-down limb bone malignant breast neoplasm mouse model neoplastic cell novel therapeutic intervention osteogenic prevent programs self-renewal skeletal small molecular inhibitor stem stem cells stemness targeted treatment therapeutic target tumor tumor microenvironment tumor progression

项目摘要

PROJECT SUMMARY/ABSTRACT In the clinic, primary breast tumors are usually surgically removed soon after diagnosis, often leaving patients “tumor-free”. However, 20-40% of breast cancer survivors will eventually suffer metastasis to distant organs, sometimes years after surgeries. Bone metastasis is the most frequently occurring metastasis of breast cancer. Our long-term goals are to elucidate the biology underlying the survival and progression of bone metastases, which will inform the design of therapeutic strategies against these latent tumor cells, through a fruitful collaboration between labs at Rice University and Baylor College of Medicine. The overall goal of this proposal is to develop bone tumor-targeting epigenetic inhibitors and demonstrate their efficacy against bone micrometastases as well as further multi-organ metastases seeding from bone lesions. Our preliminary data establish that: (1) epigenetic inhibitors modified with bisphosphonates, have superb binding affinity for bone, and exhibit enhanced bone metastasis sites targeting in vivo; and (2) epigenetic inhibitors modified with bisphosphonates exhibited improved activities for inhibiting metastatic seeding from bone lesions to other organs; and (3) an intra-iliac artery (IIA) injection, developed in our lab, can be used to effectively model the bone metastatic niche, providing a powerful platform for evaluating the therapeutic efficacy against bone metastatic cancers and “metastasis-to-metastasis” seeding from bone lesions. Based on these results, the first research direction will focus on engineering current epigenetic inhibitors for breast cancer therapy with bone- homing moiety. Next, we will study their effects on the survival and progression of breast cancer bone metastases using both syngeneic and xenograft nude mouse models. Furthermore, we will dissect the molecular mechanisms underlying the benefits of bone tumor-targeting epigenetic inhibitors. An enhanced therapeutic profile for these bone-specific epigenetic inhibitors on breast cancer will inform the extension of these treatments to other bone cancers and diseases.

项目概要/摘要在临床上，原发性乳腺肿瘤通常在诊断后不久就进行手术切除，常常导致患者离开 “无肿瘤”，然而，20-40% 的乳腺癌幸存者最终会发生远处器官转移，有时在手术后数年，骨转移是乳腺癌最常见的转移。我们的长期目标是阐明骨转移存活和进展的生物学，这将为针对肿瘤细胞的治疗策略的设计提供信息，通过富有成效的莱斯大学和贝勒医学院实验室之间的合作该提案的总体目标。开发骨肿瘤靶向表观遗传抑制剂并展示其抗骨功效微转移及其进一步的多器官转移从骨病变播种。确定：(1) 用双磷酸盐修饰的表观遗传抑制剂对骨具有极好的结合亲和力，并且展示增强的体内骨转移位点靶向；和 (2) 修饰的表观遗传抑制剂双膦酸盐具有更好的抑制其他骨转移性骨病变的活性器官；以及 (3) 我们实验室开发的髂动脉内 (IIA) 注射可用于模拟骨转移生态位，为评估骨治疗效果提供强大平台转移统计学家和骨病变的“转移到转移”播种。研究方向将集中于工程当前的表观遗传抑制剂用于乳腺癌骨治疗接下来，我们将研究它们对乳腺癌骨转移的生存和进展的影响使用同种和异种移植裸鼠模型。骨肿瘤靶向表观遗传抑制剂的益处机制。这些骨特异性表观遗传因素对乳腺癌意志的影响。其他骨癌和疾病。