Targeted therapy for breast cancer with osteolytic bone damage

乳腺癌伴溶骨性骨损伤的靶向治疗

基本信息

批准号：
8824806
负责人：
Selvarangan Ponnazhagan
金额：
$ 32.12万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-03-01 至 2020-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8824806
关键词：
Ablation Address Apoptosis Binding Biological Biological Response Modifier Therapy Bone Resorption Bone remodeling Breast Cancer Cell Breast Cancer Model Breast Cancer Patient Breast Cancer therapy Breast Diseases Breast cancer metastasis Cell Survival Cell physiology Cells Clinical Combination Drug Therapy Combined Modality Therapy Coupled Cytolysis Development Disease Equilibrium Event Fracture Future Genetic Engineering Goals Growth Health Homeostasis Homing Homology Modeling Human Hypercalcemia Immune Immune response Immunity Immunocompetent Immunosuppression Immunosuppressive Agents In Vitro Infiltration Lesion Ligand Binding Ligand Binding Domain Ligands Malignant Bone Neoplasm Malignant Neoplasms Memory Mesenchymal Stem Cells Metastatic Carcinoma Metastatic Neoplasm to the Bone Metastatic breast cancer Molecular Morbidity - disease rate Mus Myelogenous Neoplasm Metastasis Nerve compression syndrome Nuclear Organ Osteoblasts Osteoclasts Osteolytic Pathology Patients Phase I Clinical Trials Population Production Resistance Risk Role Signal Transduction Site Skeleton Staging Stem cells Suppressor-Effector T-Lymphocytes Survival Rate TNF-related apoptosis-inducing ligand TRANCE protein Testing Therapeutic Effect Translations Tumor Necrosis Factor-alpha Tumor necrosis factor receptor 11b University of Alabama at Birmingham Cancer Center Woman Work advanced disease base bisphosphonate bone cancer cell chemotherapy cytokine gemcitabine improved in vivo malignant breast neoplasm mortality mouse model mutant neoplastic cell novel novel strategies outcome forecast overexpression parathyroid hormone-related protein pre-clinical progenitor receptor stem cell therapy targeted delivery targeted treatment therapy resistant tumor tumor growth tumor microenvironment

项目摘要

DESCRIPTION (provided by applicant): Bone is the most common site of metastasis for breast cancer (BCa), which causes significant morbidity and mortality in patients with advanced disease. A vicious cycle involving BCa cells and cells in the bone microenvironment results in the activation of osteoclasts and increased bone destruction. Combination chemotherapy and bisphosphonate use for bone lesions provide very little effect on morbidity and survival. Thus, development of newer therapies that can both ameliorate bone destruction and improve survival of patients with metastatic breast disease is needed. A better understanding of the molecular events in BCa bone pathology indicates that receptor activator of nuclear factor kappa-B ligand (RANKL) stimulates the recruitment, differentiation, and activation of osteoclasts by binding to RANK. Osteoprotegerin (OPG) is a "decoy" receptor that competes with RANK for RANKL, thereby modulating the effects of RANKL. However, during metastases, endogenous OPG levels are markedly reduced. Thus, OPG remains as an effective molecule for future therapies for bone metastasis. The growth of disseminated tumor in the bone further alters the immune milieu through infiltration of myeloid-derived suppressor cells (MDSCs) that dampen the host anti-tumor immune responses. Further, we identified that MDSCs function as osteoclast progenitors directly during this vicious metastatic cascade within the bone both in mouse and in humans, enhancing bone destruction. The current proposal will address three major aspects, namely: osteolytic bone damage, tumor growth and immunosuppression using a genetically-modified stem cell approach targeting osteoclast activation, induction of tumor cell apoptosis using TNF-related apoptosis-inducing ligand (TRAIL), and using gemcitabine for MDSC ablation, respectively, in combination. The central hypothesis of the proposed study is bone-targeted delivery of genetically-engineered OPG, while retaining RANKL binding but abolishing TRAIL binding, in combination with TRAIL therapy together with targeting the MDSC population will significantly decrease osteolytic bone damage, remodel the damaged skeleton, and induce tumor cell apoptosis to improve survival. This hypothesis will be tested using an immunocompetent, preclinical mouse model of bone-disseminated BCa for possible clinical translation. Towards achieving this goal, we have recently established: a) the potential of mesenchymal stem cells (MSC) targeting RANK signaling by using OPG, b) a unique in vivo targeting strategy to enhance bone-specific homing of genetically-engineered MSC, c) the role of MDSCs in forming osteoclasts directly, and d) that depletion of MDSCs enhances anti-tumor Th1 activity in a bone metastatic BCa model. Further, since OPG also binds to TRAIL thereby increasing tumor cells survival, we have: e) identified putative TRAIL binding domain(s) on OPG by homology modeling, and f) developed a mutant OPG (OPGm) that retains RANKL binding but abolishes TRAIL binding and confirmed its biological activity both in vitro and in vivo in bone remodeling. These advances are anticipated to result in a novel treatment option for bone-disseminated BCa.

描述（由申请人提供）：骨骼是乳腺癌（BCA）转移的最常见部位，它在晚期疾病患者中引起了显着的发病率和死亡率。涉及骨微环境中BCA细胞和细胞的恶性循环导致破骨细胞的激活并增加骨骼破坏。组合化疗和双膦酸盐用于骨骼病变，对发病率和生存的影响很小。因此，需要开发新的疗法，这些疗法既可以改善骨骼破坏并改善转移性乳房疾病的患者的存活率。对BCA骨病理中分子事件的更好理解表明，核因子Kappa-B配体（RANKL）的受体激活因素通过与等级结合来刺激破骨细胞的募集，分化和激活。 Osteoprotegerin（OPG）是一种“诱饵”受体，与RANKL的等级竞争，从而调节RANKL的影响。然而，在转移过程中，内源性OPG水平明显降低。因此，OPG仍然是用于骨转移的未来疗法的有效分子。骨骼中散布的肿瘤的生长进一步改变了免疫环境，通过渗透髓样衍生的抑制细胞（MDSC）抑制宿主抗肿瘤免疫反应。此外，我们确定MDSC在小鼠和人类中的骨骼中直接在骨骼中直接充当破骨细胞祖细胞，从而增强了骨骼破坏。当前的建议将解决三个主要方面，即：使用遗传改性的干细胞方法靶向破骨细胞活化，使用TNF相关凋亡诱导的配体（TRAIL）（TRAIL）（TRAIL）（TRAIL）以及使用Gemcitabine for Gemcitabine for Gemcitabine，使用TNF相关的凋亡诱导，使用TNF相关的凋亡诱导的肿瘤细胞凋亡诱导肿瘤骨损伤，肿瘤的生长和免疫抑制。拟议的研究的中心假设是遗传工程OPG的骨靶向递送，同时保留RANKL结合但可怕的踪迹结合，结合跟踪治疗以及靶向MDSC种群的结合，将显着降低骨质水解骨骼损伤，重塑损坏的骨骼，并诱导肿瘤蜂窝per骨侵蚀性。该假设将使用骨脱落BCA的免疫能力的临床前小鼠模型进行检验，以实现临床翻译。 Towards achieving this goal, we have recently established: a) the potential of mesenchymal stem cells (MSC) targeting RANK signaling by using OPG, b) a unique in vivo targeting strategy to enhance bone-specific homing of genetically-engineered MSC, c) the role of MDSCs in forming osteoclasts directly, and d) that depletion of MDSCs enhances anti-tumor Th1 activity in a bone转移性BCA模型。此外，由于OPG还与TRAIL结合，从而增加了肿瘤细胞的存活率，因此我们具有：E）通过同源性建模确定了对OPG的假定轨迹结合结构域，并且F）开发了一种突变的OPG（OPGM），它保留了RANKL结合，但消除了Trail trail，并证实了其在骨骼中的生物学活性，并确认了骨骼的生物学活性。重塑。预计这些进步将为骨脱落的BCA提供新的治疗选择。