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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.

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