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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：
9207743
负责人：
Selvarangan Ponnazhagan
金额：
$ 33.63万
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/9207743
关键词：
Ablation Address Apoptosis Binding Biological Biological Response Modifier Therapy Bone Resorption Bone remodeling Breast Cancer Cell Breast Cancer therapy Breast Diseases Breast cancer metastasis Cancer Model Cancer Patient Cell Survival Cell physiology Combination Drug Therapy Combined Modality Therapy Coupled Cytolysis Development Disease Event Future Genetic Engineering Goals Growth 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 Mesenchymal Stem Cells Metastatic Carcinoma Metastatic Neoplasm to the Bone Metastatic breast cancer Molecular Morbidity - disease rate Mus Myelogenous Neoplasm Metastasis Nerve compression syndrome Organ Osteoblasts Osteoclasts Osteolytic Pathology Patients Phase I Clinical Trials Population Production Recruitment Activity Resistance Role Signal Transduction Site Skeleton Stem cells Suppressor-Effector T-Lymphocytes Survival Rate T memory cell TNF gene TNF-related apoptosis-inducing ligand TRANCE protein Testing Therapeutic Effect Tumor necrosis factor receptor 11b University of Alabama at Birmingham Cancer Center Woman Work advanced disease base bisphosphonate bone breast cancer survival cancer cell chemotherapy clinical translation cytokine fracture risk gemcitabine improved in vivo malignant breast neoplasm mortality mouse model mutant neoplastic cell novel novel strategies novel therapeutics outcome forecast overexpression parathyroid hormone-related protein pre-clinical progenitor public health relevance receptor 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）：骨是乳腺癌（BCa）最常见的转移部位，它会导致晚期疾病患者显着的发病率和死亡率。 BCa 细胞和骨微环境中的细胞之间的恶性循环导致破骨细胞的激活和骨质破坏的增加。联合化疗和双膦酸盐治疗骨病变对发病率和生存率影响很小。因此，需要开发既能改善骨破坏又能提高转移性乳腺疾病患者生存率的新疗法。对 BCa 骨病理学分子事件的更好理解表明，核因子 kappa-B 配体受体激活剂 (RANKL) 通过与 RANK 结合来刺激破骨细胞的募集、分化和激活。骨保护素 (OPG) 是一种“诱饵”受体，与 RANK 竞争 RANKL，从而调节 RANKL 的作用。然而，在转移过程中，内源性 OPG 水平显着降低。因此，OPG 仍然是未来骨转移治疗的有效分子。骨骼中播散性肿瘤的生长通过骨髓源性抑制细胞（MDSC）的浸润进一步改变免疫环境，从而抑制宿主的抗肿瘤免疫反应。此外，我们还发现，在小鼠和人类的骨内恶性转移级联过程中，MDSC 直接充当破骨细胞祖细胞，从而增强骨质破坏。目前的提案将解决三个主要方面，即：使用针对破骨细胞激活的转基因干细胞方法的溶骨性骨损伤、肿瘤生长和免疫抑制、使用TNF相关凋亡诱导配体（TRAIL）诱导肿瘤细胞凋亡以及使用吉西他滨进行MDSC消融，分别组合。该研究的中心假设是骨靶向递送基因工程OPG，同时保留RANKL结合但废除TRAIL结合，结合TRAIL治疗以及靶向MDSC群体将显着减少溶骨性骨损伤，重塑受损骨骼，并诱导肿瘤细胞凋亡以提高生存率。该假设将使用具有免疫活性的骨播散性 BCa 临床前小鼠模型进行测试，以进行可能的临床转化。为了实现这一目标，我们最近确定了：a) 使用 OPG 靶向 RANK 信号传导的间充质干细胞 (MSC) 的潜力，b) 增强基因工程 MSC 骨特异性归巢的独特体内靶向策略，c) MDSC 在直接形成破骨细胞中的作用，以及 d) MDSC 的消耗增强了骨中的抗肿瘤 Th1 活性转移性BCa模型。此外，由于 OPG 还与 TRAIL 结合，从而增加肿瘤细胞的存活率，因此我们：e) 通过同源建模鉴定了 OPG 上假定的 TRAIL 结合结构域，f) 开发了一种突变型 OPG (OPGm)，它保留 RANKL 结合但废除 TRAIL 结合，并在体外和体内骨中证实了其生物活性重塑。这些进展预计将为骨播散性 BCa 带来一种新的治疗选择。