Targeted therapy for breast cancer with osteolytic bone damage

乳腺癌伴溶骨性骨损伤的靶向治疗

• 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
• 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

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，在晚期疾病患者中导致显著的发病率和死亡率。涉及BCa细胞和骨微环境中的细胞的恶性循环导致破骨细胞的活化和骨破坏的增加。联合化疗和双膦酸盐用于骨病变对发病率和生存率的影响很小。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骨病理学中分子事件的更好理解表明，核因子κ-B配体受体激活剂（RANKL）通过与RANK结合刺激破骨细胞的募集、分化和活化。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，在转移期间，内源性OPG水平显著降低。因此，OPG仍然是未来治疗骨转移的有效分子。骨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，所述骨髓源性抑制细胞（MDSC）抑制宿主抗肿瘤免疫应答。此外，我们发现MDSC在小鼠和人类骨内的恶性转移级联反应中直接起破骨细胞祖细胞的作用，从而增强骨破坏。目前的提案将解决三个主要方面，即：溶骨性骨损伤，肿瘤生长和免疫抑制使用基因修饰的干细胞方法靶向破骨细胞活化，诱导肿瘤细胞凋亡使用肿瘤坏死因子相关凋亡诱导配体（TRAIL），并使用吉西他滨MDSC消融，分别组合。本研究的中心假设是基因工程OPG的骨靶向递送，同时保留RANKL结合，但消除TRAIL结合，与TRAIL治疗联合靶向MDSC群体将显著减少溶骨性骨损伤，重塑受损骨骼，并诱导肿瘤细胞凋亡以提高生存率。将使用具有免疫活性的骨播散性BCa临床前小鼠模型对该假设进行检验，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）通过使用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的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的耗竭增强骨转移性BCa模型中的抗肿瘤Th 1活性。此外，由于OPG也与TRAIL结合从而增加肿瘤细胞存活，我们已经：e）通过同源性建模鉴定了OPG上推定的TRAIL结合结构域，和f）开发了保留RANKL结合但消除TRAIL结合的突变体OPG（OPGm），并在体外和体内骨中证实了其生物活性 重塑预计这些进展将为骨播散性BCa提供一种新的治疗选择。