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(申请人提供)：骨是乳腺癌(BCA)最常见的转移部位，在晚期疾病患者中会导致显著的发病率和死亡率。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破坏的增加。联合化疗和双磷酸盐用于骨损伤对发病率和存活率影响很小。因此，开发既能改善骨破坏又能提高转移性乳腺疾病患者存活率的新疗法是必要的。对BCA骨病理中分子事件的更好理解表明，核因子kappa B受体激活剂配体(RANKL)通过与RANK结合来刺激破骨细胞的招募、分化和激活。骨保护素(OPG)是一种与RANKL竞争的“诱饵”受体，从而调节RANKL的作用。然而，在转移过程中，内源性OPG水平显著降低。因此，OPG仍然是未来骨转移治疗的有效分子。骨内播散性肿瘤的生长通过髓系来源的抑制细胞(MDSCs)的渗透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，在鼠骨和人骨的恶性转移过程中，MDSCs直接作为破骨祖细胞发挥作用，从而加强骨破坏。目前的提案将涉及三个主要方面，分别是：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，使用肿瘤坏死因子相关的凋亡诱导配体(TRAIL)诱导肿瘤细胞凋亡，以及联合使用吉西他滨治疗MDSC。这项研究的中心假设是骨靶向输送基因工程OPG，同时保留RANKL结合但取消TRAIL结合，结合TRAIL治疗和靶向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存活率。这一假设将使用免疫活性的临床前BCA小鼠模型进行验证，以进行可能的临床翻译。为了实现这一目标，我们最近建立了：a)间充质干细胞(MSC)通过使用OPG靶向RANK信号的潜力，b)独特的体内靶向策略，以增强基因工程MSC的骨特异性归巢，c)MDSCs在直接形成破骨细胞中的作用，以及d)在骨转移的BCA模型中，MDSCs的缺失增强了抗肿瘤Th1活性。此外，由于OPG还与TRAIL结合从而提高肿瘤细胞的存活率，我们已经：e)通过同源模建鉴定了OPG上可能的TRAIL结合结构域(S)，以及f)开发了一种保留RANKL结合但取消TRAIL结合的突变体OPG(OPGm)，并证实了其在体外和体内的骨组织中的生物活性 改建。这些进展有望为骨播散性BCA带来一种新的治疗选择。