Targeting VCAM1-a4b1 Signaling to Ameliorate Pulmonary Osteosarcoma Metastasis

靶向 VCAM1-a4b1 信号传导以改善肺骨肉瘤转移

• 批准号: 9375804
• 负责人: Alex Yee-Chen Huang
• 金额: $ 20.86万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-20 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9375804
• 关键词: Accounting; Adolescent; Adolescent and Young Adult; Affect; African American; Alveolar Macrophages; Antibodies; Autoimmune Diseases; Autoimmune Process; Binding; Blocking Antibodies; Bone Growth; Breathing; CRISPR/Cas technology; Cell Adhesion Molecules; Cell Line; Cells; Cervical; Child; Childhood; Clinical; Clinical Trials; Combination Drug Therapy; Combined Modality Therapy; Complex; Cytotoxic T-Lymphocytes; Data; Development; Diagnosis; Dichloromethylene Diphosphonate; Diphtheria Toxin; Disease; Disease-Free Survival; Dose; FDA approved; Foundations; Functional disorder; Future; Goals; Grant; Growth; Human; ITGAM gene; Immune; Immune response; Immune system; Immunotherapy; Inflammatory Bowel Diseases; Integrin alpha4; Integrin alpha4beta1; Integrins; Intranasal Administration; Japan; Kinetics; Label; Laser Scanning Microscopy; Ligands; Liposomes; Literature; Lung; Malignant - descriptor; Malignant Bone Neoplasm; Malignant neoplasm of prostate; Measures; Mediating; Metastatic Neoplasm to the Lung; Metastatic Osteosarcoma; Metastatic breast cancer; Modeling; Molecular; Molecular Target; Monitor; Multiple Sclerosis; Mus; Mutation; Myelogenous; Nebulizer; Neoplasm Metastasis; Operative Surgical Procedures; Outcome; Patients; Pediatric Hospitals; Peptides; Phenotype; Play; Population; Precision therapeutics; Quality of life; Regimen; Reporter; Research; Resectable; Resistance; Role; Route; Signal Transduction; Source; Stroke; Structure of parenchyma of lung; Surface; T-Lymphocyte; Testing; Texas; Therapeutic; Time; Toxic effect; Translating; Treatment Efficacy; Tumor Antigens; United States; Variant; Vascular Cell Adhesion Molecule-1; Xenograft procedure; boys; cellular targeting; chemotherapy; efficacy testing; functional outcomes; graft vs host disease; imaging approach; improved; improved outcome; in vivo; insight; long bone; lung metastatic; macrophage; malignant breast neoplasm; molecular imaging; molecular targeted therapies; mortality; natalizumab; novel strategies; osteosarcoma; overexpression; phase 1 study; pre-clinical; preclinical study; prevent; programs; public health relevance; repository; small hairpin RNA; small molecule inhibitor; success; systemic toxicity; tumor; two-photon; young adult

Project Summary / Abstract Osteosarcoma (OS) is an aggressive malignant primary bone cancer with a high propensity for lung metastasis. OS frequently originates in the long bones during periods of rapid bone growth. Consequently, OS represents the most prevalent bone cancers affecting children and adolescent and young adults (AYA), with ~400-600 cases a year and accounts roughly half of all new cases of OS diagnosed in the United States. Despite aggressive combination chemotherapy and surgery, the outcome for metastatic OS remains dismal, and the overall survival in children and AYA patients with metastatic OS has not improved significantly over the past 3 decades. A high proportion of OS patients develop pulmonary metastasis (pOS) either at the time of diagnosis (20%) or after initiation of multimodal therapy including combination chemotherapy and surgery. Unfortunately, almost all of the patients who develop surgically un-resectable pOS invariably succumb to this devastating disease. Therefore, pOS represent a disease with unmet needs. As OS contains extremely complex genetic alterations, molecular targeted precision therapy has proven challenging. Recent exciting scientific development implicates the immune system as a potential important new armamentarium as a novel approach to control or reduce pOS. In the current proposal, we identified tumor-expressed Vascular Cell Adhesion Molecule-1 (tVCAM-1) as playing a pivotal role in immune-mediated cancer metastasis by interacting with α4β1 integrin on lung macrophages (MACs), thereby implicating the pulmonary macrophages as a major culprit in the pathophysiology of metastatic OS. Compared to non-metastatic parental tumor (K7), metastatic murine OS cells (K7M2) express high surface VCAM-1, and absence of either tVCAM-1 or MACs prevents the development and ameliorates a large proportion of established pOS. Therefore, we wish to further examine our proposal that a targetable cellular and molecular mechanism, VCAM-1/ α4β1, is a primary driver of OS-MAC interaction, providing the suitable lung tissue niche for pOS in vivo. Our hypothesis is that interfering VCAM- 1/α4β1 signaling between pOS and MACs by down-regulating VCAM-1, depleting MACs or disrupting VCAM- 1-α4β1 signaling will reduce pulmonary metastasis and improve survival. Specific Aim 1: We will characterize functional outcomes of MACS and other immune cells following VCAM-1/α4β4 signaling engagement with pOS. We will compare VCAM-1lo and VCAM-1hi pOS cells for in vivo growth and associated immune responses in the lungs, and expand our observation to include testing lung metastatic potential of other human and mouse pOS cell lines and PDXs available through our own PDX repository and that of our collaborator at Texas Children's Hospital. We will characterize phenotypic and functional outcomes of various myeloid and other immune cellular compartment in the lung tissue of VCAM-1lo and VCAM-1hi pOS cells using cellular, molecular and imaging approaches. Specific Aim 2: We will test the efficacy of functional blockade of VCAM- 1/α4β1 interaction by depleting MACs with intranasal liposomal clodronate treatment or by inhibiting molecular interactions using VCAM-1 specific inhibitory peptide (iVCAM-1p) or intranasal / intratracheal administration of anti-a4 blocking antibody. In the latter scenario involving anti-α4 blocking antibody, we set a goal to obtain foundational pre-clinical, IND-enabling data for monitoring systemic and local toxicities and refining optimal dosing in order to rapidly translate findings from this current grant into Phase I studies using the FDA-approved anti-α4 antibody, Natalizumab, via the intratracheal and inhalation routes for the treatment of patients with late- stage pOS, for whom no other treatment options with demonstrable therapeutic benefits are available. Success in this high priority effort could have a profound effect in improving the outcome and quality of life for children and AYA patients afflicted with this devastating disease.

项目概要/摘要 骨肉瘤 (OS) 是一种侵袭性恶性原发性骨癌，极易发生肺癌 在骨快速生长期间，OS 经常起源于长骨。 代表影响儿童、青少年和年轻人 (AYA) 的最常见骨癌，其中 每年约 400-600 例病例，约占美国所有新诊断 OS 病例的一半。 尽管积极的联合化疗和手术，转移性 OS 的结果仍然令人沮丧， 儿童和患有转移性 OS 的 AYA 患者的总生存率与 过去 3 年来，很大一部分 OS 患者在发生肺转移 (pOS) 时发生。 诊断（20%）或开始多模式治疗（包括联合化疗和手术）后。 不幸的是，几乎所有手术无法切除的 pOS 患者都不可避免地死于这种情况。 因此，pOS 代表了一种需求未得到满足的疾病，因为 OS 包含极其严重的疾病。 复杂的基因改变，分子靶向精准治疗最近被证明具有挑战性。 科学发展表明免疫系统是一种潜在重要的新军备库 控制或减少 pOS 的方法在当前的提案中，我们鉴定了肿瘤表达的血管细胞。 粘附分子-1 (tVCAM-1) 通过相互作用在免疫介导的癌症转移中发挥关键作用 肺巨噬细胞 (MAC) 上有 α4β1 整合素，因此表明肺巨噬细胞是 与非转移性亲本肿瘤 (K7) 相比，转移性 OS 的病理生理学的罪魁祸首。 鼠 OS 细胞 (K7M2) 表达高表面 VCAM-1，缺乏 tVCAM-1 或 MAC 会阻止 因此，我们希望进一步检查我们的研究成果。 提议可靶向的细胞和分子机制 VCAM-1/α4β1 是 OS-MAC 的主要驱动因素 相互作用，为体内 pOS 提供合适的肺组织生态位。我们的假设是干扰 VCAM-。 通过下调 VCAM-1、耗尽 MAC 或破坏 VCAM，pOS 和 MAC 之间的 1/α4β1 信号传导 1-α4β1 信号传导将减少肺转移并提高生存率。具体目标 1：我们将表征。 VCAM-1/α4β4 信号传导参与后 MACS 和其他免疫细胞的功能结果 我们将比较 VCAM-1lo 和 VCAM-1hi pOS 细胞的体内生长和相关免疫反应。 肺部，并扩大我们的观察范围，包括测试其他人类的肺转移潜力 小鼠 pOS 细胞系和 PDX 可通过我们自己的 PDX 存储库以及我们的合作者的存储库获得 我们将描述各种骨髓和功能的表型和功能结果。 使用细胞，VCAM-1lo 和 VCAM-1hi pOS 细胞肺组织中的其他免疫细胞区室， 具体目标 2：我们将测试 VCAM- 功能阻断的功效。 1/α4β1 相互作用，通过鼻内脂质体氯膦酸盐治疗耗尽 MAC 或通过抑制分子 使用 VCAM-1 特异性抑制肽 (iVCAM-1p) 或鼻内/气管内给药的相互作用 在后一种涉及抗α4阻断抗体的情况下，我们设定的目标是获得抗α4阻断抗体。 用于监测全身和局部毒性并完善最佳方案的基础临床前、IND支持数据 剂量，以便使用 FDA 批准的药物快速将本次资助的结果转化为 I 期研究 抗α4抗体，那他珠单抗，通过气管内和吸入途径治疗晚期- 阶段 pOS，对于他们来说没有其他具有明显治疗效果的治疗方案可用。 在这一高度优先的努力可能会对改善儿童的成果和生活质量产生深远的影响 以及患有这种毁灭性疾病的 AYA 患者。