Development of Pharmacological Treatment of Osteochondromas

骨软骨瘤药物治疗研究进展

• 批准号: 10460410
• 负责人: MOTOMI ENOMOTO-IWAMOTO
• 金额: $ 30.29万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10460410
• 关键词: Adolescence; Agonist; Benign; Biochemical; Biological; Biological Assay; Biology; Bone Surface; Cartilage; Cartilaginous exostosis; Cells; Childhood; Chondrocytes; Chondrogenesis; Chondrogenic Neoplasm; Chondrosarcoma; Clinical Management; Deformity; Development; Differentiation and Growth; Disease Management; Disease model; Distal; Down-Regulation; EXT1 gene; EXT2 gene; Elements; Energy Metabolism; Epiphysial cartilage; Excision; Fibroblast Growth Factor; Gene Expression Profiling; Genetic Transcription; Glycolysis; Goals; Growth; Health; Heparitin Sulfate; Hereditary Multiple Exostoses; Histologic; Histopathology; Human; Hypertrophy; In Vitro; Lead; Link; Longitudinal Studies; Malignant - descriptor; Modeling; Molecular; Mus; Mutation; Nature; Nerve Pain; Nerve compression syndrome; Nuclear; Operative Surgical Procedures; Pain; Pathogenesis; Pharmacological Treatment; Pharmacology; Pharmacotherapy; Phase III Clinical Trials; Physical Function; Population; Procedures; Radiation therapy; Regulation; Research; Resistance; Signal Pathway; Signal Transduction; Site; Testing; Therapeutic; Time; Treatment Efficacy; Tumor stage; Up-Regulation; Width; beta catenin; bone; cartilaginous; combat; drug candidate; high risk; in vivo; innovation; insight; mouse model; neoplastic; neoplastic cell; novel; novel therapeutics; osteoprogenitor cell; progenitor; response; retinoic acid receptor alpha; retinoic acid receptor gamma; skeletal; smoothened signaling pathway; standard of care; stem; therapeutic target; transcriptome; transcriptome sequencing; tumor; tumor growth

Abstract Osteochondromas are the most common skeletal tumors during childhood or adolescence. The tumors grow over time and cause skeletal deformities, nerve compression, pain and other health problems. Osteochondromas are primarily treated surgically and thereby treatment for multiple osteochondromas may require repetitive surgery. Osteochondromas located at a high-risk site for surgery may be managed non- surgically, however, this increases the potential for progression to malignant chondrosarcomas. The final goal of this project is to develop non-surgical therapies that would stop osteochondroma formation and growth in an effective manner. Multiple osteochondromas can be caused by mutations in the heparan sulfate synthases EXT1 or EXT2. Research from our lab and other groups have indicated that reduction in heparan sulfate induce alterations of multiple signaling pathways, leading to osteochondromas. Our long-term studies on nuclear retinoic acid receptor gamma (RARγ) reveal that (1) pharmacologic activation of RARγ strongly inhibits ectopic cartilage formation; (2) RARγ is expressed in cartilage elements in mouse and human osteochondromas; and (3) RARγ agonists inhibited ectopic cartilage formation and induced involution of existing cartilaginous tumor masses in the osteochondroma mouse model. We hypothesize that RARγ could be a novel pharmaco-therapeutic target for osteochondromas by an anti-chondrogenic action and pro- hypertrophic action. The cell origin of osteochondromas remains to be clarified. We have recently discovered a novel cell population of chondroprogenitors contributing to appositional width growth of growth plate. These cells are Wnt-responsive skeletal progenitors and reside in growth plate and the neighboring perichondrium. We hypothesize that aberrant regulation of these progenitors induce osteochondromas and RARγ signaling ameliorates their altered nature. To test these hypotheses, we propose three aims: Aim 1, To establish therapeutic efficacy of RARγ agonists and examine their molecular actions in the mouse osteochondroma model; Aim 2, To determine the cells that contribute to osteochondroma formation and growth and their response to RARγ signaling; and Aim3, To investigate the actions of RARγ agonists on human osteochondroma cells. The study involves diverse experimental procedures encompassing drug treatment with mice, histological and molecular biological assessments of the mouse disease models, high throughput gene expression analysis and study on human tumor cells. The Project will test innovative ideas on the pathogenesis of osteochondroma and equally innovative ideas on how to combat them therapeutically.

抽象的 骨软骨瘤是儿童或青春期最常见的骨骼肿瘤。肿瘤 随着时间的推移，它们会生长并导致骨骼畸形、神经受压、疼痛和其他健康问题。 骨软骨瘤主要通过手术治疗，因此多发性骨软骨瘤的治疗可能 需要重复手术。位于手术高风险部位的骨软骨瘤可以通过非手术方式进行治疗。 然而，通过手术，这会增加进展为恶性软骨肉瘤的可能性。最终目标 该项目的目的是开发非手术疗法，以阻止骨软骨瘤的形成和生长 有效的方式。硫酸乙酰肝素合酶突变可能引起多发性骨软骨瘤 外部 1 或外部 2。我们实验室和其他小组的研究表明，硫酸乙酰肝素的减少 诱导多种信号通路的改变，导致骨软骨瘤。我们的长期研究 核视黄酸受体γ（RARγ）表明（1）RARγ的药理学激活强烈抑制 异位软骨形成； (2) RARγ在小鼠和人类的软骨元件中表达 骨软骨瘤; (3) RARγ激动剂抑制异位软骨形成并诱导软骨退化 骨软骨瘤小鼠模型中现有的软骨肿瘤块。我们假设 RARγ 可以 通过抗软骨形成作用和促软骨形成作用，成为骨软骨瘤的新型药物治疗靶点 肥大作用。骨软骨瘤的细胞起源仍有待阐明。我们最近发现了一个 有助于生长板同位宽度生长的软骨祖细胞的新细胞群。这些 细胞是 Wnt 反应性骨骼祖细胞，驻留在生长板和邻近的软骨膜中。 我们假设这些祖细胞的异常调节会诱导骨软骨瘤和 RARγ 信号传导 改善他们改变的本性。为了检验这些假设，我们提出三个目标： 目标 1，建立 RARγ激动剂的治疗效果并检查其在小鼠骨软骨瘤中的分子作用 模型;目标 2，确定有助于骨软骨瘤形成和生长的细胞及其作用 对 RARγ 信号传导的反应；目的3，研究RARγ激动剂对人类的作用 骨软骨瘤细胞。该研究涉及多种实验程序，包括药物治疗 小鼠，小鼠疾病模型的组织学和分子生物学评估，高通量基因 人肿瘤细胞的表达分析和研究。该项目将测试创新理念 骨软骨瘤的发病机制以及如何治疗骨软骨瘤的同样创新的想法。