Strategic inhibition of EGFR-family signaling using novel peptidomimetic inhibitors of HER-2 for the treatment of osteosarcoma

使用新型 HER-2 拟肽抑制剂战略性抑制 EGFR 家族信号传导以治疗骨肉瘤

• 批准号: 10579210
• 负责人: Sita Withers
• 金额: $ 22.14万
• 依托单位: LOUISIANA STATE UNIV A&M COL BATON ROUGE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10579210
• 关键词: 3-Dimensional; 3D Print; Affect; Animal Model; Breast Cancer Model; Canis familiaris; Cell Line; Cell physiology; Cells; Client; Clinical; Clinical Trials; Core Facility; Data; Development; Doctor of Philosophy; Dose; Drug Combinations; Drug Kinetics; ERBB2 gene; ERBB3 gene; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Evaluation; Excision; Exposure to; Family; Goals; HER2 inhibition; Heterodimerization; Human; Human Resources; Immune; In Vitro; Insulin-Like-Growth Factor I Receptor; Laboratories; Libraries; MAP Kinase Gene; Malignant neoplasm of lung; Measurable; Mediating; Metastatic Neoplasm to the Lung; Metastatic Osteosarcoma; Modeling; Molecular; Molecular Target; Monoclonal Antibodies; Mus; Neoplasm Metastasis; Operative Surgical Procedures; Outcome; PIK3CG gene; Pathway interactions; Persons; Pharmaceutical Preparations; Phosphotransferases; Platinum; Pre-Clinical Model; Production; Receptor Signaling; Reporting; Resistance; Schedule; Signal Pathway; Signal Transduction; Survival Rate; System; Therapeutic; Toxic effect; Translating; Tyrosine Kinase Inhibitor; Up-Regulation; Xenograft Model; Xenograft procedure; anticancer activity; anticancer research; antitumor effect; bioprinting; cancer clinical trial; candidate selection; canine model; chemotherapy; cost; drug candidate; experience; high throughput screening; high-throughput drug screening; human disease; immunogenicity; improved; improved outcome; in vivo; in vivo Model; in vivo evaluation; inhibitor; kinase inhibitor; malignant breast neoplasm; mouse model; novel; novel therapeutic intervention; oncogene addiction; optimal treatments; osteosarcoma; peptidomimetics; pre-clinical; receptor; screening; small molecule inhibitor; success; therapeutic target; tool; transcriptome sequencing; treatment response; treatment strategy; tumor; tumor microenvironment; tumor progression

Summary Osteosarcoma (PI: Sita Withers, PhD). This proposal will identify novel treatment strategies for osteosarcoma which has a 5-year survival rate of 70%. The expression of epidermal growth factor receptor HER2 is upregulated in 40% of human and canine osteosarcomas and has correlated with a poor outcome in some human studies. Using murine models of osteosarcoma and lung metastasis, Dr. Withers will evaluate EGFR:HER2 inhibitors of signaling pathways (eg, PI3K-Akt and ERK/MAPK) that have shown efficacy in a xenograft mouse model of breast cancer. The hypothesis of this proposal is that peptidomimetic HER2 heterodimerization inhibitors of EGFR-family signaling will lead to novel tools for treating metastatic OSA. Dr. Withers' approach includes evaluation in a naturally-occurring canine osteosarcoma model, which mimics more closely lung metastasis in humans, for translational information in the treatment of human osteosarcoma. Combinations of small molecule inhibitors will be identified which show in vivo efficacy against the development of osteosarcoma and also limit metastasis to the lungs. 3D printing of osteosarcoma and immune cells will be used to characterize the effects of HER2 inhibition in the context of exposure to typical features of the tumor microenvironment. Two specific aims are proposed: Aim 1 To define the effects of EGFR-family signaling inhibition on OSA cell function and signaling pathways. Aim 2 To detail the efficacy and toxicity of optimal EGFR signaling inhibition in preclinical in vivo models of OSA.

摘要骨肉瘤(PI：西塔·威瑟斯，博士)。 这项建议将确定骨肉瘤的新治疗策略，骨肉瘤的5年存活率为70%。 表皮生长因子受体HER2在40%的人和犬体内表达上调 骨肉瘤，在一些人类研究中与不良结果相关。使用小鼠模型 在骨肉瘤和肺转移方面，威瑟斯博士将评估EGFR：HER2信号通路的抑制剂(例如， PI3K-Akt和ERK/MAPK)，已经在乳腺癌的异种移植小鼠模型中显示出有效性。这个 这一提议的假设是，EGFR家族的类肽HER2异源二聚抑制物 信号转导将导致治疗转移性阻塞性睡眠呼吸暂停低通气综合征的新工具。威瑟斯博士的方法包括在一个 自然发生的犬骨肉瘤模型，它更接近于人类的肺转移， 人类骨肉瘤治疗中的翻译信息。小分子缓蚀剂的组合 将确定哪些药物在体内显示出对抗骨肉瘤发展的疗效，并限制 转移到肺部。骨肉瘤和免疫细胞的3D打印将被用来表征 在HER2抑制的背景下暴露于典型的肿瘤微环境特征。两个具体的 目的：1明确EGFR家族信号抑制对阻塞性睡眠呼吸暂停低氧细胞功能的影响。 信号通路。目的2详细说明最佳的EGFR信号抑制的有效性和毒性。 阻塞性睡眠呼吸暂停的临床前活体模型。