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：Sita Withers，博士）。 该提案将为骨肉瘤确定新的治疗策略，骨肉瘤的 5 年生存率为 70%。 40% 的人类和犬类表皮生长因子受体 HER2 表达上调 骨肉瘤，并且在一些人类研究中与不良结果相关。使用小鼠模型 骨肉瘤和肺转移，Withers 博士将评估 EGFR:HER2 信号通路抑制剂（例如， PI3K-Akt 和 ERK/MAPK）已在乳腺癌异种移植小鼠模型中显示出功效。这 该提案的假设是 EGFR 家族的拟肽 HER2 异二聚化抑制剂 信号传导将带来治疗转移性 OSA 的新工具。威瑟斯博士的方法包括在以下方面进行评估： 天然存在的犬骨肉瘤模型，更接近地模拟人类肺转移， 治疗人类骨肉瘤的转化信息。小分子抑制剂的组合 将确定其在体内对骨肉瘤的发展具有功效，并且还限制 转移至肺部。骨肉瘤和免疫细胞的 3D 打印将用于表征 在暴露于肿瘤微环境的典型特征的背景下抑制 HER2。两个具体 提出了目标： 目标 1 确定 EGFR 家族信号传导抑制对 OSA 细胞功能的影响和 信号通路。目标 2 详细说明最佳 EGFR 信号传导抑制的功效和毒性 OSA 的临床前体内模型。