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: 10360596
• 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/10360596
• 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; 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; base; bioprinting; cancer clinical trial; canine model; chemotherapy; cost; drug candidate; experience; high throughput screening; high-throughput drug screening; human disease; immunogenicity; 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.

骨肉瘤总结（PI：Sita Withers，PhD）。 该提案将确定骨肉瘤的新治疗策略，其5年生存率为70%。 表皮生长因子受体HER 2的表达在40%的人和犬中上调 在一些人类研究中，它与骨肉瘤的不良结局相关。使用小鼠模型， 骨肉瘤和肺转移，威瑟斯博士将评估EGFR：HER 2信号通路抑制剂（例如， PI 3 K-Akt和ERK/MAPK），其在乳腺癌的异种移植小鼠模型中显示出功效。的 该建议假设是EGFR家族的拟肽HER 2异源二聚化抑制剂 信号传导将导致治疗转移性OSA的新工具。威瑟斯博士的方法包括评估 自然发生的犬骨肉瘤模型，其更接近于人类肺转移， 翻译信息在人骨肉瘤治疗中的应用。小分子抑制剂的组合 其在体内显示出抗骨肉瘤发展的功效， 转移到肺部骨肉瘤和免疫细胞的3D打印将用于表征 暴露于肿瘤微环境典型特征背景下的HER 2抑制。两个具体 目的1明确EGFR家族信号传导抑制对OSA细胞功能的影响， 信号通路目的2：详细描述最佳EGFR信号传导抑制剂在治疗中的疗效和毒性。 OSA的临床前体内模型。