Disrupting insulin receptor function in breast cancer

破坏乳腺癌中的胰岛素受体功能

• 批准号: 10171816
• 负责人: Douglas Yee
• 金额: $ 34.74万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10171816
• 关键词: Adult; Biological Models; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Treatment; Breast Cancer therapy; Cancer Biology; Clinical Trials; Data; Development; Directed Molecular Evolution; Drug Targeting; ERBB2 gene; Endocrine; Engineering; Estrogen Receptor alpha; Failure; Family; Growth; Hyperinsulinism; Insulin; Insulin Antagonists; Insulin Receptor; Insulin-Like Growth Factor Receptor; Insulin-Like-Growth Factor I Receptor; Ligands; Malignant Neoplasms; Normal tissue morphology; Patients; Play; Protein Isoforms; Regulation; Regulatory Pathway; Research; Resistance; Role; Signal Transduction; Signaling Protein; Somatomedins; System; Testing; Therapeutic; Type I Insulin; Woman; base; blood glucose regulation; clinically relevant; driver mutation; effective therapy; efficacy evaluation; fetal; inhibitor/antagonist; malignant breast neoplasm; malignant phenotype; member; mortality; receptor; receptor function; synthetic protein; targeted agent; treatment strategy

Clinical trials testing type 1 insulin-like growth factor receptor (IGF-1R) inhibitors failed in endocrine- sensitive and resistant breast cancer. These trials failed to include targeting of the insulin receptor (IR) and essential component of the IGF signaling system. Further, data from patients with endocrine resistant breast cancer showed that insulin receptor (IR) is more highly expressed in breast cancer cells than IGF- 1R. While it may seem futile to target IR, data show the fetal isoform of IR, IR-A, is more highly expressed than the adult isoform IR-B in cancers. Thus, it may be possible to create a cancer specific inhibitor of a highly expressed receptor for breast cancer treatment. We hypothesize that targeting of IR alone and in combination with other breast cancer therapeutics will be an effective therapy. Moreover, specifically targeting IR-A will be cancer specific with little impact on glucose homeostasis. To test this hypothesis, we propose three specific aims: 1) Engineer IR-A antagonists using small synthetic protein ligands via directed evolution; 2) Demonstrate IR-A regulation of the breast cancer malignant phenotype compared to IR-B and define a mechanism; and 3) Evaluate the efficacy of an IR-A specific antagonist, our existing IR-A and IR-B antagonists, and IGF-1R antagonists alone and in combination in breast cancer model systems Major advances in breast cancer have been the direct result of understanding and targeting key growth regulatory signals. Based on the failure of trials targeting the IGF-1R, we now have clear evidence that IR play a critical role in breast cancer development. Just as we were at the among the first to develop IGF-1R inhibitors, we have shown that IR inhibitors also may be used to target breast cancer. Completion of this proposal will further the development of new targeted breast cancer therapies. Cancer specific IR may be accomplished by development of an IR-A specific inhibitor. Given the growing number of women with hyperinsulinemia, creating a cancer specific inhibitor of IR could have significant impact.

临床试验测试1型胰岛素样生长因子受体（IGF-1R）抑制剂在内分泌中失败 敏感和抗性乳腺癌。这些试验未能包括靶向胰岛素受体（IR） IGF信号系统的基本组成部分。此外，来自耐内分泌患者的数据 乳腺癌表明，胰岛素受体（IR）在乳腺癌细胞中比IGF-高表达 1r。虽然目标IR似乎徒劳无功，但数据显示IR，IR-A的胎儿同工型更高 比癌症中的成年同工型IR-B表示。因此，有可能创建特定于癌症的 高表达乳腺癌治疗的受体的抑制剂。 我们假设单独靶向IR并与其他乳腺癌疗法结合使用 成为一种有效的疗法。此外，专门针对IR-A将是癌症的特定于癌症 葡萄糖稳态。为了检验这一假设，我们提出了三个具体目的：1）工程师IR-A 通过定向进化，使用小合成蛋白配体的拮抗剂； 2）展示IR-A法规 与IR-B相比，乳腺癌恶性表型的表型并定义了A机制； 3）评估 IR-A特定拮抗剂，我们现有的IR-A和IR-B拮抗剂以及IGF-1R拮抗剂的功效 单独和组合乳腺癌模型系统 乳腺癌的重大进展是理解和靶向关键增长的直接结果 监管信号。基于针对IGF-1R的试验的失败，我们现在有明确的证据表明IR 在乳腺癌发育中起关键作用。就像我们在第一个开发IGF-1R的人中一样 抑制剂，我们已经表明，IR抑制剂也可以用于靶向乳腺癌。完成此操作 提案将进一步发展新的靶向乳腺癌疗法。癌症特定的IR可能是 通过开发IR-A特异性抑制剂完成。考虑到越来越多的女性 高胰岛素血症，产生癌症特异性IR抑制剂可能会产生重大影响。