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.

测试1型胰岛素样生长因子受体（IGF-1 R）抑制剂的临床试验在内分泌- 敏感和耐药乳腺癌。这些试验没有包括靶向胰岛素受体（IR） IGF信号系统的重要组成部分。此外，来自内分泌耐药患者的数据 乳腺癌研究表明，胰岛素受体（IR）在乳腺癌细胞中的表达比IGF-1更高。 1 R.虽然靶向IR似乎是徒劳的，但数据显示IR的胎儿亚型IR-A比IR的胎儿亚型IR-A更高。 在癌症中比成人同种型IR-B表达。因此，有可能创造一种癌症特异性 用于乳腺癌治疗高表达受体的抑制剂。 我们假设单独靶向IR以及与其他乳腺癌治疗方法联合使用将 是一种有效的疗法。此外，特异性靶向IR-A将是癌症特异性的，对癌症的影响很小。 葡萄糖稳态为了验证这一假设，我们提出了三个具体的目标：1）工程师IR-A 通过定向进化使用小的合成蛋白质配体的拮抗剂; 2）证明IR-A调节 乳腺癌恶性表型与IR-B相比，并定义一种机制;和3）评估 IR-A特异性拮抗剂、我们现有的IR-A和IR-B拮抗剂以及IGF-1 R拮抗剂的功效 单独和组合在乳腺癌模型系统中 乳腺癌的重大进展是理解和瞄准关键增长的直接结果。 监管信号。基于针对IGF-1 R的试验失败，我们现在有明确的证据表明，IR 在乳腺癌的发展中起着关键作用。就像我们在第一批开发IGF-1 R的人中一样， 尽管IR抑制剂的研究进展缓慢，但我们已经表明IR抑制剂也可用于靶向乳腺癌。完成本 该提案将进一步开发新的靶向乳腺癌疗法。癌症特异性IR可能是 通过开发IR-A特异性抑制剂来实现。鉴于越来越多的妇女 高胰岛素血症，产生IR的癌症特异性抑制剂可能具有显著影响。