Disrupting insulin receptor function in breast cancer

破坏乳腺癌中的胰岛素受体功能

基本信息

批准号：
10412979
负责人：
Douglas Yee
金额：
$ 33.95万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
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/10412979
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 antagonist base blood glucose regulation clinically relevant driver mutation effective therapy efficacy evaluation fetal inhibitor malignant breast neoplasm malignant phenotype member mortality receptor receptor function synthetic protein targeted agent treatment strategy

项目摘要

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-1R) 抑制剂在内分泌方面失败的临床试验敏感和耐药乳腺癌。这些试验未能包括针对胰岛素受体 (IR) 是 IGF 信号系统的重要组成部分。此外，来自内分泌抵抗患者的数据乳腺癌表明胰岛素受体 (IR) 在乳腺癌细胞中的表达水平高于 IGF- 1R。虽然以 IR 为目标似乎是徒劳的，但数据显示 IR 的胎儿同种型 IR-A 的作用更高在癌症中比成人同种型 IR-B 更表达。因此，有可能创造出一种癌症特异性的药物。用于乳腺癌治疗的高表达受体抑制剂。我们假设单独靶向 IR 以及与其他乳腺癌疗法相结合将成为一种有效的疗法。此外，专门针对 IR-A 的药物将具有癌症特异性，对葡萄糖稳态。为了检验这一假设，我们提出了三个具体目标：1）工程师 IR-A 通过定向进化使用小型合成蛋白配体的拮抗剂； 2) 展示IR-A调节与 IR-B 相比的乳腺癌恶性表型并确定机制； 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-1R 拮抗剂的功效在乳腺癌模型系统中单独和组合乳腺癌的重大进展是理解和瞄准关键生长的直接结果监管信号。基于针对 IGF-1R 的试验失败，我们现在有明确的证据表明 IR 在乳腺癌的发生发展中发挥着关键作用。正如我们是最早开发 IGF-1R 的公司之一抑制剂，我们已经证明 IR 抑制剂也可用于治疗乳腺癌。完成此该提案将进一步开发新的乳腺癌靶向疗法。癌症特异性 IR 可能是通过开发 IR-A 特异性抑制剂来实现。鉴于越来越多的女性患有高胰岛素血症，创造一种癌症特异性 IR 抑制剂可能会产生重大影响。