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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.

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-