Disrupting insulin receptor function in breast cancer

检测I型胰岛素样生长因子受体(IGF-1R)抑制剂的临床试验在内分泌- 敏感和耐药的乳腺癌。这些试验没有包括以胰岛素受体(IR)为靶点 也是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 乳腺癌研究表明，胰岛素受体(IR)在乳腺癌细胞中的表达高于IGF-1。 1R。虽然以IR为靶点似乎没有用，但数据显示，IR的胎儿亚型IR-A的水平更高 在癌症中的表达高于成体异构体IR-B。因此，有可能创造出一种癌症特异性 用于乳腺癌治疗的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药物联合使用将 是一种有效的治疗方法。此外，针对IR-A的特定靶点将是癌症特异性的，对 葡萄糖动态平衡。为了验证这一假设，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的合成蛋白配体的拮抗剂；2)展示IR-A调节 乳腺癌恶性表型与IR-B的比较，并确定机制；以及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拮抗剂的疗效 在乳腺癌模型系统中单独和联合使用 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的试验的失败，我们现在有明确的证据表明IR 在乳腺癌的发生发展中起着关键作用。就像我们是最早开发IGF-1R的人之一 抑制剂，我们已经证明IR抑制剂也可以用于靶向乳腺癌。完成这项工作 该提案将进一步开发新的靶向乳腺癌治疗方法。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，产生一种癌症特异性的IR抑制物可能会产生重大影响。

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.