Project 3 (Halushka)

胰岛素样生长因子和胰岛素系统对激素抵抗乳腺癌的调节有效且耐受性好，激素类药物如他莫昔芬和芳香酶抑制剂对雌激素受体阳性(ER“^)乳腺癌的治疗在辅助和转移环境中有着深远的影响。呃，乳腺癌占所有乳腺癌的大多数。然而，对这些药物的原发和获得性耐药是常见的，开发新的方法来克服或预防耐药性将对乳腺癌产生重大影响。胰岛素样生长因子(IGF)信号转导途径通过激活两种膜受体酪氨酸激酶：1)IGF-I受体(IGF-IR)与IGF-I和IGF-II结合；2)InsR异构体A(InsR-A)与IGF-II结合，被认为是针对ER的治疗的主要耐药途径。我们现在证明，用酪氨酸激酶抑制剂(BMS-754807)完全阻断两种胰岛素样生长因子信号受体足以在体内逆转对激素治疗的耐药性。相反，单独抑制IGF-IR并不能诱导退行性改变并导致InsR-A亚型的上调。目前尚不清楚InsR(InsR-B)的代谢异构体是否对激素治疗耐药中的增殖和生存信号起重要作用。InsR-B与Ins结合，而不是IGF-I或IGF-II。这个问题很重要，因为BMS-754807除了抑制胰岛素样生长因子-IR外，还抑制两种InsR亚型，并可能具有阻止INS对InsR-B作用的潜在代谢倾向。然而，INS信号阻断对于逆转激素治疗耐药也是有道理的。我们的首要目标是确定哪些IGF/INS信号组件是这种效果所必需的。我们假设，在多种模型中，IGF阻断足以在体内克服激素治疗抵抗，不太可能上调替代信号机制，并且在有效剂量下对乳腺癌患者是耐受的。为了验证这些假设，我们建议：1)在激素治疗抵抗模型中优化BMS-754807的组合，2)确定INS和/或InsR-A信号是否足以产生胰岛素样生长因子-IR非依赖性对激素治疗的抵抗，以及3)评估BMS-754807和来曲唑的疗效，并在乳腺癌患者中进行相关研究。

Regulation of Hormone Resistant Breast Cancer by IGF and Insulin System Signaling Both effective and tolerable, hormonal agents such as tamoxifen and aromatase inhibitors have had a profound Impact on the treatment of estrogen receptor positive (ER"^) breast cancer in the adjuvant and metastatic setting. ER+ breast cancers represent the majority of all breast cancer. However, both primary and acquired resistance to these agents is common and developing new methods to overcome or prevent resistance would have a major impact in breast cancer. Insulin-like growth factor (IGF) signaling has been implicated as a major resistance pathway to therapies directed at the ER through the activation of two membrane receptor tyrosine kinases: 1) IGF-I receptor (IGF-IR) through binding in IGF-I and IGF-II and the 2) InsR Isoform A (InsR-A) through binding of IGF-II. We now demonstrate evidence that complete blockade of both IGF signaling receptors with a tyrosine kinase inhibitor (BMS-754807) is sufficient to reverse resistance to hormonal therapy in vivo. In contrast, IGF-IR inhibition alone did not induce regression and led to upregulation of InsR-A Isoforms. It is unclear if the metabolic isoform of the InsR (InsR-B), which binds Ins, but not IGF-I or IGF-II is important to proliferation and survival signaling in hormonal therapy resistance. This question is important, as BMS-754807 inhibits both InsR isoforms in addition to IGF-IR and may have potential metabolic liabilities of blocking the action of Ins on InsR-B. However, it is also plausible that Ins signaling blockade is important to reversal of hormone therapy resistance. Our overarching goal is to determine which IGF/Ins signaling components are necessary for this effect. We hypothesize that IGF blockade is sufficient to overcome hormonal therapy resistance in vivo in multiple models, has less potential to upregulate alternative signaling mechanisms and will be tolerable at effective doses in breast cancer patients. To test these hypotheses, we propose to: 1) optimize BMS-754807 combinations in hormonal therapy resistant models, 2) determine if Ins and/or InsR-A signaling is sufficient for IGF-IR-independent resistance to homrional therapy and 3) evaluate the efficacy of BMS-754807 and letrozole and perform correlative studies in patients with breast cancer.