Project 3 (Halushka)

通过IGF和胰岛素系统信号传导调节激素抵抗性乳腺癌激素药物如他莫昔芬和芳香酶抑制剂在辅助和转移性环境中对雌激素受体阳性（ER+）乳腺癌的治疗都是有效和可耐受的。ER+乳腺癌占所有乳腺癌的大多数。然而，对这些药物的原发性和获得性耐药性都很常见，开发克服或预防耐药性的新方法将对乳腺癌产生重大影响。胰岛素样生长因子（IGF）信号传导已被认为是通过激活两种膜受体酪氨酸激酶对针对ER的疗法的主要抗性途径：1）通过结合IGF-I和IGF-II的IGF-I受体（IGF-IR）和2）通过结合IGF-II的InsR同种型A（InsR-A）。我们现在证明，用酪氨酸激酶抑制剂（BMS-754807）完全阻断两种IGF信号受体足以逆转体内对激素治疗的耐药性。相比之下，单独的IGF-IR抑制不诱导消退，并导致InsR-A亚型的上调。目前尚不清楚InsR的代谢同种型（InsR-B），其结合Ins，但不结合IGF-I或IGF-II，是否对激素治疗抵抗中的增殖和存活信号传导重要。这个问题很重要，因为BMS-754807除了抑制IGF-IR外还抑制InsR亚型，并且可能具有阻断Ins对InsR-B作用的潜在代谢责任。然而，Ins信号传导阻断对于逆转激素治疗抵抗也是重要的。我们的首要目标是确定哪些IGF/Ins信号传导组件是必要的这种效果。我们假设IGF阻断足以克服多种模型中体内激素治疗的耐药性，上调替代信号传导机制的可能性较小，并且在乳腺癌患者中在有效剂量下是可耐受的。为了检验这些假设，我们提出：1）在激素疗法抗性模型中优化BMS-754807组合，2）确定Ins和/或InsR-A信号传导是否足以对胰岛素疗法产生IGF-IR非依赖性抗性，以及3）评估BMS-754807和来曲唑的功效，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.