Inhibition of P13 Kinase as a Strategy to Abrogate Antiestrogen Resistance in Br

雌激素受体阳性(ER+)激素依赖型乳腺癌对内分泌治疗的初步反应 然而，随着更多的患者死于ER+，这些肿瘤中的许多都会产生抗药性并出现进展 乳腺癌比所有其他乳腺癌类型的总和还要多。对于这些癌症中的大多数，其机制是 从抗雌激素中逃脱仍有待发现。在当前的获奖期内，我们已经证明 磷脂酰肌醇-3激酶(PI3K)通路的激活可促进内分泌治疗的抵抗 但这一机制的论证还有待于临床进一步证实。PI3K途径总体上是 乳腺癌中最常改变的致癌途径。编码PIK3CA基因的突变 PI3K的PI10a催化亚基是乳腺癌中这一途径最常见的体细胞改变。 这些突变赋予形成PIP3的催化活性增加，并诱导生长因子-和锚定- 独立生长、对失巢细胞的抗性和抗药性。结合的小分子PAN-PI3K抑制剂 可逆地到ATP口袋的p110已经完成了第一阶段的试验。一些临床研究已经 提示ER+/PIK3CA突变肿瘤对抗雌激素的反应低于 ER+/PIK3CA野生型肿瘤。因此，我们假设抗雌激素与PI3K抑制剂相结合 与单独使用抗雌激素药物相比，对ER+/PIK3CA突变乳腺癌的治疗将更加有效。在……里面 此外，对联合治疗无效的乳腺癌会因此产生躯体改变。 与抗药性有关。为了检验这些假设，我们提出了以下目标： 目的1：测定ER+/HER2-乳腺癌患者的病理完全缓解率 用芳香酶抑制剂来曲唑和PAN-PI3K抑制剂BKM120处理 目的2：确定乳腺癌术后耐药相关的分子改变 来曲唑联合BKM120的新辅助治疗 目的3：确定在治疗后残留癌中发现的分子改变是否是因果关系 与内分泌治疗抵抗和Pisk抑制有关 相关性(请参阅说明)： 来曲唑和Pisk抑制剂(AIM 1)联合试验的阳性结果将确定 ER+/PIKSCA突变乳腺癌患者的合理治疗选择 化疗。AIMS 2和AIMS 3的结果将确定抵抗雌激素剥夺的新机制 ？Pisk抑制剂。反过来，这些机制可能代表了新的分子靶点，可以成为 未来在乳腺癌和其他依赖PI3K的癌症中的药物发现和/或临床研究。

Estrogen receptor-positive (ER+), hormone-dependent breast cancers initially respond to endocrine therapy However, many of these tumors develop drug resistance and progress, with more patients dying from ER+ breast cancer than all other breast cancer types combined. For the majority of these cancers, mechanisms of escape from antiestrogens remain to be discovered. During the current award period, we have shown that activation of the phosphatidylinositol-3 kinase (PI3K) pathway can promote resistance to endocrine therapy though demonstration of this mechanism awaits further confirmation in the clinic. The PI3K pathway is overall the most frequently altered oncogenic pathway in breast cancer. Mutations in PIK3CA, the gene encoding the p i 10a catalytic subunit of PI3K, are the most common somatic alterations of this pathway in breast cancer. These mutations confer increased PIP3-forming catalytic activity and induce growth factor- and anchorage- independent growth, resistance to anoikis, and drug resistance. Small molecule pan-PI3K inhibitors that bind reversibly to the ATP pocket of p110 have completed phase I trials. Some clinical studies have already suggested that ER+/PIK3CA mutant tumors exhibit a lower response to antiestrogens compared to ER+/PIK3CA wild-type tumors. Thus, we hypothesize that antiestrogens in combination with a PI3K inhibitor will be more effective against ER+/PIK3CA mutant breast cancers compared to the antiestrogen alone. In addition, breast cancers that do not respond to the combination will contain somatic alterations causally associated with drug resistance. To test these hypotheses, we propose the following aims: Aim 1: To determine the rate of pathological complete response in patients with ER+/HER2- breast cancer treated with the aromatase inhibitor letrozole and the pan-PI3K inhibitor BKM120 Aim 2: To identify molecular alterations potentially associated with drug resistance in breast cancers after neoadjuvant therapy with letrozole plus BKM120 Aim 3: To determine whether molecular alterations identified in post-treatment residual cancers are causally associated with resistance to endocrine therapy and inhibition of PISK RELEVANCE (See instructions): Positive results from the trial with the combination of letrozole and the PISK inhibitor (Aim 1) will identify a rational treatment option for patients with ER+/PIKSCA mutant breast cancer that does not include chemotherapy. Results from Aims 2 and 3 will identify novel mechanisms of resistance to estrogen deprivation ¿ the PISK inhibitor. These mechanisms, in turn, may represent new molecular targets that can be the focus of future drug discovery and/or clinical investigation in breast and other PI3K-depent cancers.