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

抑制 P13 激酶作为消除 Br 抗雌激素耐药性的策略

• 批准号: 8764757
• 负责人: Carlos L Arteaga
• 金额: $ 27.75万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8764757
• 关键词: 1-Phosphatidylinositol 3-Kinase; Aftercare; Anchorage-Independent Growth; Anoikis; Antiestrogen Therapy; Aromatase Inhibitors; Award; Binding; Biological Assay; Biological Markers; Biopsy; Breast; Breast Cancer Cell; Catalytic Domain; Cellularity; Clinic; Clinical Research; Clinical Trials; Copy Number Polymorphism; Cytotoxic Chemotherapy; DNA; Development; Drug resistance; ERBB2 gene; Estrogen Antagonists; Estrogen Receptor Modulators; Estrogen receptor positive; Estrogens; Exhibits; Frequencies; Future; Gene Targeting; Genes; Growth Factor; Harvest; Health; Heterogeneity; Hormones; Human; In complete remission; Instruction; Investigation; Letrozole; Malignant Neoplasms; Measures; Mediator of activation protein; Metabolic Marker; Molecular; Molecular Analysis; Molecular Target; Mutation; Natural History; Neoadjuvant Therapy; Nucleotides; Oncogenic; Open Reading Frames; Operative Surgical Procedures; Outcome; PET/CT scan; PIK3CA gene; Pathway interactions; Patients; Phase I Clinical Trials; Phenotype; Phosphotransferases; Placebos; Randomized; Randomized Clinical Trials; Residual Cancers; Resistance; Staging; System; Testing; Time; Tissues; Ultrasonography; Variant; Woman; Xenograft procedure; base; cancer type; chemotherapy; deprivation; disorder subtype; drug discovery; exome sequencing; hormone therapy; insertion/deletion mutation; kinase inhibitor; lymph nodes; malignant breast neoplasm; molecular marker; mutant; novel; overexpression; pre-clinical; resistance mechanism; response; small hairpin RNA; small molecule; tumor; tumor growth

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.

雌激素受体阳性（ER+）、激素依赖性乳腺癌最初对内分泌治疗有反应 然而，许多此类肿瘤会产生耐药性并进展，更多患者死于 ER+ 乳腺癌的发病率高于所有其他乳腺癌类型的总和 对于大多数此类癌症，其发病机制如下。 在当前的奖励期内，我们已经证明了抗雌激素的逃逸仍有待发现。 磷脂酰肌醇 3 激酶 (PI3K) 通路的激活可促进内分泌治疗的耐药性 尽管这一机制的论证有待临床的进一步证实，但 PI3K 通路是总体的。 乳腺癌中最常改变的致癌途径。PIK3CA 是编码 PIK3CA 的基因。 PI3K 的 pi 10a 催化亚基是乳腺癌中该途径最常见的体细胞改变。 这些突变赋予 PIP3 形成催化活性增加并诱导生长因子和锚定 独立生长、抗失巢凋亡和结合小分子泛 PI3K 抑制剂。 可逆地作用于p110的ATP口袋已经完成了一些临床研究。 表明 ER+/PIK3CA 突变肿瘤与抗雌激素药物相比表现出较低的反应 因此，我们捕获了抗雌激素与 PI3K 抑制剂的组合。 与单独使用抗雌激素相比，它对 ER+/PIK3CA 突变乳腺癌更有效。 此外，对这种组合没有反应的乳腺癌将包含因果性的体细胞改变 为了检验这些假设，我们提出以下目标： 目标 1：确定 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泛 PI3K 抑制剂 BKM120 治疗 目标 2：确定与乳腺癌耐药性相关的分子改变 来曲唑联合 BKM120 新辅助治疗 目标 3：确定治疗后残留癌症中发现的分子改变是否是因果关系 与内分泌治疗耐药和 PISK 抑制相关 相关性（参见说明）： 来曲唑和 PISK 抑制剂联合试验（目标 1）的积极结果将确定 ER+/PIKSCA 突变乳腺癌患者的合理治疗选择，不包括 目标 2 和 3 的结果将确定抵抗雌激素剥夺的新机制。 ¿反过来，这些机制可能代表新的分子靶点，成为研究的焦点。 乳腺癌和其他 PI3K 依赖性癌症的未来药物发现和/或临床研究。