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+）、乳腺癌依赖性乳腺癌最初对内分泌治疗有反应 然而，这些肿瘤中有许多产生耐药性并进展，更多的患者死于ER+ 乳腺癌比所有其他类型乳腺癌的总和。对于大多数这些癌症， 对抗雌激素的逃逸仍有待发现。在当前的奖励期间，我们已经表明， 磷脂酰肌醇-3激酶（PI 3 K）通路的激活可促进对内分泌治疗的抵抗 但这一机制的证明尚待临床进一步证实。PI 3 K通路总体上是 乳腺癌中最常改变的致癌途径。PIK 3CA中的突变，该基因编码 PI 3 K的β 110 α催化亚基是乳腺癌中该途径最常见的体细胞改变。 这些突变赋予增加的PIP 3形成催化活性，并诱导生长因子和锚定。 独立生长、抗失巢凋亡和耐药性。小分子pan-PI 3 K抑制剂， 可逆地与p110的ATP口袋结合的研究已经完成了I期试验。一些临床研究已经 表明ER+/PIK 3CA突变型肿瘤对抗雌激素的反应较低， ER+/PIK 3CA野生型肿瘤。因此，我们假设抗雌激素药与PI 3 K抑制剂联合使用， 与单独的抗雌激素相比，对ER+/PIK 3CA突变乳腺癌更有效。在 此外，对联合用药无反应的乳腺癌将含有因果关系上的体细胞改变， 与耐药性有关。为了验证这些假设，我们提出了以下目标： 目的1：确定ER+/HER 2-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PI 3 K抑制剂BKM 120治疗 目的2：确定与乳腺癌耐药相关的分子改变， 来曲唑联合BKM 120的新辅助治疗 目的3：确定在治疗后残留癌中鉴定的分子改变是否是因果关系。 与内分泌治疗抵抗和PISK抑制相关 相关性（参见说明）： 来曲唑和PISK抑制剂联合试验的阳性结果（目的1）将确定一种新的治疗方法， ER+/PIKSCA突变乳腺癌患者的合理治疗选择，不包括 化疗目标2和3的结果将确定对雌激素剥夺的抵抗的新机制 PISK抑制剂。反过来，这些机制可能代表了新的分子靶点，可以成为药物治疗的重点。 在乳腺癌和其他PI 3 K依赖性癌症中的未来药物发现和/或临床研究。