PKC-Mediated Inhibition of SRC-3 for the Treatment of ER+ Breast Cancer

PKC 介导的 SRC-3 抑制治疗 ER 乳腺癌

• 批准号: 8747142
• 负责人: BERT W O'MALLEY
• 金额: $ 26.04万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8747142
• 关键词: Address; Agonist; Animal Model; Aromatase Inhibition; Aromatase Inhibitors; Basic Science; Binding Sites; Breast Cancer Cell; Breast Cancer Model; Breast Carcinoma; Cancer Cell Growth; Cancer Patient; Cancer cell line; Cell Culture Techniques; Cell Line; Cell Proliferation; Clinical; Clinical Trials; Development; Disease; ERBB2 gene; Endocrine; Estrogen Receptors; Estrogens; FDA approved; Family member; Fulvestrant; Gene Expression; Genes; Hormones; Human; In Vitro; Laboratories; Ligand Binding; Malignant Neoplasms; Mediating; Mediator of activation protein; Mus; Nuclear Receptor Coactivator 3; Oncogenes; Oncogenic; Outcome; Pattern; Phase; Post-Translational Protein Processing; Protein Isoforms; Protein Kinase C; Protein Kinase C Inhibitor; Proteins; Refractory; Refractory Disease; Reporting; Resistance; Role; Signal Transduction; Site; Small Interfering RNA; Steroid Receptors; Tamoxifen; Toxic effect; Translational Research; Woman; Xenograft procedure; anticancer activity; base; cancer cell; cell growth; conventional therapy; deprivation; established cell line; hormone therapy; improved; in vivo; inhibitor/antagonist; innovation; malignant breast neoplasm; multicatalytic endopeptidase complex; overexpression; pre-clinical; protein expression; protein protein interaction; response; restoration; safety testing; small molecule; therapy resistant; tumor; upstream kinase

Steroid receptor coacfivator-3/amplified in breast cancer-1 (SRC-3/AIB1) is frequently overexpressed in breast carcinomas and can promote cell growth and resistance to endocrine therapies. In breast carcinomas overexpressing SRC-3, especially when in combination with activated HER2 signaling, the selective ER modulator (SERM) tamoxifen functions as an ER agonist. ER+/HER2+ tumors have a very poor response to tamoxifen treatment if SRC-3 is also overexpressed. Experimental targeting of SRC-3 can both a) augment the anti-estrogenic and anti-proliferative activity of tamoxifen in hormone-naive breast cancer cell lines, and b) restore the anti-estrogenic and anti-proliferative activity of tamoxifen in refractory breast cancer cell lines. Therefore, targeting SRC-3 expression and/or function is expected to enhance the activity of first-line conventional therapy and restore sensitivity in treatment-refractory breast cancer. Unfortunately, up to this point, SRC-3 has been considered "undruggable" because it lacks a natural ligand-binding site that can be inhibited by small molecule compounds and protein:protein interacfions are difficult to disrupt. Importanfiy, the stability and activity of the SRC-3 protein are strongly regulated via its post-translational modificafion (PTM) by upstream kinase signaling networks, including protein kinase C (PKC). PKC family members can phosphorylate and protect SRC-3 from proteasome-mediated degradation. Given the critical role of SRC-3 in breast cancer and the lack of FDA-approved SRC-3 targeting agents, this proposal represents an innovafive hypothesis-driven approach, based on key basic research and robust preclinical evidence, to establish PKC SMls as first-in-class inhibitors of SRC-3 expression and function and as targeted therapies for use in combination with conventional agents for ER+ breast cancer. Preliminary studies demonstrate that PKC inhibitors (including agents that have been well-tolerated in clinical trials in other diseases) can, at clinically achievable and tolerated concentrafions, decrease SRC-3 protein expression, exert anticancer activity in SRC-3-overexpressing cell lines, enhance the anticancer activity of endocrine therapy in sensifive cells lines, and restore sensitivity to endocrine therapy in resistant breast cancer cell lines and xenografts. RELEVANCE

乳腺癌1（SRC-3/AIB1）在乳腺癌中经常过度表达乳腺癌1（SRC-3/AIB1）的类固醇受体共助剂3/可以促进细胞生长和对内分泌疗法的耐药性。在过表达SRC-3的乳腺癌中，尤其是当与激活的HER2信号传导结合使用时，选择性ER调节剂（SERM）他莫昔芬充当ER激动剂。如果SRC-3也过表达，ER+/HER2+肿瘤对他莫昔芬治疗的反应很差。 SRC-3的实验靶向既可以a）提高他莫昔芬在激素 - 乳腺癌细胞系中的抗雌激素和抗增殖活性，b）恢复了他莫昔芬在难治性乳腺癌细胞系中的抗雌激素和抗增殖活性。因此，靶向SRC-3表达和/或功能有望增强一线常规疗法的活性，并恢复治疗 - 饮食性乳腺癌的敏感性。不幸的是，到目前为止，SRC-3被认为是“不可能”的，因为它缺乏天然的配体结合位点，可以被小分子化合物和蛋白质抑制：蛋白质互动很难破坏。 extixanfiy，SRC-3蛋白的稳定性和活性通过其翻译后强烈调节 上游激酶信号网络（包括蛋白激酶C（PKC））的修改（PTM）。 PKC家庭 成员可以磷酸化并保护SRC-3免受蛋白酶体介导的降解。给定批判 SRC-3在乳腺癌和缺乏FDA批准的SRC-3靶向剂中的作用，该提案 代表一种基于关键基础研究和鲁棒临床前的创新假设驱动的方法 证据，将PKC SML作为SRC-3表达和功能的第一类抑制剂，并 靶向疗法与常规剂+乳腺癌结合使用。初步的 研究表明，PKC抑制剂（包括在临床试验中良好耐受性的药物 其他疾病）可以在临床上可实现和耐受的浓度下降低SRC-3蛋白 表达，在SRC-3过表达细胞系中发挥抗癌活性，增强了抗癌的活性 敏感细胞系中的内分泌治疗，并恢复对耐药性乳腺内分泌疗法的敏感性 癌细胞系和异种移植物。 关联