Effect of CX4945 in tamoxifen resistant BCa

CX4945 在他莫昔芬耐药 BCa 中的作用

• 批准号: 10228560
• 负责人: Christopher Williams
• 金额: $ 28.4万
• 依托单位: XAVIER UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-05 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10228560
• 关键词: Antiestrogen Therapy; Antineoplastic Agents; Attenuated; Breast Carcinoma; Clinical; Degradation Pathway; Development; Diagnosis; Down-Regulation; Endocrine; Endocrine Gland Neoplasms; Estrogen Antagonists; Estrogen Receptor alpha; Estrogen Receptors; Estrogens; Genomics; Goals; Hormones; Incidence; Investigation; Lead; Length; Ligands; Mediating; Metastatic Neoplasm to Lymph Nodes; Modeling; Molecular Chaperones; Mutation; Oncogenic; Patients; Pharmacology; Phosphorylation; Phosphotransferases; Play; Protein Isoforms; Proteins; Quality of life; Receptor Signaling; Relapse; Reporting; Resistance; Role; Selective Estrogen Receptor Modulators; Signal Transduction; Tamoxifen; Testing; Tissue Microarray; Transcript; Ubiquitination; Variant; casein kinase II; efficacious treatment; estrogen disruption; estrogenic; inhibitor/antagonist; malignant breast neoplasm; non-genomic; patient derived xenograft model; preclinical study; prevent; receptor; rho; therapy resistant; tumor xenograft; tumorigenesis

Non-genomic estrogen signaling has been implicated in mediating therapeutic resistance to anti-estrogen therapies in breast carcinoma (BCa) and may contribute to the mitogenic effects of selective estrogen receptor modulators (SERMS). ERα36 [a 36 Kd transcript variant of estrogen receptor alpha (ERα)] mediates non- genomic estrogen signaling, and is implicated in anti-estrogen resistance and anti-estrogen induced mitogenesis1. Dual inhibition of ERα66 (full length ERα) and ERα36 signaling might prove to be a more efficacious mode of antihormonal therapy that avoids the acquisition of anti-estrogen induced resistance and tumorigenesis. This can be achieved by pharmacological targeting of the common posttranslational regulatory mechanisms (ie, phosphorylation) between the two isoforms. CX4945 (silmitasertib), a clinical stage CK2 inhibitor, represses protein levels of both ERα66 and ERα36. As such CX4945 might serve to uniquely disrupt oncogenic kinase signaling as well as reduces stability of ERα isoforms in BCa. We hypothesize that CX4945 inhibits both genomic and nongenomic estrogenic signaling by functioning as an indirect pan-estrogen receptor downregulator which disrupts both ERα66 and ERα36 expression in BCa. In order to test this hypothesis we will: Aim I. Investigate the role of the ERα66/36 /CK2 signaling axis in the development of tamoxifen resistance. For this aim we hypothesize that CK2 promotes the development of 4HT resistance by promoting aberrant ERα signaling. We will determine the incidence and causative role of altered ERα36 and CK2 expression in the development of tamoxifen resistance in breast cancer. Aim 2 Elucidate the mechanisms of CX4945 mediated downregulation of ERα66/36 in BCa. Here we hypothesize that pharmacological inhibition of CK2 with CX4945 renders ERα isoforms susceptible to the 26S proteasomal degradation pathway. We will ascertain the impact of CK2 mediated phosphorylation of ERα66/36 on chaperone interaction, ubiquitination and subsequently the proteolytic degradation of ERα36. Aim 3 Assess the antineoplastic efficacy of CX4945 in paired patient derived xenograft (PDX) models of 4HT sensitive and resistant models of BCa. We hypothesize that CX4945 will inhibit the progression of tamoxifen-sensitive and tamoxifen-resistant (de novo and acquired) PDX tumors. PDX tumors from endocrine sensitive patients will be used to generate models of acquired resistance, whereas de-novo resistance will be modelled using PDX from patients with Y537S mutation. The successful completion of these studies could lead to the use of CX4945 or similar CK2 inhibitors with indirect pan-ERα downregulating functions in the treatment of hormone sensitive and hormone resistant breast cancer.

非基因组雌激素信号传导与介导抗雌激素治疗耐药有关 乳腺癌（BCa）的治疗，可能有助于选择性雌激素受体的促有丝分裂作用 调节剂 (SERMS) [雌激素受体 α (ERα) 的 36 Kd 转录变体] 介导非 基因组雌激素信号传导，并参与抗雌激素抵抗和抗雌激素诱导 有丝分裂1. ERα66（全长ERα）和ERα36信号传导的双重抑制可能被证明是更有效的。 有效的抗激素治疗模式，避免获得抗雌激素诱导的耐药性 这可以通过共同翻译后调节的药理学靶向来实现。 CX4945 (silmitasertib) 的临床阶段 CK2 之间的机制（即磷酸化）。 抑制剂，抑制 ERα66 和 ERα36 的蛋白质水平，因此 CX4945 可能具有独特的破坏作用。 CX4945 会降低致癌激酶信号传导并降低 ERα 亚型的稳定性。 通过作为间接全雌激素受体抑制基因组和非基因组雌激素信号传导 下调剂，可破坏 BCa 中 ERα66 和 ERα36 的表达。 为了检验这个假设，我们将： 目标 I. 研究 ERα66/36 /CK2 信号轴在他莫昔芬耐药发展中的作用。 为此，我们追求 CK2 通过促进异常 ERα 来促进 4HT 抗性的发展 我们将确定 ERα36 和 CK2 表达改变的发生率和致病作用。 乳腺癌中他莫昔芬耐药性的发展。 目标 2 阐明 CX4945 介导的 BCa 中 ERα66/36 下调的机制。 CX4945 对 CK2 的药理学抑制使 ERα 亚型对 26S 敏感 我们将确定 CK2 介导的 ERα66/36 磷酸化对蛋白酶体降解途径的影响。 分子伴侣相互作用、泛素化以及随后的 ERα36 蛋白水解降解。 目标 3 评估 CX4945 在配对患者衍生异种移植 (PDX) 模型中的抗肿瘤功效 我们勇敢地说 CX4945 会抑制 BCa 的 4HT 敏感和耐药模型。 来自内分泌的对他莫昔芬敏感和他莫昔芬耐药的（从头和获得性）PDX 肿瘤。 敏感患者将被用来生成获得性耐药模型，而新生耐药将被用于生成耐药性模型。 使用 Y537S 突变患者的 PDX 进行建模。 这些研究的成功完成可能导致使用 CX4945 或类似的 CK2 抑制剂间接治疗 pan-ERα 下调功能在激素敏感和激素抵抗乳腺癌的治疗中。