Effect of CX4945 in tamoxifen resistant BCa

CX4945 在他莫昔芬耐药 BCa 中的作用

• 批准号: 10458662
• 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/10458662
• 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; 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转导与介导抗雌激素治疗耐药性有关 乳腺癌（BCa）的治疗，并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）。ERα36 [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，并涉及抗雌激素抗性和抗雌激素诱导的 有丝分裂ERα66（全长ERα）和ERα36信号的双重抑制可能被证明是一种更有效的方法。 有效的抗激素治疗模式，避免获得抗雌激素诱导的抗性， 肿瘤发生这可以通过药理学靶向常见的翻译后调节蛋白来实现 两种亚型之间的机制（即磷酸化）。CX 4945（silmitasertib），临床分期CK 2 抑制剂，抑制ERα66和ERα36的蛋白水平。因此，CX 4945可能会独特地破坏 致癌激酶信号传导以及降低BCa中ERα亚型的稳定性。我们假设CX4945 作为间接的泛雌激素受体，抑制基因组和非基因组雌激素信号传导 BCa中ERα66和ERα36表达的下调因子。 为了验证这一假设，我们将： 艾姆岛研究ERα66/36 /CK 2信号传导轴在他莫昔芬耐药发生中的作用。 为此，我们假设CK 2通过促进异常ERα表达而促进4-HT抵抗的发展。 发信号。我们将确定ERα36和CK 2表达改变在乳腺癌中的发生率和致病作用。 乳腺癌中他莫昔芬耐药性的发展。 目的2探讨CX4945下调BCa细胞ERα66/36的机制。这里我们 假设CX4945对CK 2的药理学抑制使ERα亚型对26 S敏感， 蛋白酶体降解途径我们将确定CK 2介导的ERα66/36磷酸化对 伴侣蛋白相互作用、泛素化和随后的ERα36的蛋白水解降解。 目的3评估CX4945在配对患者来源的异种移植物（PDX）模型中的抗肿瘤疗效， BCa的4-HT敏感和抗性模型。我们假设CX4945将抑制 他莫昔芬敏感和他莫昔芬耐药（新发和获得性）PDX肿瘤。内分泌PDX肿瘤 敏感患者将用于产生获得性耐药模型，而新生耐药将用于 使用Y 537 S突变患者的PDX建模。 这些研究的成功完成可能会导致使用CX 4945或类似的CK 2抑制剂， pan-ERα下调在激素敏感和激素抵抗乳腺癌治疗中的作用。