Effect of CX4945 in tamoxifen resistant BCa

CX4945 在他莫昔芬耐药 BCa 中的作用

• 批准号: 10673636
• 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/10673636
• 关键词: Antiestrogen Therapy; Antineoplastic Agents; 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; Length; Ligands; Mediating; Metastatic Neoplasm to Lymph Nodes; Modeling; Molecular Chaperones; Mutation; Oncogenic; Patients; Phosphorylation; Phosphotransferases; Play; Predisposition; Protein Isoforms; Proteins; Quality of life; Receptor Signaling; Relapse; Reporting; Repression; Resistance; Role; Selective Estrogen Receptor Modulators; Signal Transduction; Stimulation of Cell Proliferation; Tamoxifen; Testing; Tissue Microarray; Transcript; Ubiquitination; Variant; casein kinase II; efficacious treatment; efficacy evaluation; estrogen disruption; estrogenic; hormone therapy; inhibitor; malignant breast neoplasm; non-genomic; patient derived xenograft model; pharmacologic; 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已在介导对抗雌激素的抗药性中暗示 乳腺癌（BCA）的疗法，可能有助于选择性雌激素受体的有丝分裂作用 调节器（SERMS）。 ERα36[雌激素受体α（ERα）的36 kD转录物变体] 基因组雌激素信号传导，在抗雌激素耐药性和抗雌激素中暗示 有丝分裂生成1。双重抑制ERα66（全长ERα）和ERα36信号传导可能被证明是更多 有效的抗原可能治疗模式，避免了抗雌激素诱导的耐药性和 肿瘤发生。这可以通过公共翻译后调节的药物靶向来实现 两种同工型之间的机理（即，磷酸化）。 CX4945（Silmitasertib），临床阶段CK2 抑制剂反映ERα66和ERα36的蛋白质水平。因此，CX4945可能会唯一破坏 致癌激酶信号传导以及降低了BCA中ERα同工型的稳定性。我们假设CX4945 通过充当间接泛源性受体来抑制基因组和非基因组雌激素信号传导 下调器会破坏BCA中ERα66和ERα36的表达。 为了检验这一假设，我们将： AIM I.研究ERα66 /36 /CK2信号轴在他莫昔芬电阻发展中的作用。 为此，我们假设CK2通过促进异常ERα促进了4HT抗性的发展 信号。我们将确定改变ERα36和CK2表达在 他莫昔芬在乳腺癌中的耐药性的发展。 AIM 2阐明了CX4945在BCA中介导的ERα66/36的下调。我们在这里 假设用CX4945对CK2的药物抑制作用使ERα同工型易受26S 蛋白酶体降解途径。我们将确定CK2介导的ERα66/36磷酸化对 伴侣相互作用，泛素化以及随后的ERα36的蛋白水解降解。 AIM 3评估CX4945在配对的患者衍生型（PDX）模型中的抗肿瘤效率 BCA的4HT敏感和抗性模型。我们假设CX4945将抑制 他莫昔芬敏感的和他莫昔芬耐药（从头获得）PDX肿瘤。内分泌的PDX肿瘤 敏感的患者将用于产生获得的抗性模型，而De-Novo的阻力为 使用Y537S突变患者的PDX建模。 这些研究的成功完成可能导致使用CX4945或类似的CK2抑制剂间接使用 PAN-ERα下调在治疗骑马敏感和抗骑马乳腺癌方面的功能。

项目成果

Breast Cancer Reconstruction: Design Criteria for a Humanized Microphysiological System.

• DOI: 10.1089/ten.tea.2020.0372
• 发表时间: 2021-02
• 期刊: Tissue engineering. Part A
• 作者: Trivia P Frazier;Christopher Williams;M. Henderson;T. Duplessis;Emma Rogers;Xiying Wu;K. Hamel;E. Martin;O. Mohiuddin;Shahensha Shaik;R. Devireddy;B. Rowan;Daniel Hayes;J. Gimble

NURR1 Is Differentially Expressed in Breast Cancer According to Patient Racial Identity and Tumor Subtype.

• DOI: 10.3390/biomedinformatics2040045
• 发表时间: 2022-12
• 期刊: BioMedInformatics