Target, Function and Mechanism of LLS30 in Castration Resistant Prostate Cancer

LLS30在去势抵抗性前列腺癌中的作用靶点、作用及机制

• 批准号: 10619596
• 负责人: PARAMITA M. GHOSH
• 金额: --
• 依托单位: VA NORTHERN CALIFORNIA HEALTH CARE SYS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10619596
• 关键词: ABCB1 gene; Acetates; Affect; Alternative Splicing; Androgen Antagonists; Androgen Receptor; Antineoplastic Agents; Binding; Biopsy; CYP17A1 gene; Cancer Patient; Castration; Cell Adhesion; Cell Line; Cell Nucleus; Cell Proliferation; Cells; Data; Development; Drug resistance; Future; Galectin 1; Generations; Goals; Health; Invaded; Ligand Binding Domain; Luteinizing Hormone-releasing Hormone Agonist; Malignant neoplasm of prostate; Mediating; Microtubule Stabilization; Microtubules; Modeling; Multi-Drug Resistance; Nuclear; Nuclear Envelope; Nuclear Import; Nuclear Pore; Nuclear Pore Complex; Nuclear Translocation; Patients; Pharmaceutical Preparations; Play; Prednisone; Protocols documentation; Publications; RNA Splicing; Recommendation; Recurrence; Regulation; Reporting; Research; Resistance; Resistance development; Role; STAT3 gene; Serum; Specific qualifier value; Testing; Time; Tumor-Derived; Variant; Veterans; Veterans Health Administration; abiraterone; androgen deprivation therapy; benzimidazole; castration resistant prostate cancer; cell growth; chemotherapy; comparative efficacy; cytotoxic; docetaxel; drug candidate; enzalutamide; inhibitor; migration; neoplastic cell; novel; patient derived xenograft model; patient response; prevent; prostate cancer cell line; prostate cancer model; response; treatment duration; treatment pattern; tumor

SUMMARY: Treatment patterns for metastatic castration-resistant prostate cancer (mCRPC) at the US Veterans Health Administration (VHA) have changed substantially in the past few years. VHA patients with mCRPC are still treated with androgen deprivation therapy (ADT) with luteinizing hormone releasing hormone (LHRH) agonists initially. Nevertheless, a recent publication demonstrated that currently, 77% VHA mCRPC patients who progress on ADT are being further treated with 2nd generation anti-androgens: the CYP17A1 inhibitor abiraterone (ABI) with prednisone or the androgen receptor (AR) inhibitor enzalutamide (ENZA), while 23% are treated with the chemotherapy agent docetaxel. A post hoc analysis reported that docetaxel was the most common and effective first subsequent therapy (FST) among patients who progressed following protocol- specified treatment with ABI. However, the median docetaxel treatment duration among these patients was 4.2 months; hence, our goal is to find ways to prolong the efficacy of docetaxel in post-ABI VHA mCRPC patients. Multiple studies have pointed to a role for Galectin-1 (Gal-1) in tumor formation and aggressiveness in docetaxel resistant CRPC. We demonstrate that Gal-1 was elevated in CRPC, while inhibition of Gal-1 inhibited cell growth, invasion and migration. Based on these observations, we have now developed a novel Gal-1 inhibitor, LLS30, which is benzimidazole-based, and is therefore less toxic and of superior efficacy compared to conventional and existing Gal-1 inhibitors. LLS30 demonstrated significant cytotoxic effects in Gal-1 expressing, but not Gal-1 low, CRPC cell lines, and disrupted cell adhesion in high Gal1 cells. LLS30 also sensitized ABI-resistant cell lines to docetaxel in models of mCRPC that expressed high Gal-1. Based on these observations, we hypothesize that ABI/ENZA treatment promotes Gal-1 expression, and Gal-1 nuclear translocation, where it induces the formation of AR splice variants that induce resistance to ABI/ENZA. We propose that Gal-1 targeting to the nuclear envelope is mediated by microtubule dynamics, which is prevented by subsequent treatment with docetaxel; and by nuclear pore entry, which may be prevented by LLS30. Docetaxel resistance is often traced to the expression and activation of p-glycoprotein (p-gp), which promotes multi-drug resistance. Studies have shown that Gal-1 induces p-gp expression; hence LLS30 will prevent docetaxel resistance by suppressing p-gp expression and also inhibit Gal-1 nuclear localization. Aim 1: To determine the mechanism of Gal-1 involvement in docetaxel resistance and a potential role for LLS30 in overcoming that resistance will test the hypothesis that AR activity suppresses Gal-1 expression and/or subcellular localization, and whether nuclear Gal-1 induces resistance to ABI/ENZA by promoting expression of AR splice variants that lack the AR-LBD. Further, we will determine whether LLS30 prevents Gal- 1 nuclear localization by inhibiting its binding to the nuclear pore complex. Cooperation between docetaxel and LLS30 to impede progression in ABI/ENZA-resistant CRPC models by inhibiting Gal-1 nuclear translocation will also be investigated, especially in view of a role of p-gp. Aim 2: Test the role of Gal-1 in mediating the effects of the novel inhibitor LLS30 on the response of patient derived xenograft (PDX) models of ABI- resistant CRPC to docetaxel. PDX tumors derived from biopsy material of patients with post-ABI CRPC to docetaxel will be used to evaluate the effects of LLS30 on the response of CRPC to docetaxel. We will examine whether castration, LLS30 and/or docetaxel affect Gal-1 localization in the tumor, and whether translocation of Gal-1 by LLS30 or docetaxel correlate with the expression of AR and its splice variants. Aim 3. To investigate the relationship between serum Gal-1 levels and docetaxel treatment in patients who progress on ABI/ENZA treatment for mCRPC at the VANCHCS. Here we will test the hypothesis that serum levels of Gal- 1 in patients with post-ABI/ENZA CRPC correlate with their subsequent response to docetaxel. Patient Criteria and Plan. Also, we will determine whether docetaxel or treatments with ABI or ENZA affects serum gal-1 levels.

摘要：美国转移性去势抵抗性前列腺癌 (mCRPC) 的治疗模式 退伍军人健康管理局 (VHA) 在过去几年中发生了巨大变化。 VHA 患者 mCRPC 仍采用促黄体生成素释放激素的雄激素剥夺疗法 (ADT) 进行治疗 (LHRH) 最初激动。然而，最近的一份出版物表明，目前，77% 的 VHA mCRPC ADT 进展的患者正在进一步接受第二代抗雄激素治疗：CYP17A1 抑制剂阿比特龙 (ABI) 与泼尼松或雄激素受体 (AR) 抑制剂恩杂鲁胺 (ENZA)，同时 23% 接受化疗药物多西他赛治疗。事后分析报告称，多西紫杉醇是 在按照方案进展的患者中最常见和有效的首次后续治疗（FST） ABI 指定治疗。然而，这些患者的中位多西紫杉醇治疗持续时间为 4.2 月；因此，我们的目标是找到延长多西他赛对 ABI VHA mCRPC 患者疗效的方法。 多项研究指出半乳糖凝集素 1 (Gal-1) 在肿瘤形成和侵袭性中发挥作用 多西紫杉醇耐药的 CRPC。我们证明 Gal-1 在 CRPC 中升高，而 Gal-1 的抑制 抑制细胞生长、侵袭和迁移。基于这些观察，我们现在开发了一种新颖的 Gal-1 抑制剂 LLS30，基于苯并咪唑，因此毒性较小且疗效优越 与传统的和现有的 Gal-1 抑制剂相比。 LLS30 在以下细胞中表现出显着的细胞毒性作用 CRPC 细胞系表达 Gal-1，但不表达 Gal-1 低，并且在高 Gal1 细胞中细胞粘附被破坏。 LLS30 还在表达高 Gal-1 的 mCRPC 模型中使 ABI 耐药细胞系对多西紫杉醇敏感。 基于这些观察结果，我们假设 ABI/ENZA 治疗促进 Gal-1 表达，并且 Gal-1 核易位，诱导 AR 剪接变体的形成，从而诱导对 ABI/ENZA 的抗性。 我们认为 Gal-1 靶向核膜是由微管动力学介导的，即 通过随后的多西紫杉醇治疗可以预防；并通过核孔进入，这可以通过以下方式阻止 LLS30。多西紫杉醇耐药性通常可追溯到 p-糖蛋白 (p-gp) 的表达和激活， 促进多重耐药性。研究表明Gal-1诱导p-gp表达；因此 LLS30 将 通过抑制 p-gp 表达来预防多西紫杉醇耐药性，并抑制 Gal-1 核定位。 目标 1：确定 Gal-1 参与多西紫杉醇耐药的机制及其潜在作用 LLS30 克服耐药性将检验 AR 活性抑制 Gal-1 表达的假设 和/或亚细胞定位，以及核 Gal-1 是否通过促进 ABI/ENZA 诱导抗性 缺乏 AR-LBD 的 AR 剪接变体的表达。此外，我们将确定 LLS30 是否可以防止 Gal- 1 通过抑制其与核孔复合物的结合来实现核定位。多西紫杉醇与多西紫杉醇的合作 LLS30 通过抑制 Gal-1 核易位来阻止 ABI/ENZA 抗性 CRPC 模型的进展 还需要进行研究，特别是考虑到 p-gp 的作用。目标 2：测试 Gal-1 在介导 新型抑制剂 LLS30 对 ABI 患者来源的异种移植 (PDX) 模型反应的影响 CRPC 对多西紫杉醇耐药。 PDX 肿瘤源自 ABI 后 CRPC 患者的活检材料 多西他赛将用于评估LLS30对CRPC对多西他赛反应的影响。我们将检查 去势、LLS30 和/或多西紫杉醇是否影响 Gal-1 在肿瘤中的定位，以及是否易位 LLS30 或多西紫杉醇的 Gal-1 与 AR 及其剪接变体的表达相关。目标 3. 调查 病情进展患者血清 Gal-1 水平与多西紫杉醇治疗之间的关系 VANCHCS 的 ABI/ENZA 治疗 mCRPC。在这里，我们将检验以下假设：Gal-的血清水平 ABI/ENZA CRPC 患者中的 1 与他们随后对多西他赛的反应相关。患者标准 和计划。此外，我们还将确定多西他赛或 ABI 或 ENZA 治疗是否影响血清 gal-1 水平。