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cast割前列腺癌（MCRPC）的治疗模式 在过去的几年中，退伍军人卫生管理局（VHA）发生了很大变化。 VHA患者 MCRPC仍接受雄激素剥夺治疗（ADT）的治疗 （LHRH）激动剂最初。尽管如此，最近的出版物表明目前有77％的VHA MCRPC 在ADT上进展的患者正在用第二代抗雄激素进一步治疗：CYP17A1 用泼尼松或雄激素受体（AR）抑制剂enzalutamide（ENZA）抑制剂阿比罗酮（ABI），而抑制剂 23％用化学疗法剂多西他赛治疗。事后分析报告说多西他赛是 根据方案进行进展的患者，最常见和有效的首次治疗（FST） - 用ABI的指定治疗。但是，这些患者的多西他赛治疗持续时间为4.2 月份；因此，我们的目标是找到延长多西他赛在Abi后VHA MCRPC患者中的功效的方法。 多项研究指出了乳糖素1（GAL-1）在肿瘤形成和侵略性中的作用 多西他赛抗CRPC。我们证明了GAL-1在CRPC中升高，而GAL-1的抑制作用 抑制细胞生长，侵袭和迁移。基于这些观察，我们现在已经开发了一本小说 GAL-1抑制剂LLS30，基于苯咪唑，因此毒性较小，有效性很高 与常规和现有的GAL-1抑制剂相比。 LLS30在 GAL-1表达，但不表达CRPC细胞系和高gal1细胞中的细胞粘附。 LLS30 在表达高gal-1的MCRPC模型中，还将抗ABI耐药细胞系敏感。 基于这些观察结果，我们假设ABI/ENZA治疗促进了GAL-1的表达，而GAL-1 核易位，它诱导诱导对ABI/ENZA的抗性的AR剪接变体的形成。 我们提出，靶向核包膜的GAL-1是由微管动力学介导的， 随后对多西他赛的治疗阻止；并通过核孔进入 LLS30。多西他赛的耐药性通常可追溯到P-糖蛋白（P-gp）的表达和激活，这 促进多药电阻。研究表明，GAL-1诱导P-gp表达。因此，lls30 will 通过抑制P-gp表达并抑制GAL-1核定位，以防止多西他赛的耐药性。 目的1：确定GAL-1参与多西他赛电阻的机制和潜在的作用 对于LLS30，在克服抗性时将检验AR活性抑制GAL-1表达的假设 和/或亚细胞定位，以及核gal-1是否通过促进促进ABI/ENZA的抗性 缺乏AR-LBD的AR剪接变体的表达。此外，我们将确定lls30是否阻止了gal- 1核定位通过抑制其与核孔复合物的结合。多西他赛和 LLS30通过抑制GAL-1核易位来阻止ABI/ENZA抗CRPC模型的进展 还可以研究，特别是鉴于P-gp的作用。 AIM 2：测试GAL-1在介导的作用 新型抑制剂LLS30对ABI的患者衍生异种移植（PDX）模型的反应的影响 抗多西他赛的CRPC。 PDX肿瘤源自后ABI CRPC患者的活检材料 多西他赛将用于评估LLS30对CRPC对多西他赛响应的影响。我们将检查 cast割，LLS30和/或多西他赛是否会影响肿瘤中的GAL-1定位，以及是否易位 lls30或多西他赛的GAL-1与AR的表达及其剪接变体相关。目标3。调查 进展的患者中血清gal-1水平与多西他赛治疗之间的关系 ABI/ENZA治疗MCRPC在Vanchcs。在这里，我们将测试以下假设。 1患有ABI/ENZA CRPC的患者与随后对多西他赛的反应相关。患者标准 并计划。另外，我们将确定多西他赛或使用ABI或ENZA治疗会影响血清GAL-1水平。