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: 9891795
• 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 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9891795
• 关键词: 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; 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; P-Glycoprotein; Patients; Pattern; Pharmaceutical Preparations; Play; Prednisone; Protocols documentation; Publications; RNA Splicing; Recurrence; Regulation; Reporting; Research; Resistance; Resistance development; Role; STAT3 gene; Serum; Specific qualifier value; Testing; Time; Tumor-Derived; Variant; Veterans; Xenograft Model; Xenograft procedure; abiraterone; androgen deprivation therapy; base; benzimidazole; castration resistant prostate cancer; cell growth; chemotherapy; comparative efficacy; cytotoxic; docetaxel; drug candidate; health administration; inhibitor/antagonist; migration; neoplastic cell; novel; patient response; prevent; prostate cancer cell line; prostate cancer model; response; treatment duration; tumor; tumor xenograft

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.

总结：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仍接受促黄体激素释放激素的雄激素剥夺治疗（ADT） （LHRH）激动剂。然而，最近的一篇出版物表明，目前，77%的VHA mCRPC ADT治疗进展的患者正在接受第二代抗雄激素治疗：CYP 17 A1 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），而 23%的患者接受化疗药物多西他赛治疗。一项事后分析报告称，多西他赛是 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）- 接受ABI治疗。然而，这些患者中多西他赛的中位治疗持续时间为4.2 因此，我们的目标是找到延长多西他赛在ABI VHA后mCRPC患者中疗效的方法。 多项研究已经指出半乳糖凝集素-1（Gal-1）在肿瘤形成和侵袭性中的作用。 多西他赛耐药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，我们现在已经开发了一种新的 Gal-1抑制剂，LLS 30，基于苯并咪唑，因此毒性较小，具有上级功效 与常规和现有的Gal-1抑制剂相比。LLS 30显示出显著的细胞毒性作用， Gal-1表达，但不Gal-1低，CRPC细胞系，并破坏高Gal 1细胞中的细胞粘附。LLS30 在表达高Gal-1的mCRPC模型中，也使ABI耐药细胞系对多西他赛敏感。 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，其中它诱导AR剪接变体的形成，所述变体诱导对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， 通过多西他赛后续治疗预防;以及通过核孔进入，这可以通过以下方法预防： LLS30。多西他赛耐药通常可追溯到p-糖蛋白（p-gp）的表达和活化， 促进多药耐药性。研究表明Gal-1诱导p-gp表达;因此LLS 30将 通过抑制p-gp表达和抑制Gal-1核定位来预防多西他赛耐药性。 目的1：确定Gal-1参与多西他赛耐药的机制，以及Gal-1在多西他赛耐药中的潜在作用。 LLS 30在克服该抗性中的作用将检验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诱导对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LLS 30是否阻止Gal- 1通过抑制其与核孔复合物的结合来进行核定位。多西他赛与 LLS 30通过抑制Gal-1核易位阻止ABI/ENZA耐药CRPC模型的进展， 还可以进行研究，特别是考虑到P-gp的作用。目的2：测试Gal-1在介导细胞凋亡中的作用。 新型抑制剂LLS 30对ABI患者来源的异种移植物（PDX）模型的反应的作用- 多西他赛耐药CRPC。源自ABI后CRPC患者活检材料的PDX肿瘤， 多西他赛将用于评价LLS 30对CRPC对多西他赛反应的影响。我们将研究 去势、LLS 30和/或多西他赛是否影响Gal-1在肿瘤中的定位， LLS 30或多西他赛诱导的Gal-1表达与AR及其剪接变异体的表达相关。目标3.探讨 多西他赛治疗进展患者血清Gal-1水平与多西他赛治疗的关系 在VANCHCS接受ABI/ENZA治疗mCRPC。在这里，我们将测试的假设，血清中的半乳糖- 1例ABI/ENZA后CRPC患者与其随后对多西他赛的应答相关。患者标准 和计划。此外，我们将确定多西他赛或ABI或ENZA治疗是否会影响血清gal-1水平。