Therapeutic Targeting of The Long Noncoding RNA SCHLAP1 in Aggressive Prostate Cancer

长非编码 RNA SCHLAP1 在侵袭性前列腺癌中的治疗靶向

基本信息

批准号：
10577329
负责人：
Amanda E Hargrove
金额：
$ 22.22万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-12 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10577329
关键词：
American Architecture Binding Binding Proteins Binding Sites Biological Biological Assay Biological Markers Blood Cause of Death Cell Survival Cells Cessation of life Chromatin Chromatin Remodeling Factor Chromosomes Clinical Complex DNA DNA Binding Data Development Evaluation Evolution Follow-Up Studies Future Genomics Goals Invaded Knowledge Laboratories Lead Libraries Ligands Longterm Follow-up Malignant neoplasm of prostate Maps Mass Spectrum Analysis Metastatic Prostate Cancer Modeling Molecular Neoplasm Metastasis New Agents Oncogenic Oncology Outcome Patient-Focused Outcomes Pharmaceutical Preparations Phenotype Primates Process Proliferating Prostate Prostate Cancer therapy Proteins RNA Resistance Role SWI/SNF Family Complex Scaffolding Protein Site Structure Therapeutic Therapeutic Agents Transcript Untranslated RNA Urine Work cancer cell cell motility enzalutamide exosome hormone therapy improved in vivo insight intermolecular interaction knock-down liquid biopsy men migration mortality multiple datasets novel novel therapeutic intervention novel therapeutics overexpression precision medicine prevent prostate cancer progression protein complex screening small molecule standard of care success therapeutic target therapeutically effective therapy resistant tool validation studies

项目摘要

Prostate cancer (PCa) is a leading cause of death among American men. Nearly all of these deaths are due to the evolution of therapy resistance and metastatic spread. As such, there is an urgent, unmet need to develop new agents to treat therapy-resistant, metastatic PCa. The long noncoding RNA (lncRNA) Second Chromosome Locus Associated with Prostate 1 (SChLAP1) has been identified as the top RNA associated with prostate cancer-specific mortality and metastasis from multiple datasets with long-term follow up. Knockdown/overexpression of SChLAP1 is associated with changes to pro-metastatic phenotypes, such as invasion and colony formation. Targeting this critical cellular regulator has been elusive, however, and its mechanism of action in promoting PCa therapy resistance and metastasis has not been fully elucidated. For example, an interaction between SChLAP1 and the SWI/SNF complex has been implicated in PCa progression in some studies, but not in others. This gap in knowledge regarding the molecular function of SChLAP1 prevents effective therapeutic targeting of SChLAP1. Recent work by our team and others has revealed a complex RNA architecture within SChLAP1 as well as protein binding regions localized to highly structured and primate-conserved regions of the transcript. This compelling evidence for functional RNA structures, combined with the availability of SChLAP1 as a biomarker in urine and blood, renders targeting of lncRNA SChLAP1 a promising precision medicine-based treatment approach for men with aggressive PCa. The overall objectives of the proposed work are to: 1) identify and characterize protein interactors and chromatin-binding sites critical to SChLAP1 oncogenic activity and 2) validate drug-like ligands identified in recent screens as tool molecules for targeting structured regions of SChLAP1, including inhibition of these interactions and SChLAP1-driven phenotypes. The central hypothesis is that the mechanism of SChLAP1 involves interactions with both protein and chromatin, and that targeting these interactions will inhibit SChLAP1-driven phenotypes and reveal novel therapeutic avenues to treat metastatic, treatment-resistant PCa. In Aim 1, unbiased sequencing and mass spectrometry-based approaches will identify chromatin regions and proteins bound by SChLAP1 in cells, and these interactions will be interrogated in an array of phenotypic assays to evaluate their role in proliferation, cancer cell survival, migration/invasion, and resistance to standard-of-care hormone therapy. In Aim 2, ligands of conserved SChLAP1 substructures will be validated in phenotypic assays, and their effects on molecular interactions will be interrogated. Expected outcomes of this work will be as follows: 1) comprehensive biological insight into targetable intermolecular interactions for SChLAP1 and 2) identification of small molecules that inhibit SChLAP1:protein interactions and subsequent phenotypes in PCa. This work will set the stage for a future R01 proposal focused on in vivo validation studies for small molecules targeting SChLAP1 and the development of an exosome-based liquid biopsy for SChLAP1, with the ultimate goal of yielding a precision medicine-based strategy for aggressive and treatment-resistant PCa while also helping to establish lncRNA targeting as a therapeutic paradigm in oncology.

前列腺癌（PCA）是美国男性死亡的主要原因。几乎所有这些死亡都是由于治疗耐药性和转移性扩散的进化。因此，有一个紧急，未满足的需要开发新代理商治疗耐治疗的转移性PCA。长的非编码RNA（LNCRNA）第二染色体基因座相关前列腺1（Schlap1）已被确定为与前列腺癌特异性死亡率相关的最高RNA，来自多个数据集的转移具有长期随访。 Schlap1的敲低/过表达是相关的随着反转移表型的变化，例如入侵和菌落形成。靶向这个关键细胞但是，监管机构难以捉摸，及其在促进PCA治疗耐药性和转移方面的作用机制尚未完全阐明。例如，Schlap1与SWI/SNF复合物之间的相互作用已经在某些研究中与PCA的进展有关，但在其他研究中却没有。关于分子的知识差距 SCHLAP1的功能可防止Schlap1的有效治疗靶向。我们的团队和其他人最近的工作揭示了Schlap1中的复杂RNA架构以及局限于高度结构化的蛋白质结合区域和成绩单的灵长类动物区域。这种具有功能性RNA结构的令人信服的证据，合并随着Schlap1作为尿液和血液中的生物标志物的可用性，靶向lncRNA schlap1 a有希望的具有侵略性PCA男性的基于精密医学的治疗方法。拟议工作的总体目标是：1）识别和表征蛋白质相互作用者，并且对于Schlap1致癌活性至关重要的染色质结合位点，2）验证最近在最近发现的药物样配体屏幕作为用于靶向Schlap1结构化区域的工具分子，包括抑制这些相互作用和 Schlap1驱动的表型。中心假设是Schlap1的机理涉及与蛋白质和染色质，以及针对这些相互作用的蛋白质会抑制Schlap1驱动的表型并揭示治疗转移性，耐药性PCA的新型治疗途径。在AIM 1中，公正的测序和质量基于光谱法的方法将鉴定细胞中由Schlap1结合的染色质区域和蛋白质，而这些相互作用将在一系列表型测定中审问，以评估其在癌细胞中的增殖中的作用生存，迁移/入侵以及对护理标准激素治疗的抵抗力。在AIM 2中，保守的配体 Schlap1子结构将在表型测定中进行验证，它们对分子相互作用的影响将是询问。这项工作的预期结果将如下：1）对目标的全面生物学见解 Schlap1和2）鉴定抑制Schlap1：蛋白质的小分子的分子间相互作用 PCA中的相互作用和随后的表型。这项工作将为未来的R01提案奠定舞台针对Schlap1的小分子的体内验证研究和基于外泌体的液体的发展 Schlap1的活检，其最终目标是产生基于精确医学的侵略性和耐药性PCA同时还有助于将lncRNA靶向作为肿瘤学的治疗范式。