Role and Theranostics Potential of Enolase in Prostate Cancer Health Disparities

烯醇化酶在前列腺癌健康差异中的作用和治疗潜力

基本信息

批准号：
10649164
负责人：
FRANKIE G ALMAGUEL
金额：
$ 18.65万
依托单位：
LOMA LINDA 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：
2023-04-03 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10649164
关键词：
Active Sites Affect African ancestry Autoantibodies Biological Biological Markers Biological Testing Boron Cell surface Cells Characteristics Chemoresistance Clinical Clinical Research Development Diagnostic Diagnostic Imaging Disparity Effectiveness Enzymes European ancestry FOLH1 gene Future Genes Genetic Homology Modeling Image Immune Immune Targeting Immune response Incidence Inflammatory Invaded Lead Libraries Life Style Malignant neoplasm of prostate Metabolism Metastatic Prostate Cancer Molecular Neoplasm Metastasis Organoids Outcome Pathway interactions Patients Permeability Positron-Emission Tomography Post-Translational Protein Processing Pre-Clinical Model Process Proliferating Property Prostatic Neoplasms Protein Isoforms Proteins Race Radiolabeled Radionuclide therapy Resistance Role Specificity Structure-Activity Relationship Surface Surface Antigens Testing Therapeutic Toxic effect Tumor Antigens X-Ray Computed Tomography advanced prostate cancer anti-tumor immune response antitumor effect cancer biomarkers cancer gene expression cancer health disparity cancer immunobiology clinical effect design differential expression enolase immunoreactivity innovation insight men migration mortality mortality disparity nanomolar neoplastic cell neuroendocrine differentiation new therapeutic target novel novel therapeutics patient derived xenograft model patient subsets pharmacokinetics and pharmacodynamics pharmacophore prostate cancer cell prostate cancer cell line prostate cancer model racial disparity racial diversity response small molecule small molecule inhibitor socioeconomics taxane theranostics therapy resistant tomography transcriptome sequencing tumor

项目摘要

Men of African ancestry (AA) have a higher incidence and mortality from prostate cancer (PCa) than men of European ancestry (EA). These disparities are driven by the interplay between socioeconomic, lifestyle, environmental, and biological/genetic factors. Growing evidence indicates that AA and EA men have differences in their PCa immunobiology resulting in the differential expression of inflammatory gene pathways. These differences may impact the anti-tumor immune response including the immune targeting of cell surface tumor associated antigens (TAAs). There is an urgency to understand the molecular mechanisms underlying these race-related differences and to harness them for identifying novel therapeutic targets. In this multi-PI exploratory application, we propose to investigate differences in anti-tumor autoantibody responses to the glycolytic enzyme enolase (ENO) in AA and EA men with PCa and exploit these differences for guiding the development of small molecules targeting this protein as novel theranostics agents for advanced PCa. The rationale for the proposed studies is supported by several key observations: 1) ENO, particularly the ENO1 isoform, is emerging as a cell surface TAA with characteristics of an ideal theranostics target, whereas the ENO2 isoform could be a theranostic biomarker for NEPC tumors; 2) AA and EA men with PCa produce a differential autoantibody response to ENO; 3) this response has a distinctive impact on the migration of chemoresistant PCa cells; 4) the expression of ENO2, a cell surface NEPC marker, but not that of ENO1, is lost in PCa cells with NEPC markers as they transition to taxane resistance; and 5) we have initiated the design and characterization of novel boron- based ENO1-targeting small molecules that will be evaluated for their antitumor activity and theranostics potential in pre-clinical models of chemoresistant AA and EA PCa. These observations support the hypothesis that EA and AA patients with PCa have distinctive immune responses to ENO that differentially affect tumor cell properties, and that these responses may reveal tumor vulnerabilities that could be exploited for the development of novel PCa theranostics agents. Aim 1 will determine the mechanisms underlying the differential reactivity and antitumor effects of anti-ENO autoantibodies in AA and EA men with PCa. Aim 2 will synthesize and functionally characterize novel boron-based small molecule ENO1 compounds as potential therapeutics for PCa. The proposed study has high relevance as it will uncover the biological basis for the race-related differential anti- ENO immunoreactivity. This will provide key insights into immune determinants contributing to PCa mortality disparities. The study will also establish ENO as a potential theranostic target for advanced PCa, which could lead to innovative clinical strategies to reduce overall PCa mortality and its racial disparities.

非洲血统的男性（AA）比前列腺癌（PCA）的发病率和死亡率更高欧洲血统（EA）。这些差异是由社会经济，生活方式，环境和生物/遗传因素。越来越多的证据表明AA和EA男子有差异在其PCA免疫生物学中导致炎症基因途径的差异表达。这些差异可能会影响抗肿瘤免疫反应，包括细胞表面肿瘤的免疫靶向相关抗原（TAAS）。有一个迫切需要了解这些分子机制与种族有关的差异，并利用它们来识别新颖的治疗靶标。在这个多PI探索性中应用，我们建议研究抗肿瘤自身抗体对糖酵解酶的差异 AA和具有PCA的EA的Enolase（Eno），并利用这些差异来指导小型的发展靶向该蛋白作为晚期PCA的新型疗法剂的分子。提议的理由研究得到了几个关键观察的支持：1）ENO，尤其是ENO1同工型，正在作为细胞出现具有理想疗法靶标的特征的表面TAA，而ENO2同工型可能是 NEPC肿瘤的疗法生物标志物； 2）AA和EA患有PCA的人会产生差异自身抗体对Eno的回应； 3）这种反应对化学耐药性PCA细胞的迁移具有明显的影响； 4） ENO2的表达是一种细胞表面NEPC标记，而不是ENO1的表达在带有NEPC标记的PCA细胞中丢失当他们过渡到紫杉烷耐药时； 5）我们已经启动了新型硼的设计和表征基于ENO1靶向的小分子将评估其抗肿瘤活性和疗法学在化学抗性AA和EA PCA的临床前模型中的潜力。这些观察结果支持假设 EA和AA患者患有PCA的患者对ENO具有明显的免疫反应，从而影响肿瘤细胞这些属性，这些反应可能揭示出可以利用开发的肿瘤脆弱性新型PCA Theranostics代理。 AIM 1将确定差异反应性和抗Eno自身抗体在AA和具有PCA的EA男性的抗肿瘤作用。 AIM 2将合成并在功能上进行将新型的基于硼的小分子ENO1化合物表征为PCA的潜在疗法。这拟议的研究具有很高的相关性，因为它将发现与种族相关的差异抗的生物学基础 ENO免疫反应性。这将提供对有助于PCA死亡率的免疫决定因素的关键见解差异。该研究还将建立ENO作为高级PCA的潜在疗法靶标，这可能导致创新的临床策略，以降低PCA的总体死亡率及其种族差异。