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 (AA) 男性的前列腺癌 (PCa) 发病率和死亡率高于非洲血统男性 (AA) 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 型男性和 EA 型男性之间存在差异他们的 PCa 免疫生物学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（TAA）。迫切需要了解这些现象背后的分子机制种族相关的差异，并利用它们来确定新的治疗靶点。在这个多 PI 探索中应用中，我们建议研究抗肿瘤自身抗体对糖酵解酶反应的差异患有 PCa 的 AA 和 EA 男性中的烯醇化酶 (ENO) 并利用这些差异来指导小细胞的发育靶向该蛋白质的分子作为晚期 PCa 的新型治疗诊断剂。拟议的理由研究得到了几个关键观察结果的支持：1) ENO，特别是 ENO1 亚型，正在作为细胞出现表面 TAA 具有理想治疗诊断目标的特征，而 ENO2 亚型可能是 NEPC 肿瘤的治疗诊断生物标志物； 2) 患有 PCa 的 AA 和 EA 男性会产生差异性自身抗体对 ENO 的反应； 3) 这种反应对化疗耐药性 PCa 细胞的迁移具有独特的影响； 4）在具有 NEPC 标记的 PCa 细胞中，ENO2（细胞表面 NEPC 标记）的表达丢失，但 ENO1 的表达不丢失当它们转变为紫杉烷抗性时； 5）我们已经开始了新型硼的设计和表征基于 ENO1 的靶向小分子，将评估其抗肿瘤活性和治疗诊断学在化疗耐药 AA 和 EA PCa 临床前模型中具有潜力。这些观察结果支持了假设患有 PCa 的 EA 和 AA 患者对 ENO 具有独特的免疫反应，对肿瘤细胞有不同的影响特性，并且这些反应可能揭示肿瘤的脆弱性，可用于开发新型 PCa 治疗诊断剂。目标 1 将确定差异反应性和潜在机制抗 ENO 自身抗体对患有 PCa 的 AA 和 EA 男性的抗肿瘤作用。目标2将综合并功能化描述新型硼基小分子 ENO1 化合物作为 PCa 的潜在疗法。这拟议的研究具有很高的相关性，因为它将揭示与种族相关的差异抗病毒的生物学基础 ENO 免疫反应性。这将为了解导致 PCa 死亡率的免疫决定因素提供重要见解差异。该研究还将 ENO 确立为晚期 PCa 的潜在治疗诊断目标，这可能导致创新的临床策略，以降低前列腺癌的总体死亡率及其种族差异。