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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.

非洲裔男性前列腺癌（PCa）的发病率和死亡率高于非洲裔男性