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

• 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
• 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

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)的男性前列腺癌(PCA)的发病率和死亡率高于 欧洲血统(EA)。这些差距是由社会经济、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男性之间存在差异 在其PCA免疫生物学中导致炎症基因通路的差异表达。这些 差异可能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)。迫切需要了解其背后的分子机制。 与种族相关的差异，并利用这些差异来确定新的治疗靶点。在这个多PI的探索中 应用，我们建议研究糖酵解酶在抗肿瘤自身抗体反应中的差异。 AA和EA患者PCa中烯醇化酶(ENO)的变化及其在指导Small发病中的作用 以此蛋白为靶点的分子作为治疗晚期前列腺癌的新型治疗药物。建议的理由是 研究得到了几个关键观察结果的支持：1)ENO，特别是ENO1亚型，正在作为一个细胞出现 表面TAA具有理想的治疗靶点的特征，而ENO2异构体可以是 NEPC肿瘤的鼻咽癌生物标志物；2)患有前列腺癌的AA和EA患者产生不同的自身抗体 对eNO的反应；3)这种反应对化疗耐药的前列腺癌细胞的迁移有独特的影响；4) 在带有NEPC标记的PCa细胞中，细胞表面NEPC标志物ENO2的表达缺失，但不表达ENO1 随着它们转变为紫杉烷抗性；以及5)我们已经启动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抗癌作用 化疗耐药AA和EA PCA临床前模型的潜力。这些观察结果支持这一假说 EA和AA患者对ENO有不同的免疫反应，从而不同地影响肿瘤细胞 属性，这些反应可能揭示了肿瘤的脆弱性，可以被利用来开发 新型PCA治疗药物。目标1将确定不同反应性和 抗ENO自身抗体在AA和EA患者前列腺癌中的抗肿瘤作用。目标2将合成和功能 表征新型含硼小分子ENO1化合物作为治疗前列腺癌的潜在药物。这个 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 ENO免疫反应。这将为免疫决定因素导致前列腺癌死亡率提供关键的见解 差距。这项研究还将使ENO成为高级PCA的潜在治疗靶点，这可能 导致创新的临床战略，以减少总体前列腺癌死亡率及其种族差异。