Administrative Diversity Supplement to: "Role and Theranostics Potential of Enolase in Prostate Cancer Health Disparities"

行政多样性补充：“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: 10819907
• 负责人: FRANKIE G ALMAGUEL
• 金额: $ 6.36万
• 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: 2023-04-05 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10819907
• 关键词: Affect; African ancestry; Autoantibodies; Biological; Biological Markers; Boron; Cell surface; Characteristics; Chemoresistance; Clinical; Development; Disparity; Enzymes; European ancestry; Genes; Genetic; Immune; Immune Targeting; Immune response; Incidence; Inflammatory; Life Style; Malignant neoplasm of prostate; Molecular; Pathway interactions; Patients; Pre-Clinical Model; Property; Protein Isoforms; Proteins; Race; Resistance; Role; Therapeutic; Tumor Antigens; advanced prostate cancer; anti-tumor immune response; antitumor effect; cancer health disparity; cancer immunobiology; design; differential expression; enolase; immunoreactivity; innovation; insight; men; migration; mortality; mortality disparity; neoplastic cell; new therapeutic target; novel; prostate cancer cell; racial disparity; response; small molecule; socioeconomics; taxane; theranostics; therapy resistant; 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非洲血统（AA）的男性。 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男性有差异， 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应答，包括细胞表面肿瘤的免疫靶向， 相关抗原（TAAs）。有一个紧迫性，以了解这些分子机制的基础 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探索性 应用，我们建议研究抗肿瘤自身抗体对糖酵解酶反应的差异 在AA和EA男性与PCa的烯醇化酶（ENO），并利用这些差异指导小的发展， 分子靶向这种蛋白质作为新的治疗诊断剂先进的前列腺癌。建议的理由 研究得到了以下几个关键观察结果的支持：1）ENO，特别是ENO 1亚型，正在以细胞形式出现 表面TAA具有理想治疗诊断学靶点的特征，而ENO 2亚型可能是治疗诊断学靶点。 NEPC肿瘤的治疗诊断生物标志物; 2）AA和EA男性PCa产生差异性自身抗体 对ENO的反应; 3）这种反应对化学抗性PCa细胞的迁移具有独特的影响; 4）ENO对PCa细胞的迁移具有显著的影响。 在具有NEPC标志物的PCa细胞中，细胞表面NEPC标志物ENO 2的表达丢失，但ENO 1的表达不丢失 因为它们过渡到紫杉烷抗性;和5）我们已经开始设计和表征新的硼- 基于ENO 1的靶向小分子，将评估其抗肿瘤活性和治疗诊断学 在化学抗性AA和EA PCa的临床前模型中的潜力。这些观察结果支持了 EA和AA合并PCa患者对ENO有不同的免疫反应， 这些反应可能揭示了肿瘤的脆弱性，这些脆弱性可以被利用来开发 新型前列腺癌治疗诊断剂。目标1将确定差异反应性的机制， 抗ENO自身抗体对AA和EA患者PCa的抗肿瘤作用目标2将综合和功能 表征作为PCa潜在治疗剂的新型硼基小分子ENO 1化合物。的 拟议的研究具有高度的相关性，因为它将揭示种族相关的差异性抗- ENO免疫反应性。这将提供关键的见解免疫决定因素有助于PCa死亡率 差距。该研究还将确立ENO作为晚期PCa的潜在治疗诊断靶点， 导致创新的临床策略，以减少整体PCa死亡率和种族差异。