The ODC A allele as a driver and therapeutic target of aggressive prostate cancer in African American men

ODC A 等位基因作为非裔美国男性侵袭性前列腺癌的驱动因素和治疗靶点

• 批准号: 10560516
• 负责人: Jong Y. Park
• 金额: $ 23.16万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-02 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10560516
• 关键词: Acceleration; Adenine; African American; Alleles; American; Anabolism; Automobile Driving; Biochemical; Biological; Biological Assay; Cancer Patient; Cations; Cell Line; Cell Proliferation; Cell physiology; Cells; Characteristics; Chemoprevention; Chemopreventive Agent; Clinical; Clinical Pathology; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; DL-alpha-Difluoromethylornithine; DNA; Data; Development; Discrimination; Disease; Enzymes; Epithelial Cells; European; Family history of; Frequencies; Future; Gene Expression; Genes; Genetic; Genetic Variation; Genotype; Goals; Growth; Guanine; Human; Impairment; Incidence; Invaded; Malignant neoplasm of prostate; Metabolic; Modeling; Operative Surgical Procedures; Ornithine Decarboxylase; Ornithine Decarboxylase Inhibitor; Pathway interactions; Patient risk; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Phase; Phenotype; Play; Polyamines; Prevention trial; Prognostic Marker; Property; Prospective cohort; Prostate; Prostate Cancer therapy; Prostatic Neoplasms; Proteins; Race; Recurrence; Research; Research Project Grants; Retrospective cohort; Risk; Role; Sampling; Single Nucleotide Polymorphism; Techniques; Testing; Therapeutic; Tissues; Tumor Biology; VCaP; Variant; Xenograft procedure; base; cancer health disparity; cell motility; genetic approach; genetic association; genome editing; health disparity; high risk men; men; mortality; predictive marker; prime editing; programs; promoter; prostate cancer cell; prostate cancer cell line; prostate cancer risk; racial health disparity; screening; success; therapeutic target; transcriptome; transport inhibitor; tumor; tumor xenograft; tumorigenic

Project Summary The rates of prostate cancer (PCa) incidence and mortality are much higher in African American men (AAM) versus European American men (EAM), and genetic variations between these races play a critical role. Our studies have shown that expression of genes that direct polyamine biosynthesis are significantly elevated in AAM versus EAM PCa, suggesting this pathway may play important roles in driving this cancer health disparity. Ornithine decarboxylase (ODC) is the first and rate-limiting enzyme of polyamine biosynthesis. Notably, the ODC gene has a single nucleotide polymorphism (SNP) at base +316 in which adenine (A) is substituted for guanine (G), and this SNP augments ODC promoter activity. Importantly, the ODC A allele is more common in AAM than EAM, suggesting prostate tumors in AAM having an ODC A allele will have increased ODC levels and that this drives aggressive prostate tumor biology. Furthermore, difluoromethylornithine (DFMO), a selective ODC inhibitor, is a highly effective chemoprevention agent in high-risk men harboring at least one ODC A allele, suggesting the ODC A allele will predict AAM PCa patients that benefit from DFMO treatment. These data support our hypothesis that the ODC A allele is both a driver of aggressive prostate tumor biology and a targetable vulnerability in African American men. To test this hypothesis, in Aim 1 we will use an allelic discrimination assay to test ~3,800 DNA samples (~1,520 AAM: ~2,280 EAM) from PCa cases and controls for the presence of the ODC A allele to: (i) establish its frequency in both races; and (ii) assess if the ODC A allele connotes worse patient outcomes. In Aim 2, we will generate three sets of isogenic PCa cell lines by CRISPR-based prime editing, where we will test if PCa cells with an ODC A allele have increased levels of ODC and polyamines and have more aggressive biological phenotypes compared to isogenic PCa cells with ODC G alleles. In Aim 3, we will test if treatment of our isogenic cells with DFMO and a polyamine transport inhibitor (polyamine blockage therapy) has differential effects on the phenotypes of PCa cells having ODC A versus ODC G alleles. Finally, we will also test if there are differential effects of polyamine blocking therapy on primary PCa tissue explants from AAM having an ODC A allele versus AAM with only ODC G alleles. We submit the proposed studies will benefit African American PCa patients by establishing the ODC A allele as a prognostic biomarker that will be useful for doctors to assess patient risk, and as a predictive biomarker that forecasts the success of DFMO as a chemotherapeutic treatment.

项目摘要 前列腺癌（PCa）的发病率和死亡率在非洲裔美国人（AAM）中要高得多 与欧洲裔美国男性（EAM）相比，这些种族之间的遗传变异发挥着关键作用。我们 研究表明，指导多胺生物合成的基因的表达显著升高， AAM与EAM PCa，表明该途径可能在推动这种癌症健康方面发挥重要作用 差距 鸟氨酸脱羧酶（ODC）是多胺生物合成的第一个酶和限速酶。特别是 ODC基因在碱基+316处具有单核苷酸多态性（SNP），其中腺嘌呤（A）被取代， 鸟嘌呤（G），并且该SNP增强ODC启动子活性。重要的是，ODC A等位基因在以下人群中更常见： AAM比EAM，表明具有ODC A等位基因的AAM中的前列腺肿瘤将具有增加的ODC水平 而这驱动了前列腺肿瘤生物学的发展。此外，二氟甲基鸟氨酸（DFMO）， 选择性ODC抑制剂，是一种高效的化学预防剂，用于高危男性， ODC A等位基因，表明ODC A等位基因将预测受益于DFMO治疗的AAM PCa患者。 这些数据支持我们的假设，即ODC A等位基因是侵袭性前列腺肿瘤的驱动因素， 生物学和非裔美国人的目标脆弱性。为了验证这一假设，在目标1中，我们将 使用等位基因鉴别试验检测来自PCa病例的约3，800份DNA样本（约1，520 AAM：约2，280 EAM） 和对照的ODC A等位基因的存在，以：（i）确定其在两个种族中的频率;和（ii）评估是否 ODC-A等位基因意味着更差的患者结果。在目标2中，我们将产生三组等基因PCa细胞， 通过基于CRISPR的引物编辑，我们将测试具有ODC A等位基因的PCa细胞是否增加了 与同基因PCa相比，ODC和多胺水平更高，生物学表型更具侵袭性 具有ODC G等位基因的细胞。在目标3中，我们将测试是否用DFMO和多胺处理我们的同基因细胞， 转运抑制剂（多胺阻断疗法）对PCa细胞的表型具有不同的作用， ODC A与ODC G等位基因。最后，我们还将测试多胺封闭是否有不同的效果 对来自具有ODC A等位基因的AAM与仅具有ODC G的AAM的原代PCa组织外植体的治疗 等位基因。 我们提交了拟议的研究将通过建立ODC A使非洲裔美国PCa患者受益 等位基因作为一种预后生物标志物，将有助于医生评估患者的风险，并作为一种预测 预测DFMO作为化疗治疗的成功的生物标志物。