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.

项目概要 非裔美国男性 (AAM) 的前列腺癌 (PCa) 发病率和死亡率要高得多 与欧洲裔美国男性 (EAM) 相比，这些种族之间的遗传变异起着至关重要的作用。我们的 研究表明，指导多胺生物合成的基因表达显着升高 AAM 与 EAM PCa 相比，表明该通路可能在推动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也是限速酶。值得注意的是， 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)，该 SNP 增强了 ODC 启动子活性。重要的是，ODC A 等位基因更常见于 AAM 高于 EAM，表明 AAM 中具有 ODC A 等位基因的前列腺肿瘤的 ODC 水平会升高 这推动了前列腺肿瘤的侵袭性生物学发展。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，适用于至少携带一种疾病的高危男性 ODC A 等位基因，表明 ODC A 等位基因将预测 AAM PCa 患者从 DFMO 治疗中受益。 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 生物学和非裔美国男性的目标脆弱性。为了检验这个假设，在目标 1 中我们将 使用等位基因区分测定法检测前列腺癌病例中的约 3,800 个 DNA 样本（约 1,520 个 AAM：约 2,280 个 EAM） 并控制 ODC A 等位基因的存在，以： (i) 确定其在两个种族中的频率； (ii) 评估是否 ODC A 等位基因意味着患者预后较差。在目标 2 中，我们将生成三组同基因 PCa 细胞 通过基于 CRISPR 的 Prime 编辑，我们将测试带有 ODC A 等位基因的 PCa 细胞是否增加 与同基因 PCa 相比，ODC 和多胺水平更高，并且具有更具侵袭性的生物表型 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 细胞的表型有不同的影响 ODC A 与 ODC G 等位基因。最后，我们还将测试多胺阻断是否存在差异效应 具有 ODC A 等位基因的 AAM 与仅具有 ODC G 的 AAM 的原发性 PCa 组织外植体的治疗 等位基因。 我们提交的拟议研究将通过建立 ODC A 使非裔美国 PCa 患者受益 等位基因作为预后生物标志物，有助于医生评估患者风险，并作为预测 预测 DFMO 作为化疗治疗是否成功的生物标志物。