Pilot Project 5

试点项目5

• 批准号: 10762320
• 负责人: BO HAN
• 金额: $ 5.53万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-20 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10762320
• 关键词: Address; African American population; Black Bear; Black race; California; Cancer Etiology; Caring; Cells; Cessation of life; Cytidine Deaminase; DCK gene; Data Set; Deoxycytidine Kinase; Diagnosis; Drug Kinetics; Drug usage; Education; Epidermal Growth Factor Receptor; Epigenetic Process; Exposure to; Fc Receptor; Florida; Fluorouracil; Formulation; Gene Expression; Genetic; Goals; High Prevalence; Human; Incidence; Investigation; Leucovorin; Malignant Neoplasms; Measures; Metabolism; Modeling; Mus; Nucleoside Transporter; Operative Surgical Procedures; Organoids; Pancreas; Pancreatic Ductal Adenocarcinoma; Patients; Phosphorylation; Pilot Projects; Population Heterogeneity; Proteins; Publishing; RNA; Resistance; Risk; SNP genotyping; Safety; Sampling; Solubility; Surface; Survival Rate; Systemic Therapy; Testing; Toxic effect; Treatment Efficacy; Variant; Wild Type Mouse; anticancer activity; anticancer research; chemotherapy; cohort; design; efficacy evaluation; efficacy testing; enzyme activity; ethnic diversity; experience; experimental study; gemcitabine; health equity; improved; in vivo; irinotecan; lipophilicity; mortality; mouse model; multi-ethnic; nanoparticle; oxaliplatin; pancreatic PDX models; pancreatic ductal adenocarcinoma cell; pancreatic neoplasm; patient derived xenograft model; patient stratification; personalized chemotherapy; protein expression; racial difference; racial diversity; response; subcutaneous; targeted delivery; therapy outcome; treatment choice; tumor; tumor growth; tumor xenograft; uptake

ABSTRACT – Pilot Project 5 Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive human malignancies and the survival rate remains stagnant with a 5-year survival rate of only 5-8%. Black/African Americans (B/AA) individuals experience the highest prevalence and lowest overall survival rates of PDAC compared to their White counterparts. FOLFIRINOX (5-fluorouracil, leucovorin, oxaliplatin, and irinotecan) is often the preferred chemotherapy treatment choice for patients with PDAC, but considerable toxicities have limited its use. The decreased expression of nucleoside transporters due to genetic and epigenetic reasons appeared to account for Gem resistance. In addition, deoxycytidine kinase (dCK), which is responsible for Gem phosphorylation into the active form, is postulated to correlate with Gem efficacy. To address these challenges, we have modified Gem to 4-(N)- stearoylGem (4NSG) to: i) block the CDA attack on Gem, and ii) increase Gem transport into PDAC cells. Our recent results revealed highly expressed epidermal growth factor receptors (EGFR) in pancreatic tumor samples. Guided by our recently published and unpublished results, we hypothesize that optimized 4NSG nanoparticles with surface-modified anti-EGFR antibody (4NSGnpcetu) will improve the therapeutic efficacy of Gem. We propose the following specific aims to address this hypothesis. Aim 1: Test the efficacy of 4NSGnpcetu, in B/AA, and White patient-derived organoid models (PDOs) with stroma and in primary PDAC cells. Aim 2: Evaluate the therapeutic efficacy of 4NSGnpcetu in PDAC PDX mouse models bearing subcutaneous tumors from B/AA and White patients. Aim 3: Measure dCK RNA/protein expression in PDAC PDX tumor models and SNP genotypes in PDAC cases and controls in the MultiEthnic dataset. Our studies will determine whether racial differences in dCK variant, gene expression, and protein activity can correlate with improved Gem efficacy in B/AA and /or White PDAC patients. The valuable information obtained will significantly advance the overall goal of improving the response and survival rate in PDAC patients.

摘要 – 试点项目 5 胰腺导管腺癌（PDAC）是最具侵袭性的人类恶性肿瘤之一，其生存率 率仍然停滞不前，5年生存率仅为5-8%。黑人/非裔美国人 (B/AA) 个人 与白人相比，PDAC 的患病率最高，总体存活率最低 同行。 FOLFIRINOX（5-氟尿嘧啶、亚叶酸、奥沙利铂和伊立替康）通常是​​首选 化疗是PDAC患者的治疗选择，但相当大的毒性限制了其使用。这 由于遗传和表观遗传原因，核苷转运蛋白的表达减少似乎可以解释 宝石抗性。此外，脱氧胞苷激酶 (dCK) 负责 Gem 磷酸化成 活性形式，被假定与宝石功效相关。为了应对这些挑战，我们修改了 Gem 4-(N)- 硬脂酰Gem (4NSG) 可以：i) 阻止 CDA 对 Gem 的攻击，以及 ii) 增加 Gem 向 PDAC 的传输 细胞。我们最近的结果显示胰腺中高度表达表皮生长因子受体（EGFR） 肿瘤样本。根据我们最近发布和未发布的结果，我们假设优化的 4NSG 表面修饰的抗 EGFR 抗体 (4NSGnpcetu) 纳米颗粒将提高治疗效果 宝石。我们提出以下具体目标来解决这一假设。目标 1：测试 4NSGnpcetu 的功效， 在 B/AA 和带有基质的白人患者来源的类器官模型 (PDO) 和原代 PDAC 细胞中。目标 2： 评估 4NSGnpcetu 在带有皮下肿瘤的 PDAC PDX 小鼠模型中的治疗效果 B/AA 和白人患者。目标 3：测量 PDAC PDX 肿瘤模型和 SNP 中的 dCK RNA/蛋白表达 多种族数据集中 PDAC 病例和对照的基因型。我们的研究将确定种族是否 dCK 变体、基因表达和蛋白质活性的差异可能与 Gem 功效的改善相关 B/AA 和/或白人 PDAC 患者。获得的有价值的信息将显着推进总体目标 提高 PDAC 患者的反应和生存率。