Pilot Project 5

摘要-试点项目5 胰腺导管腺癌（PDAC）是人类最具侵袭性的恶性肿瘤之一， 5年生存率仅为5- 8%。黑人/非裔美国人（B/AA） 与白色人相比， 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。的 由于遗传和表观遗传的原因，核苷转运蛋白的表达减少， 宝石抗性。此外，负责Gem磷酸化进入细胞的脱氧胞苷激酶（dCK） 活性形式，被认为与Gem功效相关。为了应对这些挑战，我们修改了Gem 至4-（N）-硬脂酰基Gem（4 NSG）以：i）阻断CDA对Gem的攻击，和ii）增加Gem转运至PDAC 细胞我们最近的研究结果显示，在胰腺癌组织中，表皮生长因子受体（EGFR）的表达非常高。 肿瘤样本根据我们最近发表和未发表的结果，我们假设优化的4 NSG 具有表面修饰的抗EGFR抗体（4 NSGnpcetu）的纳米颗粒将改善EGFR的治疗功效。 创业板我们提出以下具体目标来解决这一假设。目的1：检测4 NSGnpcetu的疗效， 在B/AA和具有基质的白色患者来源的类器官模型（PDO）和原代PDAC细胞中。目标二： 评价4 NSGnpcetu在携带来自人的皮下肿瘤的PDAC PDX小鼠模型中的治疗功效。 B/AA和白色患者。目的3：测量PDAC PDX肿瘤模型中dCK RNA/蛋白表达和SNP 多种族数据集中PDAC病例和对照的基因型。我们的研究将决定种族 dCK变体、基因表达和蛋白质活性的差异可能与Gem在以下方面的改善功效相关： B/AA和/或白色PDAC患者。获得的宝贵信息将大大推进总体目标 改善PDAC患者的反应和生存率。

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 Guided by our recently published and unpublished results, we hypothesize that optimized 4NSG nanoparticles with surface-modified anti-EGFR antibody (4NSGnpcetu) will improve the therapeutic efficacy of Gem.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.