Pilot Project 5

摘要-试点项目5 胰腺导管腺癌是人类侵袭性最强、存活率最高的恶性肿瘤之一。 死亡率仍然停滞不前，5年存活率仅为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 对口单位。FOLFIRINOX(5-氟尿嘧啶、亚叶酸钙、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，但其相当大的毒性限制了其使用。这个 由于遗传和表观遗传原因导致的核苷转运体表达减少似乎是 宝石阻力。此外，脱氧胞苷激酶(DCK)负责将Gem磷酸化成 活性形式，被认为与宝石功效相关。为了应对这些挑战，我们修改了Gem 4-(N)-硬脂酰宝石(4NSG)：i)阻止CDA对Gem的攻击，ii)增加Gem向PDAC的传输 细胞。我们最近的研究结果显示，在胰腺中高表达表皮生长因子受体(EGFR)。 肿瘤样本。根据我们最近发表和未发表的结果，我们假设优化了4NSG 表面修饰的抗EGFR抗体纳米粒(4NSGnpcetu)将提高慢性粒细胞白血病的治疗效果 宝石。我们提出了以下具体目标来解决这一假设。目的1：检测4NSGnpcetu的疗效。 在B/AA和White患者衍生的带有间质的器官模型(PDO)和原代PDAC细胞中。目标2： 4NSGnpcetu对PDAC-PDX小鼠皮下移植瘤的治疗作用 B/AA和白人患者。目的：检测DCK RNA/蛋白在PDAC、PDX肿瘤模型和SNP中的表达 多种族数据集中PDAC病例和对照的基因型别。我们的研究将确定种族问题 DCK变异、基因表达和蛋白质活性的差异可能与Gem疗效的改善有关 B/AA和/或白色PDAC患者。所获得的有价值的信息将大大推进总体目标 提高PDAC患者的疗效和存活率。

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 Guided by our recently published and unpublished results, we hypothesize that optimized 4NSG nanoparticles with surface-modified anti-EGFR antibody (4NSGnpcetu) will improve the therapeutic efficacy of Gem.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