癌症治疗针对细胞内独特的代谢紊乱逐渐成为解决胰导管腺癌（PDAC）等难治性实体肿瘤的关键策略，这些肿瘤在肿瘤微环境中对极度的营养匮乏表现出抵抗性。尼古丁酸腺嘌呤二核苷酸（NAD）参与多种代谢途径，尼嘌呤腺苷转移酶（NAMPT）是促进NAD合成的关键细胞内酶之一。C末端结合蛋白1和2（CtBP）是NAD依赖的致癌转录因子和脱氢酶，其核化一个表观遗传复合物，调控一系列负责癌症增殖和转移的基因。由于CtBP的寡聚化和致癌转录共调控活动需要足够的细胞内NAD，我们假设NAD耗竭将加强CtBP抑制作用，提高细胞抑制效果。事实上，通过NAMPT抑制剂GMX1778耗竭细胞内NAD，能够增强RNAi介导的CtBP1/2敲除或CtBP脱氢酶抑制剂4-氯苯基-2-羟基亚胺丙酸诱导的PDAC细胞生长抑制效果，最高可达10倍，而未转化的胰导管细胞不受影响。NAMPT/CtBP抑制剂联合使用的生长抑制效果与CtBP1/2二聚化的抑制，CtBP2与CoREST表观遗传调节因子的相互作用以及致癌靶基因TIAM1的转录活化在药效动力学上相关。此外，这种治疗组合在免疫缺陷小鼠的PDAC细胞系异种移植瘤中强烈抑制了肿瘤生长，没有观察到毒性。总体而言，我们的数据表明，联合靶向CtBP和NAD耗竭是一种有前景的PDAC治疗策略。

Cancer therapies targeting metabolic derangements unique to cancer cells are emerging as a key strategy to address refractory solid tumors such as pancreatic ductal adenocarcinomas (PDAC) that exhibit resistance to extreme nutrient deprivation in the tumor microenvironment. Nicotinamide adenine dinucleotide (NAD) participates in multiple metabolic pathways and Nicotinamide phosphoribosyl transferase (NAMPT) is one of the key intracellular enzymes that facilitate the synthesis of NAD. C-terminal Binding Proteins 1 and 2 (CtBP) are paralogous NAD-dependent oncogenic transcription factors and dehydrogenases that nucleate an epigenetic complex regulating a cohort of genes responsible for cancer proliferation and metastasis. As adequate intracellular NAD is required for CtBP to oligomerize and execute its oncogenic transcriptional coregulatory activities, we hypothesized that NAD depletion would synergize with CtBP inhibition, improving cell inhibitory efficacy. Indeed, depletion of cellular NAD via the NAMPT inhibitor GMX1778 enhanced growth inhibition induced by either RNAi-mediated CtBP1/2 knockdown or the CtBP dehydrogenase inhibitor 4-chlorophenyl-2-hydroxyimino propanoic acid as much as 10-fold in PDAC cells, while untransformed pancreatic ductal cells were unaffected. The growth inhibitory effects of the NAMPT/CtBP inhibitor combination correlated pharmacodynamically with on-target disruption of CtBP1/2 dimerization, CtBP2 interaction with the CoREST epigenetic regulator, and transcriptional activation of the oncogenic target gene TIAM1. Moreover, this same therapeutic combination strongly attenuated growth of PDAC cell line xenografts in immunodeficient mice, with no observable toxicity. Collectively, our data demonstrate that targeting CtBP in combination with NAD depletion represents a promising therapeutic strategy for PDAC.