HHSN2612012000131/HHSN26100010Base Contract Title: Preclinical Efficacy and Intermediate Endpoint Biomarkers. Task Order Title: Preclinical Studies to Evaluate the Combination of Metformin and As

胰腺癌（PC）仍然是一种毁灭性的疾病，5年生存率低，是美国男性和女性癌症相关死亡的第四大原因。缺乏早期检测方法和无效的治疗方案导致预后不良。胰腺上皮内病变（PanIN）是有证据表明在发展为侵袭性胰腺导管腺癌（PDAC）之前多年缓慢进展的前体。因此，开发一种有效的化学预防治疗，旨在抑制PanIN的进展，可以提供一个重要的策略，以减少PC的负担。 胰腺癌的病因学和实验室研究表明，炎症在胰腺肿瘤的发生中起着重要作用。阿司匹林和其他NSAID显示出作为化学预防剂的前景，因为它们对炎症的作用归因于抑制考克斯酶和调节NFκB或STAT 3途径。此外，阿司匹林的使用与胰腺癌风险降低有关。然而，长期使用阿司匹林有潜在的剂量相关的不良反应，如胃肠道刺激和出血。因此，需要开发一种PC的化学预防策略，证明低剂量阿司匹林的疗效。 据报道，糖尿病、肥胖和慢性胰腺炎会增加PC的风险。糖尿病患者使用二甲双胍与包括PC在内的几种癌症的风险降低有关。实验室研究表明，二甲双胍可抑制细胞增殖，这可能是通过诱导AMPK和抑制mTOR途径介导的。总之，这些观察结果表明二甲双胍可能是PC化学预防的有用药物。二甲双胍的临床使用可能会因某些高危患者中罕见但严重的代谢性酸中毒不良反应而复杂化。因此，仔细选择患者或降低临床剂量可能是管理化学预防使用该药物风险的有用策略。 阿司匹林和二甲双胍可能通过重叠和独立的机制介导其对细胞增殖和炎症的影响。然而，它们似乎没有重叠的不利影响。这两种药物已经被FDA批准用于人类。这些都是有利于其用于联合治疗的潜在用途的重要因素。此外，最近报道的体外研究表明，这两种药物联合使用可能会显示出协同作用。因此，动物模型研究将是评估二甲双胍和阿司匹林联合用于PC化学预防的风险获益比改善潜力的重要下一步。

Pancreatic cancer (PC) remains a devastating disease with a low 5-year survival rate and for both men and women is the fourth leading cause of cancer related deaths in the US. The lack of early detection methods and ineffective therapeutic options contribute to the poor prognosis. Pancreatic intraepithelial lesions (PanINs) are precursors that evidence suggests progress slowly over many years prior to developing into invasive pancreatic ductal adenocarcinoma (PDAC). Therefore, developing an effective chemoprevention treatment aimed at inhibiting the progression of PanINs could provide an important strategy to reduce the burden of PC. The etiology of PC and laboratory studies suggests that inflammation plays a significant role in pancreatic tumorigenesis. Aspirin and other NSAIDs show promise as chemopreventive agents due to their effects on inflammation that are attributed to inhibition of COX enzymes and modulation of NFκB or STAT3 pathways. Furthermore, the use of aspirin is associated with a decreased risk of pancreatic cancer. However, long term use of aspirin has potential dose related adverse effects such as gastrointestinal irritation and bleeding. Therefore, developing a chemopreventive strategy for PC that demonstrates efficacy with lower doses of aspirin is desirable. Diabetes, obesity and chronic pancreatitis are reported to increase the risk of PC. Metformin use in patients with diabetes has been associated with a decreased risk of several cancers including PC. Laboratory studies demonstrate that metformin inhibits cell proliferation that may be mediated by inducing AMPK and inhibiting the mTOR pathway. Taken together, these observations suggest metformin may be a useful agent for PC chemoprevention. The clinical use of metformin can be complicated by a rare but serious adverse effect of metabolic acidosis in some at risk patients. Therefore careful patient selection or lower clinical doses may be helpful strategies to manage risk for the chemopreventive use of this agent. Aspirin and metformin likely mediate their effects on cell proliferation and inflammation through both overlapping and independent mechanisms. However, they do not appear to have overlapping adverse effects. Both agents are already approved for use in humans by the FDA. These are all important factors that favor their potential use for combination therapy. In addition, recently reported in vitro studies indicate these two agents may display synergistic effects in combination. Therefore, animal model studies will be an important next step in assessing the potential for improved risk to benefit ratio for the combined use of metformin and aspirin for chemoprevention of PC.