Pancreatic cancer (PC), with a 5 year survival of <7%, is one of the most fatal of all human cancers. The highly aggressive and metastatic character of this disease poses a challenge that current therapies are failing, despite significant efforts, to meet. This review examines the current status of the 35 small molecule inhibitors targeting pancreatic cancer in clinical trials and the >50 currently under investigation. These compounds inhibit biological targets spanning protein kinases, STAT3, BET, HDACs and Bcl-2 family proteins. Unsurprisingly, protein kinase inhibitors are overrepresented. Some trials show promise; a phase I combination trial of vorinostat 11 and capecitabine 17 gave a median overall survival (MoS) of 13 months and a phase II study of pazopanib 15 showed a MoS of 25 months. The current standard of care for metastatic pancreatic ductal adenocarcinoma, fluorouracil/folic acid (5-FU, Adrucil®), and gemcitabine (GEMZAR®) afforded a MoS of 23 and 23.6 months (EPAC-3 study), respectively. In patients who can tolerate the FOLFIRINOX regime, this is becoming the standard of treatment with a MoS of 11.1 months. Clinical study progress has been slow with limited improvement in patient survival relative to gemcitabine 1 monotherapy. A major cause of low PC survival is the late stage of diagnosis, occurring in patients who consider typical early stage warning signs of aches and pains normal. The selection of patients with specific disease phenotypes, the use of improved efficient drug combinations, the identification of biomarkers to specific cancer subtypes and more effective designs of investigation have improved outcomes. To move beyond the current dire condition and paucity of PC treatment options, determination of the best regimes and new treatment options is a challenge that must be met. The reasons for poor PC prognosis have remained largely unchanged for 20 years. This is arguably a consequence of significant changes in the drug discovery landscape, and the increasing pressure on academia to deliver short term ‘media’ friendly short-term news ‘bites’. PC research sits at a pivotal point. Perhaps the greatest challenge is enacting a culture change that recognises that major breakthroughs are a result of blue sky, truly innovative and curiosity driven research.

中文翻译：

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胰腺癌中的小分子抑制剂

胰腺癌 (PC) 的 5 年生存率 <7%，是所有人类癌症中最致命的一种。这种疾病的高度侵袭性和转移性特征提出了挑战，尽管付出了巨大的努力，但当前的治疗方法仍无法应对。本综述探讨了临床试验中 35 种针对胰腺癌的小分子抑制剂以及目前正在研究的超过 50 种小分子抑制剂的现状。这些化合物可抑制蛋白激酶、STAT3、BET、HDAC 和 Bcl-2 家族蛋白等生物靶标。毫不奇怪，蛋白激酶抑制剂的比例过高。一些试验显示出希望；但也有一些试验显示出希望。伏立诺他11和卡培他滨17的 I 期联合试验显示中位总生存期 (MoS) 为 13 个月，帕唑帕尼15的 II 期研究显示中位总生存期 (MoS) 为 25 个月。目前转移性胰腺导管腺癌的护理标准，氟尿嘧啶/叶酸（5-FU，Adrucil®）和吉西他滨（GEMZAR®）的 MoS 分别为 23 个月和 23.6 个月（EPAC-3 研究）。对于能够耐受 FOLFIRINOX 方案的患者，这正在成为 MoS 为 11.1 个月的治疗标准。相对于吉西他滨1单药疗法，临床研究进展缓慢，患者生存率改善有限。PC 存活率低的一个主要原因是诊断的晚期，发生在认为疼痛的典型早期预警信号正常的患者中。选择具有特定疾病表型的患者、使用改进的有效药物组合、识别特定癌症亚型的生物标志物以及更有效的研究设计都改善了结果。为了摆脱目前的严峻状况和 PC 治疗方案的匮乏，确定最佳方案和新的治疗方案是必须应对的挑战。PC预后不良的原因20年来基本没有变化。这可以说是药物发现领域发生重大变化的结果，以及学术界提供短期“媒体”友好的短期新闻“片段”的压力越来越大。PC 研究正处于关键时刻。也许最大的挑战是进行文化变革，认识到重大突破是蓝天、真正创新和好奇心驱动研究的结果。