Sun Jufeng, Russell Cecilia C, Scarlett Christopher J, McCluskey Adam
Chemistry , School of Environmental & Life Sciences , The University of Newcastle , Newcastle , Callaghan , NSW 2308 , Australia . Email:
Medicinal Chemistry , School of Pharmacy , Binzhou Medical University , Yantai , 264003 , China.
RSC Med Chem. 2020 Jan 24;11(2):164-183. doi: 10.1039/c9md00447e. eCollection 2020 Feb 1.
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 and capecitabine gave a median overall survival (MoS) of 13 months and a phase II study of pazopanib 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 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.
胰腺癌（PC）的5年生存率低于7%，是所有人类癌症中最致命的癌症之一。这种疾病具有高度侵袭性和转移性，这带来了一个挑战，即尽管付出了巨大努力，但目前的治疗方法仍无法应对。本综述考察了35种在临床试验中靶向胰腺癌的小分子抑制剂的现状以及另外50多种正在研究中的抑制剂。这些化合物抑制的生物学靶点包括蛋白激酶、信号转导和转录激活因子3（STAT3）、溴结构域和额外终端结构域（BET）、组蛋白去乙酰化酶（HDAC）以及B细胞淋巴瘤-2（Bcl-2）家族蛋白。不出所料，蛋白激酶抑制剂占比过高。一些试验显示出了希望；伏立诺他与卡培他滨的I期联合试验的中位总生存期（MoS）为13个月，帕唑帕尼的II期研究显示MoS为25个月。转移性胰腺导管腺癌目前的标准治疗方案，即氟尿嘧啶/叶酸（5-FU，商品名：阿糖胞苷）和吉西他滨（商品名：健择），其MoS分别为23个月和23.6个月（欧洲胰腺癌研究组-3[EPAC-3]研究）。对于能够耐受FOLFIRINOX方案的患者，该方案正成为标准治疗方法，其MoS为11.1个月。临床研究进展缓慢，相对于吉西他滨单药治疗，患者生存率的改善有限。胰腺癌生存率低的一个主要原因是诊断较晚，发生在那些将典型的早期疼痛等警示信号视为正常的患者身上。选择具有特定疾病表型的患者、使用改进的高效药物组合、识别特定癌症亚型的生物标志物以及更有效的研究设计已经改善了治疗结果。为了摆脱目前胰腺癌治疗的严峻状况和有限的治疗选择，确定最佳治疗方案和新的治疗选择是必须应对的挑战。胰腺癌预后不良的原因在20年来基本没有变化。这可以说是药物研发格局发生重大变化以及学术界面临越来越大的压力，要提供短期“媒体”友好型短期新闻“片段”的结果。胰腺癌研究正处于一个关键节点。也许最大的挑战是实现一种文化变革，即认识到重大突破是由大胆创新、真正具有创新性和好奇心驱动的研究带来的。
