Pancreatic ductal adenocarcinoma (PDAC) is associated with poor survival. Of all newly diagnosed patients, only about 20% can benefit from a potentially curative surgical resection, the remaining 80% presenting with unresectable locally advanced (LAPC) or metastatic (MPC) disease. Currently, there are limited therapeutic options for LAPC and MPC patients. Furthermore, despite intensive research efforts to better understand the molecular bases of PDAC and the biological relevance of its tumor microenvironment, treatments still largely consist of classical cytotoxic chemotherapy agents. Several studies of genetic and epigenetic sequencing have demonstrated the existence of 4 molecular PDAC subtypes, with heterogeneous genetic characteristics and different biological behaviour: squamous, pancreatic progenitor, immunogenic and aberrantly differentiated endocrine exocrine (ADEX). These distinct subtypes derive from alterations at multiple levels. Apart from the DNA repair pathway, however, none of these has so far been validated as a clinically relevant therapeutic target. Also, PDAC is unique from an immunological perspective and many studies have recently tried to elucidate the role of intratumoral effector T-cells, RAS oncogene, immunosuppressive leukocytes and desmoplastic reaction in maintaining the immunological homeostasis of this disease. However, there still remains much to be learned about the mechanisms whereby the pancreatic immune microenvironment promotes immune escape of cancer cells. Furthermore, while therapies targeting the stroma as well as immunotherapies hold promise for the future, these are not yet standard of care. This review aims to outline the state-of-the-art of LAPC and MPC treatment, highlighting data on the target therapies failure and current ongoing clinical trials on new promising therapeutic strategies.

中文翻译：

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胰腺癌的新治疗靶标。

胰腺导管腺癌（PDAC）与不良的生存率相关。在所有新诊断的患者中，只有约20％的患者可以从可能治愈的手术切除中受益，其余80％的患者患有不可切除的局部晚期（LAPC）或转移性（MPC）疾病。目前，LAPC和MPC患者的治疗选择有限。此外，尽管进行了深入的研究以更好地了解PDAC的分子基础及其肿瘤微环境的生物学相关性，但治疗仍主要由经典的细胞毒性化学治疗剂组成。遗传和表观遗传测序的一些研究表明，存在4种分子PDAC亚型，它们具有异质的遗传特征和不同的生物学行为：鳞状，胰腺祖细胞，免疫原性和异常分化的内分泌外分泌（ADEX）。这些不同的亚型源自多个层次的改变。但是，除DNA修复途径外，迄今尚无一种途径被确认为临床上相关的治疗靶标。同样，从免疫学的角度来看，PDAC是独特的，最近许多研究试图阐明肿瘤内效应T细胞，RAS癌基因，免疫抑制白细胞和增生反应在维持该疾病的免疫稳态方面的作用。然而，关于胰腺免疫微环境促进癌细胞免疫逃逸的机制仍然有很多研究。此外，尽管针对基质的疗法以及免疫疗法在未来具有前景，但这些还不是标准的治疗方法。