Pancreatic Ductal AdenoCarcinoma (PDAC) is one of the most lethal human malignancies and a major health problem, causing around 350,000 deaths per year worldwide. The prognosis is poor, with around 5% of patients alive at 5 years after diagnosis. Over recent decades, detailed genetic analysis of tumors has resulted in the identification and validation of crucial genes that are mutated and dysregulated in a tumor-specific manner, indicating a genetic dependency in the development of these tumors, and suggesting that it could be possible to take advantage of these mutations as potential therapeutic targets, where specific drugs are available.
Unfortunately, after a highly enthusiastic period, we must recognize that these types of targets can be effectively utilized for only a small percentage of patients; firstly, because relevant drugs are not available, and secondly, because the mutated genes are not druggable. This is the case for PDAC, in which the mutations are relatively conserved between tumors (KRAS, P53, SMAD4, CDKN2A, MLL3, TGFBR2, ARID1A, and SF3B1) but targetable genes remain extremely rare since some of them do not present direct enzymatic activity to be inhibited or because their protein-protein interaction-based activity remain technically unattainable for the moment.
Almost all recent phase II and III clinical trials implemented in unselected PDAC populations showed no robust survival benefits, probably because they were tested in unselected PDAC populations that were highly heterogeneous. In fact, a major impediment to the effective treatment of PDAC is the molecular heterogeneity of the disease, reflected in diverse clinical response patterns to therapy. This heterogeneity is shown by the dissimilar evolution observed in patients with PDAC, with a survival time that can range from 2-3 months to more than 5 years after diagnosis, and with a strong difference in susceptibility to treatment with classical as well as novel drugs. This may be explained by the fact that each PDAC is controlled by a combination of several modifications of intracellular pathways, which will result in variable susceptibility to drugs, metastasis development, and therefore, survival. Unfortunately, until now no proposed treatments have taken into account this heterogeneity. In fact, the drugs received by patients suffering from PDAC are chosen according to their general performance status and the stage of their disease. No study of the tumor can predict its responsiveness to the treatment, nor give a prognosis to the disease progression.