Targeting epigenetic modifications and gene expression in pancreatic cancer: antitumoral effect of combined therapies

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Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive carcinoma with a poor prognosis, and there is no effective treatment to date. Among the chemotherapeutic drugs used to treat PDAC, Gemcitabine (dFdC) and FOLFIRINOX (folinic acid, 5-fluorouracil, irinotecan, oxaliplatin) are the first choice and the reference treatment. The clinical aspects that might help PDAC develop drug resistance includes tumor heterogeneity, development of extracellular matrix, epithelial mesenchymal transition, and upregulated drug transporters. Consequently, there is an urgent need to test new therapeutic targets to improve prognosis and survival of pancreatic cancer patients. The goal of this project is to find a combined therapy for PDAC that improves the limited therapeutic efficacy of Gemcitabine. The proposed therapy is based on novel epigenetic protein inhibitors, alone or in combination with the silencing of relevant genes implicated in tumor progression. The therapeutic effect will be tested in human pancreatic cell lines and the best combinations will be tested in a murine xenograft tumor model. The use of epigenetic protein inhibitors, such as those targeting DNA methyltransferases (DNMT), histone deacetylase (HDAC), Bromodomain and extraterminal domain (BET) proteins and sirtuins (SIRTs) has emerged as an alternative therapeutic strategy for PDAC treatment. Epigenetic modifications affect the transcription of genes via histone modification, DNA methylation, non-coding RNAs or alteration of chromatin accessibility. This network provides the cells with various tools that can dramatically affect its transcriptome without the need of inducing any irreversible changes at the level of the nucleotide sequence. Mutations in relevant oncogenes, such as KRAS and TP53, play a role in the pathophysiology of PDAC. KRAS induces de overexpression of some transcription factors, like Yes-associated protein (YAP1) and Fos-like 1 antigen (FOSL1), causing tumor progression. Therefore, targeting the expression of YAP and FOSL1, by small interfering ribonucleic acid (siRNA), can be an effective therapeutic approach to avoid tumour progression and metastasis. Moreover, the use of liposomes for the encapsulation of the siRNA (lipoplexes) can help in the transport of these labile nucleic acids, and in the transfection into the tumor cells. Similarly, liposomes will be used for the encapsulation of the epigenetic inhibitors, which are highly hydrophobic, for their use in vivo. Encapsulation of the drugs in a nanoparticle, could increase the accumulation of the drug in the tumor by passive targeting. As a consequence, the therapeutic dose used in vivo and the side effects would be reduced.

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