Targeting apoptosis pathways in pancreatic cancer

Abstract

Pancreatic cancer - here in particular pancreatic ductal adenocarcinoma (PDAC) - is still a highly therapy refractory disease. Amongst the mechanisms by which PDAC cells could escape any non-surgical therapy, anti-apoptotic protection seems to be the most relevant one. PDAC cells have acquired resistance to apoptotic stimuli such as death ligands (FasL, TRAIL) or anti-cancer drugs (gemcitabine) by a great number of molecular alterations either disrupting an apoptosis inducing signal or counteracting the execution of apoptosis. Thus, PDAC cells exhibit alterations in the EGFR/MAPK/Ras/raf1-, PI3K/Akt-, TRAIL/TRAF2-, or IKK/NF-κB pathway accompanied by deregulations in the expression of apoptosis regulators such as cIAP, Bcl2, XIAP or survivin. Along with protection against apoptosis, PDAC cells also overexpress histone deacetylases (HDACs) giving rise to epigenetic patterns of chemoresistance and to acetylation of other regulatory proteins, as well. With respect to the multitude of anti-apoptotic pathways, a great number of molecular targets might be of high potential in novel therapy strategies. Thus, natural compounds as well as novel synthetic drugs are considered to be used in single or combined therapy of PDAC. A number of proteasome and HDAC inhibitors or selective inhibitors of IKK, EGFR, Akt and mTOR have been widely explored in preclinical settings and clinical studies. Even though these early studies encouraged an application in a clinical setting, most of the trials have been rather disappointing yet. Thus, new molecular targets and novel concepts of combination therapies need to get access into clinical trials - either in neoadjuvant/adjuvant or in palliative treatments.