Report of the EORTC-PAMM Meeting, Brussels, March 16-18th, 2009

Abstract

For the first time, the 2009 Pharmacology and Molecular Mechanisms (PAMM) winter meeting was organized in connection with the EGAM (EORTC Groups Annual Meeting) in Brussels. Furthermore, the PAMM participated in an additional plenary session together with the PathoBiology Group and the functional imaging group during the EGAM itself, in which the Laboratory Research Division summarized their expertise in translational research and gave an overview of what it can offer to the Disease Oriented Groups. The emphasis of the joint meeting was on novel concepts in cancer treatment and on new approaches to monitor therapy and implement personalized strategies. Three main subtopics could be possibly canvassed out of whole meeting, namely, (a) apoptosis and signalling, (b) cancer stem cells, (c) cancer genome and epigenome profiling. (a) Targeting apoptosis Most anti-cancer therapies act by triggering apoptosis in cancer cells. Therefore, defects in apoptosis programmes, for example aberrant expression of anti-apoptotic proteins, may render cancer cells resistant to treatment. Indeed, deregulation of apoptosis is one of the hallmarks of malignant cells, allowing their survival in the context of an altered genome and in harsh tumour environments with low levels of oxygen and nutrients. Understanding of the molecular mechanisms underlying apoptosis suppression in cancer has provided rationales for the design of apoptosis targeted therapies. One strategy was illustrated by Simone Fulda (University Children’s Hospital, Ulm, Germany) and involves the targeting of inhibitors of apoptosis proteins (IAPs), which are expressed at high levels in many human cancers and block apoptosis by inhibiting effector caspases. Fulda showed how targeting XIAP (one member of the IAP family) by RNA interference-mediated knockdown or small molecule inhibitors cooperates with TRAIL (tumour-necrosis-related apoptosis-induced ligand) to suppress growth in both in vitro and in vivo models of pancreatic cancer and in childhood acute leukaemia cells [14,25]. In this context, IAP inhibitors appear to be promising therapeutic tools, and they have recently entered early clinical trials in the form of small peptides. Nadia Zaffaroni (Fondazione IRCCS Istituto Nazionale dei tumouri, Milan, Italy) showed promising in vitro and in vivo data on ‘survivin’ inhibition, another member of the IAP family of apoptosis inhibitors. Survivin is a bifunctional protein that in addition to acting as a suppressor of programmed cell death also plays a central role in cell division. Owing to its massive up-regulation in human tumours and its involvement in cancer progression and treatment resistance, survivin is currently undergoing extensive investigation as a promising target for new anti-cancer interventions. Zaffaroni showed how the down-regulation of this protein, accomplished by means of various strategies (including the use of antisense oligonucleotides, small interfering RNAs, ribozymes, dominant negative mutants and small molecules antagonists) reduced tumour growth potential, increased the apoptotic rate and sensitized tumour cells to chemo- and radiotherapeutic agents in different tumour pre-clinical models [18]. The first survivin inhibitors have already reached the clinic: the YM155 molecule is currently in phase 1–2 studies [22]. However, due to its central role in promoting cell division in normal cells, the effects of survivin disruption on normal tissues and the related possible toxicities must be further investigated. Frank A Kruyt (University Medical Center Groningen, the Netherlands) presented his work on bortezomib, an interesting compound that can reversibly inhibit the proteasome and induce mitochondrial-dependent apoptosis [26]. Kruyt argued that bortezomib may be an interesting targeting moiety for non-small-cell lung cancer (NSCLC), a disease with poor survival rates, which represents 80–85% of lung cancer cases. The combined administration of TRAIL/bortezomib proved highly effective in inducing mitochondrial-dependent apoptosis in both in vitro and in vivo models of NSCLC. Mechanistic studies are ongoing to better understand the favourable drug interactions. In the clinic, recombinant TRAIL preparations and agonistic antibodies are under examination and combination strategies are in progress, including mapatumumab (TRAIL-R1/DR4 mAb) and bortezomib in multiple myeloma [6–8].