Viral Therapy for Cancer

Productive viral infection mimics oncogenic transformation in several respects, and some of the same molecular mechanisms employed by viruses and cancer cells to disrupt essential homeostatic mechanisms. These similarities serve as a basis for razvoj''oncolytic''viruse that are designed specifically to target and kill cancer cells. Although some targeting strategies include engineering the virus so that they bind specifically to cancer, even more attractive approach involves the development of viruses that can replicate in cancer cells that contain certain defects in the homeostatic control. For example, a product of adenovirus E1B place is a protein that specifically interferes with the function of p53, thereby undermining the host p53-dependent antiviral response that would otherwise result in inhibition of DNA synthesis and / or apoptosis. Mutant forms of adenoviruses that lack E1B 55K should only replicate in cells with defective p53 function, ie cancer. Several groups have developed E1B mutant adenoviruses for cancer therapy, and promising results were obtained with several of them, including Onyx Pharmaceuticals'. Another promising approach exploits the presence of active Ras mutants.

Rhabdoviruses are RNA viruses that are being developed as oncolytic agents. Its tumor selectivity refers mainly to the fact that tumor cells are often resistant to the antiviral effects of type I interferons (IFNs), which can completely prevent viral replication in normal cells. Removing viruses mechanisms that suppress autocrine IFN production increased oncolytic activity, a further reduction of toxicity to normal host tkiva.Istraživači have designed a synthetic lethal RNAi screen to identify cytoprotective pathways that restrict the killing of tumor cells induced by rhabdovirus Maraba in three different human cancer cell lines. Njihova''hitove''su enriched for genes that function within two of the three main ways that correspond to endoplasmic reticular (ER) stress, commonly referred to as unfolded protein response (UPR). Specifically, the display is turned on and IRE1/XBP1 ATF6 pathways, and downstream genes involved in the transport of protein aggregates from the ER to proteasome in cytoprotection. It is also important to identify a group of novel small molecule inhibitor of IRE1, which is also sensitive to the tumor but not normal cells in oncolytic effects of viruses in vitro and in xenografts.

Thus, if the inhibitor can be further optimized to increase its potency, there is a good chance that these preclinical observations can be translated to patients with cancer. At first glance it might seem strange that hits PERK/eIF2a arm of the UPR are not identified, but in fact it makes sense. Phosphorylation of eIF2a results in global downregulation of CAP-dependent host translation, so that viruses have evolved many different mechanisms to prevent eIF2a phosphorylation or downstream effects in normal cells. Furthermore, we have observed that many tumor cells display increased eIF2a phosphorylation or translational arrest response to proteotoxic and ER stress, so this is the hand of UPR was disabled in a large subset of cancer anyway. In the cancer connection between the proteasome and autophagy is disrupted, which can also be advantageous to productive viral infection, if autophagy plays somerole it limiting. One can also predict the overthrow of the UPR, or ER-associated degradation (ERAD) components would result in the accumulation of protein aggregates in the ER and after a viral infection dramatically deteriorating situation overwhelming, but stressed the ER-Golgi network with increased protein synthetic load.

Indeed, inhibition of the UPR is not due to features of ER stress in infected cells, but they are resolved quickly and did not lead to obvious increase in the accumulation of protein aggregates, strongly suggesting that the sensitivity caused by pretreatment with UPR inhibitors is not caused by this mechanism. Instead, inhibition of the UPR seems da''preduvjet''stanice later virus induced cell death, upregulating expression of caspase adapter protein RAIDD and promoting activation of caspase-2, and the overthrow of the caspase-2 almost completely rescued synthetic lethal interactions between the UPR and the inhibition of viral of infection. Recent work by Doug Green group showed that RAIDD-mediated activation of caspase-2 controls the stress response transcription factor, HSF-1, suggesting that heatshocked protein and / or other (possibly ER-based?) Molecular Chaperones may play a pivotal role in the control of stressinduced caspase-2 activation.

left unresolved the molecular mechanisms that link the UPR inhibition of RAIDD and upregulation of viral infection to caspase-2 activation. It seems likely that some (perhaps subtle) perturbation of protein aggregates distance plays a role, but how, and especially why, at low stress levels, which appears to be fully resolved prior to viral infection, sets the stage for subsequent apoptosis awaits further research.

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