Viral Therapy for Cancer

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of productive viral infection mimics oncogenic transformation in several aspects, some of the same molecular mechanisms employed by viruses and cancer cells to disrupt essential homeostatic mechanisms. These similarities serve as the basis for the development of oncolytic viruses'''' that are designed to specifically target and kill cancer cells. While some focused strategies include engineering viruses so that they bind specifically to cancer, even more attractive approach involves the development of viruses that can replicate only in cancer cells that contain certain defects in the homeostatic control. For example, a product of the adenovirus E1B locus is a protein that specifically interferes with p53 function, thus undermining the host p53-dependent antiviral response, which would otherwise lead to 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 suppress viral replication in normal cells. Elimination of viral mechanisms that suppress the autocrine IFN production increased oncolytic activity, while further reducing toxicity to normal host tissues. Researchers have designed a synthetic lethal RNAi screen to identify cytoprotective pathways that limit the killing of tumor cells induced by the Maraba Rhabdovirus in three different human cancer cell lines. Their'' hits'' are enriched for genes that function within two of the three main ways that correspond to endoplasmic reticular (ER) stress, commonly referred to as subsequent protein response (UPR). More specifically, the screen involved in IRE1/XBP1 and ATF6 pathways, as well as the acquisition of genes involved in the transport of aggregates of proteins from the ER to the proteasome in cytoprotection. It is important, the group has found a new small molecule inhibitors that IRE1 is also sensitive to the tumor but not normal cells to the oncolytic effects of viruses in vitro and in xenografts.

Therefore, if the inhibitor can be further optimized to increase its strength, there is a good chance that these preclinical findings can be translated to patients with cancer. At first glance it might seem strange that struck within 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 translation of host, so that viruses have evolved many different mechanisms to prevent eIF2a phosphorylation or its effects in the acquisition of normal cells. Furthermore, many have observed that tumor cells do not represent increased eIF2a phosphorylation or translational arrest in response to ER stress and proteotoxic, so this is a hand UPR is disabled in a large subset of cancer anyway. In these cancers coupling between the proteasome and autophagy is disrupted, which can also be useful for productive viral infection, if autophagy plays somerole in this limit. It can also be provided to the couch for the UPR, or ER-associated collapse (ERAD) components would cause the accumulation of protein aggregates within the ER and after a viral infection dramatically deteriorating situation overcomes the already stressed ER-Golgi network with increased protein synthetic load.

Indeed, inhibition of the UPR features cause ER stress in infected cells, but are resolved quickly and did not lead to obvious increase in the accumulation of protein aggregates, strongly suggesting that the sensitization induced by pretreatment with Ctrl inhibitor is not caused by this mechanism. Instead, inhibition of the UPR appears to'' condition'' cells in the virus subsequently induced cell death by upregulating expression of caspase adapter protein, RAIDD, and promote the activation of caspase-2, and couches of caspase-2 was almost completely rescued the synthetic lethal interactions App inhibition and viral infections. Recent work from Doug Green groups demonstrated that RAIDD-mediated activation of caspase-2 controls the stress response transcription factor, HSF-1, which means that heatshocked proteins and / or other (possibly ER-based?) Molecular Chaperones may play a central role in control of stressinduced activation of caspase-2.

left unresolved the molecular mechanisms of inhibition of the UPR leading to increased RAIDD and viral infection to caspase-2 activation. It seems likely that some (perhaps subtle) perturbation of protein total cleaning plays a role, but how and why in particular, to low levels of stress, which appears to be fully resolved prior to viral infection, sets the stage for subsequent apoptosis awaits further investigation.

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