Transcriptional Targeting in Cancer Gene Therapy

Cancer gene therapy has been one of the most exciting areas of therapeutic research in the past decade. In this review, we discuss strategies to restrict transcription of transgenes to tumour cells. A range of promoters which are tissue-specific, tumour-specific, or inducible by exogenous agents are presented. Transcriptional targeting should prevent normal tissue toxicities associated with other cancer treatments, such as radiation and chemotherapy. In addition, the specificity of these strategies should provide improved targeting of metastatic tumours following systemic gene delivery. Rapid progress in the ability to specifically control transgenes will allow systemic gene delivery for cancer therapy to become a real possibility in the near future

Strategies in Gene Therapy for Glioblastoma

Glioblastoma (GBM) is the most aggressive form of brain cancer, with a dismal prognosis and extremely low percentage of survivors. Novel therapies are in dire need to improve the clinical management of these tumors and extend patient survival. Genetic therapies for GBM have been postulated and attempted for the past twenty years, with variable degrees of success in pre-clinical models and clinical trials. Here we review the most common approaches to treat GBM by gene therapy, including strategies to deliver tumor-suppressor genes, suicide genes, immunomodulatory cytokines to improve immune response, and conditionally-replicating oncolytic viruses. The review focuses on the strategies used for gene delivery, including the most common and widely used vehicles (i.e., replicating and non-replicating viruses) as well as novel therapeutic approaches such as stem cell-mediated therapy and nanotechnologies used for gene delivery. We present an overview of these strategies, their targets, different advantages, and challenges for success. Finally, we discuss the potential of gene therapy-based strategies to effectively attack such a complex genetic target as GBM, alone or in combination with conventional therapy

Signal transduction and epigenetic mechanisms in the control of microglia activation during neuroinflammation

Activation of microglia is a common denominator and a pathophysiological hallmark of the central nervous system (CNS) disorders. Damage or CNS disorders can trigger inflammatory responses in resident microglia and initiate a systemic immune system response. Although a repertoire of inflammatory responses differs in those diseases, there is a spectrum of transcriptionally activated genes that encode various mediators such as growth factors, inflammatory cytokines, chemokines, matrix metalloproteinases, enzymes producing lipid mediators, toxic molocules, all of which contribute to neuroinflammation. The initiation, progression and termination of inflammation requires global activation of gene expression, postranscriptional regulation, epigenetic modifications, changes in chromatin structure and these processes are tightly regulated by specific signaling pathways. This review focuses on the function of "master regulators" and epigenetic mechanisms in microglia activation during neuroinflammation. We review studies showing impact of epigenetic enzyme inhibitors on microglia activation in vitro and in vivo, and critically discuss potential of such molecules to prevent/moderate pathological events mediated by microglia under brain pathologies.(1)

The regulation of the JNK cascade and programmed cell death by NF-κB: mechanisms and functions

The nuclear factor κB (NF-κB) family is an evolutionarily conserved family of transcription factors that play a central role in immune and inflammatory responses. They also play a pivotal role in cell survival, whereby activation of NF-κB antagonizes programmed cell death induced by tumor necrosis factor receptors and other cell death signals. The prosurvival function of NF-κB has been implicated in a wide range of biological processes, including the development and homeostasis of the immune system and liver. It has also been implicated in the pathogenesis of numerous diseases, including cancer, chronic inflammation, and certain hereditary disorders. The protective activity of NF-κB can also hamper tumor cell killing inflicted by radiation or chemotherapeutic drugs, thereby promoting resistance to cancer treatments. This prosurvival activity of NF-κB involves the suppression of sustained c-Jun N-terminal kinase (JNK) activation and of the accumulation of cytotoxic reactive oxygen species. NF-κB mediates this function by inducing the transcription of target genes, whose products inhibit the JNK signaling pathway and suppress accumulation of reactive oxygen species through their antioxidant functions. The development of specific inhibitors that target the critical downstream NF-κB-regulated genes that promote survival in cancer and other diseases potentially holds a key to developing specific and effective therapeutic strategies to combat these disorders

The intersection between DNA damage response and cell death pathways

Apoptosis is a finely regulated process that serves to determine the fate of cells in response to various stresses. One such stress is DNA damage, which not only can signal repair processes but is also intimately involved in regulating cell fate. In this review we examine the relationship between the DNA damage/repair response in cell survival and apoptosis following insults to the DNA. Elucidating these pathways and the crosstalk between them is of great importance, as they eventually contribute to the etiology of human disease such as cancer and may play key roles in determining therapeutic response. This article is part of a Special Issue entitled “Apoptosis: Four Decades Later”

Uncovering Dual Roles for PERK Signaling During Experimentally Induced Pancreatitis

Pancreatitis is characterized by inappropriate activation of digestive enzyme precursors, or zymogens, local and systemic inflammation, dysregulation of cellular calcium (Ca2+), and induction of the unfolded protein response (UPR). The UPR consists of three distinct pathways all of which are activated during pancreatitis. However, the molecular roles of each remain unclear. The protein kinase RNA (PKR)-like ER kinase (PERK) pathway reduces general protein translation by phosphorylating eIF2!, and is activated within minutes of initiating pancreatic damage. Microarray analysis carried out by our lab revealed robust upregulation of the PERK pathways members Activating Transcription Factor (ATF) 3 and stanniocalcin (STC) 2. The roles of ATF3 and STC2 within the context of PERK signaling and pancreatitis are not well known. Thus, the goal of this study was to define the roles of STC2 and ATF3 during pancreatitis. Gene expression analysis revealed significant increases in STC2 during cerulein induced pancreatitis (CIP) and mice overexpressing STC2 (STC2Tg) exhibited decreased pancreatitis severity as evidenced by the maintenance of acinar cell differentiation markers, lower levels of serum amylase compared to wild type (WT) and a decreased necrosis to apoptosis ratio. Conversely, ATF3 appears to function in an opposite fashion to STC2 during pancreatitis. Chromatin immunoprecipitation (ChIP) of pancreatic tissue following CIP showed that ATF3 bound the Mist1 promoter, recruited Histone Deacteylasee (HDAC) 5 and repressed Mist1 expression, leading to loss of the acinar cell phenotype. Human and mouse pancreatitis tissue samples reveal mutually exclusive expression of ATF3 and MIST1, illustrating clinical relevance for ATF3. Mice lacking Atf3 (Atf3-/-) exhibited a similar phenotype to STC2Tg mice, with increased maintenance of cellular junctions and cell polarity. These findings suggest that these mediators of the PERK pathway lead to opposing outcomes, and that this pathway plays a dual role of both protection and injury during pancreatitis