Expert opinion on therapeutic targets
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Expert Opin. Ther. Targets · Jun 2009
ReviewTargeting ASK1 in ER stress-related neurodegenerative diseases.
The accumulation of malfolded proteins in the endoplasmic reticulum (ER) induces ER stress, leading to the disturbance of ER function. To restore ER function and ER homeostasis, cells possess a highly specific ER quality control system termed the unfolded protein response (UPR), which increases the capacity of protein folding and reduces the amount of malfolded proteins. In case of prolonged ER stress or malfunction of the UPR, apoptosis signaling is activated. ⋯ Apoptosis signal-regulating kinase 1 (ASK1), a member of the MAPK kinase kinase (MAP3K) family, is activated by ER stress and mediates apoptosis. Recent studies have shown that the ASK1 pathway is involved in ER stress-induced neuronal cell death and contributes to the pathogenesis of neurodegenerative diseases. In this review, we summarize the molecular mechanisms of the UPR and ER stress-induced apoptosis and the possible roles of ASK1 activation in neurodegenerative diseases.
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Expert Opin. Ther. Targets · Apr 2009
ReviewAnti-VEGF therapies for malignant glioma: treatment effects and escape mechanisms.
Glioblastoma multiforme (GBM) has a very poor prognosis and novel treatment strategies are urgently needed. GBM appears to be an optimal target for anti-angiogenic therapy as the tumour shows a high degree of endothelial cell proliferation and pro-angiogenic growth factor expression. ⋯ Anti-angiogenic therapy has fulfilled the proof of concept in glioma animal models. In glioma patients, the efficacy of anti-angiogenic mono-therapies initially has been disappointing. However recent clinical trials combining bevacizumab, an anti-VEGF antibody, with chemotherapy reported very encouraging response rates. Although randomized phase III clinical trials with anti-angiogenic molecules are not yet available for GBM patients, this treatment regimen is already applied off protocol in several clinical centers. It should be kept in mind though that tumours can develop escape mechanisms. In particular invasive cells, which migrate away from the highly vascularized tumour core, are not targeted by anti-angiogenic therapies. In our opinion, the future of anti-angiogenic therapy will rely on a combination strategy including chemotherapy and drugs that target invasive glioma cells.
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Expert Opin. Ther. Targets · Jan 2009
ReviewThe angiopoietin-Tie2 system as a therapeutic target in sepsis and acute lung injury.
Sepsis and acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) are life-threatening syndromes characterised by inflammation and increased vascular permeability. Amongst other factors, the angiopoietin-tyrosine kinase with immunoglobulin-like and EGF-like domains 2 (Tie2) system is involved. ⋯ The angiopoietin-Tie2 system controls the responsiveness of the endothelium to inflammatory, hyperpermeability, apoptosis and vasoreactive stimuli. Angiopoietin-2 provokes inflammation and vascular hyperpermeability, while angiopoietin-1 has a protective effect. Targeted angiopoietin-2 inhibition with RNA aptamers or blocking antibodies is a potential anti-inflammatory and anti-vascular hyperpermeability strategy in the treatment of sepsis and ALI/ARDS.
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Expert Opin. Ther. Targets · Jan 2009
ReviewTRP channels as emerging targets for pain therapeutics.
The transient receptor potential (TRP) superfamily of ion channels are a large and diverse group that have received increased attention in recent years. The sub-family of thermo-TRPs which are regulated by temperature, among other physical and chemical stimuli, are of particular interest for the development of potential pain therapeutics. ⋯ Vanilloid-type TRP 1 (TRPV1) is the most well studied and advanced member of the family, with selective agonists and antagonists already in clinical use or development, respectively. Among other thermo-TRPs (including TRPV2 - 4, Ankyrin type TRP 1 (TRPA1) and melastatin type TRP 8 (TRPM8)), TRPA1 and TRPM8 are emerging as promising novel pain targets.
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Present treatment of medulloblastoma, the most common malignant brain tumor in children, includes surgery, radiotherapy and chemotherapy. In spite of radical treatment, only about 70% of patients survive. Also side effects of the treatment are severe, mostly due to applied radiotherapy. ⋯ The quest for a better treatment modalities includes better risk stratification methods, including molecular profiling of individual tumors and a search for new small molecules capable of inhibiting hyperactive signaling pathways. Several candidates for such agents are being tested presently.