Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P42345 (mTOR)
 26,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of the antiangiogenic cytokine PEDF on key steps in retinal angiogenesis, specifically endothelial cell proliferation and vascular tubule formation, and the regulation of PEDF expression in retinal capillary endothelial cells were evaluated. HUVECs were co-cultured with fibroblasts to construct a model of angiogenesis using the Angiokit assay, and image analysis software was used to measure the effects of PEDF and VEGF on vascular tubule formation. Quantitative real-time PCR analysis was used to determine the expression of PEDF in microvascular endothelial cells exposed to glucose 20 mM, insulin 100 nM and VEGF 10 ng/ml. PEDF inhibited endothelial cell proliferation and significantly decreased the number of tubules (629+93 AU vs 311+31, p=0.001), number of branching points (145+19 AU vs 46+5, p=0.03) and total tubule length (4848+748 AU vs 11,172+2353, p=0.001). In bovine retinal capillary endothelial cells (BRCECs), PEDF mRNA and protein expression was suppressed by insulin (22%) in a rapamycin-sensitive manner; wortmannin had no effect. PEDF mRNA expression was also significantly reduced in the presence of high glucose (23%) and VEGF (25%). In conclusion, PEDF inhibits key steps in the angiogenic response of BRCECs, including endothelial cell proliferation and vascular tubule formation. Gene expression of PEDF is negatively regulated by glucose, insulin (via an mTOR-dependent pathway) and VEGF.
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PMID:Antiangiogenic effects and transcriptional regulation of pigment epithelium-derived factor in diabetic retinopathy. 2021 95

The past decade has witnessed a dramatic improvement in the therapeutic options in multiple myeloma (MM). Several novel biologically targeted agents are in clinical use and have resulted in improved outcomes. However, the disease remains incurable, underscoring the need for continued efforts towards understanding MM biology, better risk stratification and exploitation of novel therapeutic approaches. Novel agents that target tumor and stromal compartments can be categorized as those that target protein dynamics (e.g., heat shock protein 90 and the ubiquitin-proteasome system), intracellular signaling kinases (e.g., JAK/STAT, PI3k/Akt/mTOR and MAPK pathways), cell cycle molecular machinery (e.g., cyclin-dependent kinase inhibitor and Aurora kinase inhibitors), membrane-bound receptors (e.g., IGF-1, VEGF and CD40), epigenetic modulators (e.g., DNA methyltransferase and histone deacetylase), tumor vasculature and microenvironment (e.g., angiogenesis and integrins) and agents modulating anti-MM immune responses. This article focuses on a series of new therapeutic targets that have shown promising preclinical results and early evidence of anti-MM activity in clinical studies, either alone or in combination with other conventional or novel anti-MM treatments.
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PMID:Novel therapeutic targets for multiple myeloma. 2022 97

Diabetic nephropathy (DN) is characterized by a plethora of signaling abnormalities that together ultimately result in the clinical and pathologic hallmarks of DN, namely progressive albuminuria followed by a gradual decline in glomerular filtration rate leading to kidney failure, and accompanied by podocyte loss, progressive glomerular sclerosis and, ultimately, progressive tubulointerstitial fibrosis. Over the past few years, the general understanding of the abnormalities in signaling pathways that lead to DN has expanded considerably. In this review, some of the important pathways that appear to be involved in driving this process are discussed, with special emphasis on newer findings and insights. Newer concepts regarding signaling changes in bradykinin, mTOR, JAK/STAT, MCP-1, VEGF, endothelial nitric oxide synthase, activated protein C and other pathways are discussed.
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PMID:Abnormalities in signaling pathways in diabetic nephropathy. 2022 2

Hypoxia-inducible factor (HIF) plays an important role in renal tumourigenesis. In the majority of clear cell RCC (ccRCC), the most frequent and highly vascularized RCC subtype, HIF is constitutively activated by inactivation of the von Hippel-Lindau gene. Of the HIF subunits, HIF-2alpha appears to be more oncogenic than HIF-1alpha, in that HIF-2alpha activates pro-tumourigenic target genes. In addition, recent studies indicate that HIF-1alpha, more than HIF-2alpha, can undergo proteasomal degradation in VHL - /- RCC cells. A more detailed understanding of the molecular basis of hypoxia and angiogenesis in renal carcinogenesis has set the stage for the development of targeted therapies, inhibiting multiple HIF-related pathways, such as the phosphatidylinositol 3-kinase-AKT-mTOR, RAS/RAF/MAP, and VEGF signalling routes. However, despite the positive results of these targeting agents in progression-free survival, clinical resistance remains an issue. Recent pre-clinical studies have suggested new targeting approaches such as inhibition of HIF-driven key metabolic enzymes and have introduced new HIF targeting agents, such as histone deacetylase inhibitors, with successful anti-neoplastic effects. In this review, we discuss existing and novel findings about RCC carcinogenesis, with subsequent clinical implications.
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PMID:VHL and HIF signalling in renal cell carcinogenesis. 2022 41

Several studies have established a link between aberrant PI(3)K-Akt-mTOR- and Ras-Raf-MEK-Erk1/2 signaling and neuroendocrine tumor disease. In this study, we comparatively investigate the antitumor potential of novel small-molecule inhibitors targeting mTOR (RAD001), mTOR/PI(3)K (NVP-BEZ235) and Raf (Raf265) on human NET cell lines of heterogeneous origin. All inhibitors induced potent antitumor effects which involved the induction of apoptosis and G0/G1 arrest. However, the dual mTOR/PI(3)K inhibitor NVP-BEZ235 was more efficient compared to the single mTOR inhibitor RAD001. Consistently, NVP-BEZ235 prevented the negative feedback activation of Akt as observed after treatment with RAD001. Raf265 inhibited Erk1/2 phosphorylation but strongly induced Akt phosphorylation and VEGF secretion, suggesting the existence of a compensatory feedback loop on PI3K-Akt signaling. Finally, combined treatment with RAD001 or NVP-BEZ235 and Raf265 was more efficient than single treatment with either kinase inhibitor. Together, our data provide a rationale for dual targeting of PI(3)K-Akt-mTOR- and Ras-Raf-MEK-Erk1/2 signaling in NET disease.
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PMID:Compensatory activation of Akt in response to mTOR and Raf inhibitors - a rationale for dual-targeted therapy approaches in neuroendocrine tumor disease. 2035 70

Gastroenteropancreatic (GEP) endocrine tumors are hypervascular tumors able to synthesize and secrete high amounts of VEGF. We aimed to study the regulation of VEGF production in GEP endocrine tumors and to test whether some of the drugs currently used in their treatment, such as somatostatin analogues and mTOR inhibitors, may interfere with VEGF secretion. We therefore analyzed the effects of the somatostatin analogue octreotide, the mTOR inhibitor rapamycin, the PI3K inhibitor LY294002, the MEK1 inhibitor PD98059 and the p38 inhibitor SB203850 on VEGF secretion, assessed by ELISA and Western blotting, in three murine endocrine cell lines, STC-1, INS-r3 and INS-r9. Octreotide and rapamycin induced a significant decrease in VEGF production by all three cell lines; LY294002 significantly inhibited VEGF production by STC-1 and INS-r3 only. We detected no effect of PD98059 whereas SB203850 significantly inhibited VEGF secretion in INS-r3 and INS-r9 cells only. By Western blotting analysis, we observed decreased intracellular levels of VEGF and HIF-1alpha under octreotide, rapamycin and LY294002. For rapamycin and LY294002, this effect was likely mediated by the inhibition of the mTOR/HIF-1/VEGF pathway. In addition to its well-known anti-secretory effects, octreotide may also act through the inhibition of the PI3K/Akt pathway, as suggested by the decrease in Akt phosphorylation detected in all three cell lines. In conclusion, our study points out to the complex regulation of VEGF synthesis and secretion in neoplastic GEP endocrine cells and suggests that the inhibition of VEGF production by octreotide and rapamycin may contribute to their therapeutic effects.
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PMID:VEGF secretion by neuroendocrine tumor cells is inhibited by octreotide and by inhibitors of the PI3K/AKT/mTOR pathway. 2038 30

Advanced renal cell carcinoma is associated with a poor prognosis and is refractory to standard chemotherapy. Recent progress in the understanding of molecular biology and pathogenesis of renal cell cancer has been translated into the development of new therapeutic strategies. The management of metastatic RCC has been revolutionized with the development of targeted molecular therapies against VEGF-VEGFR and mTOR. Randomized phase III clinical trials demonstrated clinical benefit for patients with advanced RCC in overall survival and progression free survival. At the moment, six molecules have been approves in advanced RCC: cytokines (IL-2 and IFN), antiangiogenic therapies (sunitinib, sorafenib, bevacizumab) and mTOR inhibitors (Temsirolimus, everolimus). Nephrectomy is an important component of the multimodality treatment of mRCC. Prospective trials will be assessed the value of nephrectomy in patients treated by antiangiogenic therapies. Large randomized trial are ongoing to evaluate these new therapies in adjuvant setting.
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PMID:[Renal cell carcinoma management and therapies in 2010]. 2041 1

Advanced or metastatic renal carcinoma represents a frequent disease in oncologic practice. Few years ago, in immunotherapy era, treatments had quickly reached deadlock. New therapies targeting vascular endothelial growth factors and their receptors (VEGF-R), sorafenib, sunitinib and bevacizumab, and the mammalian target of rapamycin (mTOR), temsirolimus and everolimus, have modified these patients prognosis and their quality of life in a few years. Nevertheless, patients included in randomized trials presented severe inclusion criteria. Then in the daily practice, patients have distinctive characteristics which were not evaluated in large pivotal studies: poor performance status, older patients, renal dysfunction, cerebral metastases or non clear cell renal cancer. In published trials, a few data concerning these situations are reported, and these studies have often included small samples, were retrospective or not randomised. However compared to global population, tolerance have not been very different in geriatric patients, or patients with poor performance status, or with central neurological metastases, or with papillary and chromophobe sub-types. On the contrary progression free or overall survivals increases are more difficult to confirm. Also before starting treatment, ratio between potential benefit and possible toxicities have to be evaluated. In patients with renal insufficiency, VEGF receptor inhibitors seem to be cautiously initiated at reduced doses, and to be increased according to tolerance. Due to these poor proof levels, clinical trials are needed for these specific populations.
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PMID:[Advanced renal carcinomas with special situations. How to treat them?]. 2041 7

Treatment options for patients with metastatic renal cell carcinoma (RCC) have changed dramatically, and a new paradigm has evolved. IFN-alpha and IL-2 were previously mainstays of therapy, but since December 2005, six new agents have been approved in the USA for the treatment of advanced RCC. Three of these new agents are multitargeted kinase inhibitors, including sunitinib, sorafenib, and recently pazopanib, two target the mTOR (temsirolimus and everolimus), and one is a humanized monoclonal antibody (bevacizumab in combination with IFN-alpha) that targets VEGF. Sunitinib has emerged as the standard of care for treatment-naive RCC patients, with the recently approved bevacizumab and IFN-alpha combination providing an additional option for this population. The recent approval of pazopanib, based on the results from sequential Phase II and III clinical trials demonstrating improved overall response rates and progression-free survival, provides yet another option for front-line therapy. The current article examines the pazopanib preclinical and clinical data, provides an overview of the development of this tyrosine kinase inhibitor, and provides some speculation concerning its role in RCC therapy.
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PMID:Pazopanib: a multikinase inhibitor with activity in advanced renal cell carcinoma. 2046 94

VEGF receptor blockage has been reported to increase serum VEGF. We hypothesized that mTOR inhibition by everolimus counteracts VEGF induction by sunitinib resulting in an improved anti-tumor activity of sunitinib. In vitro, sunitinib in combination with everolimus did not outperform the respective monotherapies. In vivo, monotherapies reduced tumor growth by 60%, whereas the combination of sunitinib and everolimus led to an almost complete tumor growth inhibition. This superior anti-tumor activity coincided with attenuation of VEGF peaks. In conclusion mTOR inhibition by everolimus counteracts VEGF induction by sunitinib and results in significant reduction of tumor burden and long-lasting tumor growth control.
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PMID:mTOR inhibition by everolimus counteracts VEGF induction by sunitinib and improves anti-tumor activity against gastric cancer in vivo. 2047 Nov 60


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