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)

Kaposi's sarcoma (KS) is a spindle-shaped vascular cell tumor that occurs in the skin, lymphoid, respiratory and gastrointestinal tissues. It may resemble aggressive malignant neoplasm in HIV-related or in post-transplant types but classic form may behave as benign, potentially controllable and reversible hyperplasia. KS lesions from the onset are dispersed and multicentric. KS probability increases in solid organ transplant recipients (approximately 3/1000 patients). KS occurrence is associated with: type and dose of immunosuppression, chronic stimulation by foreign allograft antigens, viral infections (Herpes virus 8), anti rejection and induction therapy, etc. 90% of KS cases appear as dark blue or purplish macular lesions that may form nodular tumors. Histological picture shows networks of spindle shaped cells and vascular spaces surrounded by an endothelial cell layer. There is no uniform schema of KS treatment in renal transplant recipients. Immunosuppression must be reduced to the lowest levels which preserve allograft function. CsA should be converted to mofetil mycophenolate or mTOR-inhibitors. After conversion to MMF regression of KS was observed, although low therapeutic MMF doses seem to be appropriate. Sirolimus seems to inhibit the growth of established vascularized tumors and this effect is best realized with relatively low immunosuppressive doses of drug.
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PMID:Kaposi's sarcoma in renal transplant recipients. 1621 35

Sirolimus (SRL) is a mammalian target of rapamycin inhibitor that, in contrast to cyclosporine (CsA), has been shown to inhibit rather than promote cancers in experimental models. At 3 mo +/- 2 wk after renal transplantation, 430 of 525 enrolled patients were randomly assigned to remain on SRL-CsA-steroids (ST) or to have CsA withdrawn and SRL troughs increased two-fold (SRL-ST). Median times to first skin and nonskin malignancies were compared between treatments using a survival analysis. Mean annualized rates of skin malignancy were calculated, and the relative risk was determined using a Poisson model. Malignancy-free survival rates for nonskin malignancies were compared using Kaplan-Meier estimates and the log-rank test. At 5 yr, the median time to a first skin carcinoma was delayed (491 versus 1126 d; log-rank test, P = 0.007), and the risk for an event was significantly lower with SRL-ST therapy (relative risk SRL-ST to SRL-CsA-ST 0.346; 95% confidence interval 0.227 to 0.526; P < 0.001, intention-to-treat analysis). The relative risks for both basal and squamous cell carcinomas were significantly reduced. Kaplan-Meier estimates of nonskin cancer were 9.6 versus 4.0% (SRL-CsA-ST versus SRL-ST; P = 0.032, intention-to-treat analysis). Nonskin cancers included those of the lung, larynx, oropharynx, kidney, gastrointestinal tract, prostate, breast, thyroid, and cervix as well as glioma, liposarcoma, astrocytoma, leukemia, lymphoma, and Kaposi's sarcoma. Patients who received SRL-based, calcineurin inhibitor-free therapy after CsA withdrawal at month 3 had a reduced incidence of both skin and nonskin malignancies at 5 yr after renal transplantation compared with those who received SRL therapy combined with CsA. Longer follow-up and additional trials are needed to confirm these promising results.
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PMID:Sirolimus therapy after early cyclosporine withdrawal reduces the risk for cancer in adult renal transplantation. 1643 6

Kaposi's sarcoma-associated herpesvirus (KSHV) is linked to three different human cancers: Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. The Kaposi's sarcoma lesion expresses high levels of angiogenic factors and is comprised of a mixed cell population, including endothelial cells that are infected with KSHV. We find that the KSHV K1 protein is expressed in Kaposi's sarcoma lesions and can immortalize and extend the life span of primary human umbilical vein endothelial cells in culture. Vascular endothelial growth factor (VEGF) is critical for the survival of endothelial cells, and we show that expression of K1 in endothelial cells resulted in increased levels of secreted VEGF and the activation of key signaling pathways, including the VEGF/VEGF receptor and the phosphatidylinositol-3'-OH-kinase (PI3K) pathway. The SH2 binding motifs present in the cytoplasmic tail of K1 were critical for K1's ability to activate these pathways. Activation of PI3K by K1 results in activation of Akt kinase and mammalian target of rapamycin and inactivation of the proapoptotic proteins FKHR, glycogen synthase kinase-3, and Bad, which are events indicative of cell survival. Because activation of the PI3K pathway is critical for transformation of many human cells, we suggest that PI3K activation by K1 is involved in endothelial cell immortalization and contributes to KSHV-associated tumorigenesis. We also report that K1 enhances angiogenesis in vivo and increases tumor vasculature and tumor size.
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PMID:Immortalization of primary endothelial cells by the K1 protein of Kaposi's sarcoma-associated herpesvirus. 1658 91

The Kaposi's sarcoma-associated herpesvirus (KSHV), the infectious causative agent of Kaposi's sarcoma (KS), encodes a G protein-coupled receptor (vGPCR) implicated in the initiation of KS. Here we demonstrate that Kaposi's sarcomagenesis involves stimulation of tuberin (TSC2) phosphorylation by vGPCR, promoting the activation of mTOR through both direct and paracrine mechanisms. Pharmacologic inhibition of mTOR with rapamycin prevented vGPCR sarcomagenesis, while overactivation of this pathway was sufficient to render endothelial cells oncogenic. Moreover, mice haploinsufficient for TSC2 are predisposed to vascular sarcomas remarkably similar to KS. Collectively, these results implicate mTOR in KS initiation and suggest that the sarcomagenic potential of KSHV may be a direct consequence of the profound sensitivity of endothelial cells to vGPCR dysregulation of the TSC2/mTOR pathway.
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PMID:The TSC2/mTOR pathway drives endothelial cell transformation induced by the Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor. 1690 12

The antitumor potency of the mTOR inhibitor rapamycin (sirolimus) is the subject of intense investigations. Primary effusion lymphoma (PEL) appears as an AIDS-defining lymphoma and like Kaposi sarcoma has been linked to Kaposi sarcoma-associated herpesvirus (KSHV). We find that (1) rapamycin is efficacious against PEL in culture and in a murine xenograft model; (2) mTOR, its activator Akt, and its target p70S6 kinase are phosphorylated in PEL; (3) rapamycin inhibits mTOR signaling as determined by S6 phosphorylation; (4) KSHV transcription is unaffected; (5) inhibition of IL-10 signaling correlates with drug sensitivity; and (6) addition of exogenous IL-10 or IL-6 can reverse the rapamycin growth arrest. This validates sirolimus as a new treatment option for PEL.
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PMID:Rapamycin is efficacious against primary effusion lymphoma (PEL) cell lines in vivo by inhibiting autocrine signaling. 1708 22

Kaposi sarcoma is the most common cancer among HIV-infected individuals and one of the most common cancers in sub-Saharan Africa. Kaposi sarcoma lesions are highly vascularized, and comprised of spindle-shaped tumor cells. Kaposi sarcoma herpesvirus is etiologically linked to Kaposi sarcoma development and encodes genes that contribute to cellular transformation, evasion of apoptosis, aberrant angiogenesis and an inflammatory tumor microenvironment. The study of Kaposi sarcoma herpesvirus-driven malignancies has provided a model of oncogenesis and identified some of the key steps and, therefore, therapeutic targets of Kaposi sarcoma development. However, current Kaposi sarcoma treatments are not specific and rely on reconstitution of the immune system and systemic administration of cytotoxic agents. Recent studies have demonstrated that mechanism-based therapeutics, such as vascular endothelial growth factor A or mammalian target of rapamycin inhibitors, are promising therapeutic approaches bridging basic research with clinical practice.
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PMID:Kaposi sarcoma as a model of oncogenesis and cancer treatment. 1728 30

Kaposi's sarcoma (KS) is an enigmatic vascular neoplasm that has reached epidemic proportions in parts of the developing world and is a leading cause of morbidity and mortality among the AIDS population. Unfortunately, KS is still difficult to manage therapeutically, especially in its most advanced clinical manifestations. The recent identification of the KS-associated herpesvirus (KSHV or HHV8) as its viral etiologic agent has prompted renewed interest in the molecular pathogenesis of this disease. Emerging evidence now points to a single KSHV gene, vGPCR, as essential for KS development, providing a unique opportunity to expose new targets for the treatment of this tumor. In this regard, recent work has identified the Akt/TSC/mTOR signaling cascade as a critical pathway in vGPCR sarcomagenesis. Indeed, pharmacological inhibition of mTOR with rapamycin has shown promising results in preventing vGPCR tumorigenesis in an animal model for KS. These observations are further validated by coincident reports demonstrating the efficacy of rapamycin (sirolimus) as an immunossuppresive and anti-tumoral solution for posttransplant KS patients. Collectively, these data suggest that inhibition of the Akt/TSC/mTOR signaling pathway may provide a novel molecular-based approach for the treatment of patients who currently have a paucity of therapeutic options.
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PMID:Akt/TSC/mTOR activation by the KSHV G protein-coupled receptor: emerging insights into the molecular oncogenesis and treatment of Kaposi's sarcoma. 1732 74

Increasing success in renal transplantation and longer patient survival has meant that post-transplant malignancies are having an increasing impact on long-term graft and patient survival. Choice of the immunosuppressive agents provides one of the controllable risk factors for the development of malignancies in this population. Calcineurin inhibitors (CNIs) are associated with an increased incidence of cancers, whereas the proliferation signal inhibitors (PSIs), everolimus and sirolimus have demonstrated anti-oncogenic effects in pre-clinical models and are currently being investigated as anti-cancer agents in clinical trials. There is increasing evidence demonstrating a lower incidence of post-transplant malignancies in renal transplant recipients receiving PSI-based immunosuppression compared with those receiving CNIs. Conversion from CNIs to PSIs has been shown to lead to the regression of Kaposi's sarcoma in renal transplant recipients and is now part of accepted standard care for this tumour in this setting. The anti-cancer properties of PSI-based regimens have the potential to combine the dual benefits of immunosuppression without the use of CNIs and the direct anti-oncogenic effects through their inhibition of the mammalian target of rapamycin (mTOR) signalling pathway. In the absence of formal clinical trial evidence on the best way to use PSIs in this setting, a workshop was held to provide practical guidance on immunosuppressive strategies in the context of malignancy, given the current state of knowledge.
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PMID:Use of proliferation signal inhibitors in the management of post-transplant malignancies--clinical guidance. 1745 17

Post-transplant malignancy is recognised as being a major limitation to the success of solid organ transplantation and it is currently considered one of the unavoidable costs of long-term immunosuppressive therapy. However, the continual introduction of new immunosuppressive drugs and the growing knowledge about their different oncogenic profiles, requires a continuous evaluation of the available evidence on this topic. The incidence and risk of malignancy is elevated in solid organ transplant recipients compared with the general population. As proof of the relationship between immunosuppressive therapy and post-transplant malignancy, epidemiological data reveal that the length of exposure to immunosuppressive therapy and the intensity of therapy are clearly related to the post-transplant risk of malignancy, and that once cancer has developed, more intense immunosuppression can translate into more aggressive tumour progression in terms of accelerated growth and metastasis and lower patient survival. The association between malignancy and immunosuppressive therapy is mediated through several pathogenic factors. Indirectly, immunosuppressive drugs greatly increase the post-transplant risk of malignancy by impairing cancer surveillance and facilitating the action of oncogenic viruses. However, the direct pro- and anti-oncogenic actions of immunosuppressants also play an important role. The cancer-promoting effect of calcineurin inhibitors, independently of depressed immunosurveillance, has been demonstrated in recent years, and currently only mammalian target of rapamycin (mTOR) inhibitors have shown simultaneous immunosuppressive and antitumour properties. Reports of the initial results of the reduced incidence of cancer in organ transplant recipients receiving mTOR inhibitor therapy strongly indicate separate pathways for pharmacological immunosuppression and oncogenesis. The role of mTOR inhibitors has been firmly established for the treatment of post-transplant Kaposi's sarcoma and its role in the management of patients with other post-transplant malignancies should be clarified as soon as possible. Prevention of morbidity and mortality resulting from post-transplant malignancy should become a main endpoint in solid organ transplant programmes, and the choice and management of immunosuppressive therapy in each phase of transplantation plays a central role in this objective. Although comprehensive and rigorous information about the management of immunosuppressive therapy in transplant recipients at risk of or affected by cancer is still lacking, new experimental and clinical data about mTOR inhibitors offers novel approaches to this problem.
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PMID:Immunosuppressive therapy and malignancy in organ transplant recipients: a systematic review. 1752 Dec 18

Discovered in fungi in the remote Easter Island, sirolimus (rapamycin) shows potential beyond its obvious antiproliferative and immunosuppressant activity. Studies have demonstrated that sirolimus acts as a vascular endothelial growth factor inhibitor, providing prospective therapeutic benefits and possible prevention of tuberous sclerosis and Kaposi's sarcoma. Its ability to decrease keratinocyte proliferation may help patients with psoriasis. In those with tuberous sclerosis complex, it may prevent the development of hamartomas and reduce or eliminate them once grown by blocking the mammalian target of rapamycin, a critical regulatory kinase. A great advantage for this drug is in the decreased risk of malignancies, including Kaposi's sarcoma, associated with its use compared with other immunosuppressants, namely calcineurin inhibitors. This review will focus on the pharmacology and potential uses of sirolimus.
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PMID:Sirolimus (rapamycin): from the soil of Easter Island to a bright future. 1758 72


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