The change of immunosuppressive regimen from calcineurin inhibitors to mammalian target of rapamycin (mTOR) inhibitors and its effect on malignancy following heart transplantation

Mammalian target of rapamycin (mTOR) inhibitors have been shown to reduce proliferation of lymphoid cells; thus, their use for immunosuppression after heart transplantation (HT) may reduce post-transplant lymphoproliferative disorder (PTLD) risk. This study sought to investigate whether the sirolimus (SRL)-based immunosuppression regimen is associated with a decreased risk of PTLD compared with the calcineurin inhibitor (CNI)-based regimen in HT recipients. We retrospectively analyzed 590 patients who received HTs at two large institutions between 1 June 1988 and 31 December 2014. Cox proportional-hazard modeling was used to examine the association between type of primary immunosuppression and PTLD after adjustment for potential confounders, including Epstein–Barr virus (EBV) status, type of induction therapy, and rejection. Conversion from CNI to SRL as primary immunosuppression occurred in 249 patients (42.2%). During a median follow-up of 6.3 years, 30 patients developed PTLD (5.1%). In a univariate analysis, EBV mismatch was strongly associated with increased risk of PTLD (HR 10.0, 95% CI: 3.8–26.6; p < 0.001), and conversion to SRL was found to be protective against development of PTLD (HR 0.19, 95% CI: 0.04–0.80; p = 0.02). In a multivariable model and after adjusting for EBV mismatch, conversion to SRL remained protective against risk of PTLD compared with continued CNI use (HR 0.12, 95% CI: 0.03–0.55; p = 0.006). In conclusion, SRL-based immunosuppression is associated with lower incidence of PTLD after HT. These findings provide evidence of a benefit from conversion to SRL as maintenance therapy for mitigating the risk of PTLD, particularly among patients at high PTLD risk.

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Src kinase activity coordinates cell adhesion and spreading with activation of mammalian target of rapamycin in pancreatic endocrine tumour cells

Endocrine Related Cancer ◽

10.1530/erc-10-0153 ◽

2011 ◽

Vol 18 (5) ◽

pp. 541-554 ◽

Cited By ~ 23

Author(s):

Alessia Di Florio ◽

Laura Adesso ◽

Simona Pedrotti ◽

Gabriele Capurso ◽

Emanuela Pilozzi ◽

...

Keyword(s):

Cell Cycle ◽

Cell Adhesion ◽

Microarray Analysis ◽

Mammalian Target Of Rapamycin ◽

Mtor Inhibitors ◽

Target Of Rapamycin ◽

Cell Cycle Regulators ◽

Inhibition Of Proliferation ◽

Pancreatic Endocrine Tumours ◽

Independent Marker

Pancreatic endocrine tumours (PETs) are rare and heterogeneous neoplasms, often diagnosed at metastatic stage, for which no cure is currently available. Recently, activation of two pathways that support proliferation and invasiveness of cancer cells, the Src family kinase (SFK) and mammalian target of rapamycin (mTOR) pathways, was demonstrated in PETs. Since both pathways represent suitable targets for therapeutic intervention, we investigated their possible interaction in PETs. Western blot and immunofluorescence analyses indicated that SFK and mTOR activity correlate in PET cell lines. We also found that SFKs coordinate cell adhesion and spreading with activation of the mTOR pathway in PET cells. Live cell metabolic labelling and biochemical studies demonstrated that SFK activity enhance mTOR-dependent translation initiation. Furthermore, microarray analysis of the mRNAs associated with polyribosomes revealed that SFKs regulate mTOR-dependent translation of specific transcripts, with an enrichment in mRNAs encoding cell cycle proteins. Importantly, a synergic inhibition of proliferation was observed in PET cells concomitantly treated with SFK and mTOR inhibitors, without activation of the phosphatidylinositol 3-kinase/AKT pro-survival pathway. Tissue microarray analysis revealed activation of Src and mTOR in some PET samples, and identified phosphorylation of 4E-BP1 as an independent marker of poor prognosis in PETs. Thus, our work highlights a novel link between the SFK and mTOR pathways, which regulate the translation of mRNAs for cell cycle regulators, and suggest that crosstalk between these pathways promotes PET cell proliferation.

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Combinations of Cytotoxic Drugs, Ionizing Radiation, and Mammalian Target of Rapamycin (mTOR) Inhibitors

Multimodal Concepts for Integration of Cytotoxic Drugs - Medical Radiology ◽

10.1007/3-540-35662-2_9 ◽

2006 ◽

pp. 127-137

Author(s):

Jann N. Sarkaria

Keyword(s):

Ionizing Radiation ◽

Mammalian Target Of Rapamycin ◽

Mtor Inhibitors ◽

Cytotoxic Drugs ◽

Target Of Rapamycin

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Advances in the therapeutic use of mammalian target of rapamycin (mTOR) inhibitors in dermatology

Journal of the American Academy of Dermatology ◽

10.1016/j.jaad.2015.01.014 ◽

2015 ◽

Vol 72 (5) ◽

pp. 879-889 ◽

Cited By ~ 26

Author(s):

Alexander L. Fogel ◽

Sharleen Hill ◽

Joyce M.C. Teng

Keyword(s):

Mammalian Target Of Rapamycin ◽

Mtor Inhibitors ◽

Therapeutic Use ◽

Target Of Rapamycin

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The Role of mTOR Inhibitors in Liver Transplantation: Reviewing the Evidence

Journal of Transplantation ◽

10.1155/2014/845438 ◽

2014 ◽

Vol 2014 ◽

pp. 1-45 ◽

Cited By ~ 40

Author(s):

Goran B. Klintmalm ◽

Björn Nashan

Keyword(s):

Metabolic Syndrome ◽

Liver Transplantation ◽

Renal Function ◽

De Novo ◽

Immunosuppressive Agents ◽

Mammalian Target Of Rapamycin ◽

Calcineurin Inhibitors ◽

Mtor Inhibitors

Despite the success of liver transplantation, long-term complications remain, includingde novomalignancies, metabolic syndrome, and the recurrence of hepatitis C virus (HCV) and hepatocellular carcinoma (HCC). The current mainstay of treatment, calcineurin inhibitors (CNIs), can also worsen posttransplant renal dysfunction, neurotoxicity, and diabetes. Clearly there is a need for better immunosuppressive agents that maintain similar rates of efficacy and renal function whilst minimizing adverse effects. The mammalian target of rapamycin (mTOR) inhibitors with a mechanism of action that is different from other immunosuppressive agents has the potential to address some of these issues. In this review we surveyed the literature for reports of the use of mTOR inhibitors in adult liver transplantation with respect to renal function, efficacy, safety, neurological symptoms,de novotumors, and the recurrence of HCC and HCV. The results of our review indicate that mTOR inhibitors are associated with efficacy comparable to CNIs while having benefits on renal function in liver transplantation. We also consider newer dosing schedules that may limit side effects. Finally, we discuss evidence that mTOR inhibitors may have benefits in the oncology setting and in relation to HCV-related allograft fibrosis, metabolic syndrome, and neurotoxicity.

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Conversion of Calcineurin Inhibitors With Mammalian Target of Rapamycin Inhibitors After Kidney Transplant

Experimental and Clinical Transplantation ◽

10.6002/ect.2012.0118 ◽

2012 ◽

Vol 11 (1) ◽

pp. 12-16

Author(s):

Hassan Nikoueinejad ◽

◽

Alireza Soleimani ◽

Abbas Mirshafiey ◽

Aliakbar Amirzargar ◽

...

Keyword(s):

Kidney Transplant ◽

Mammalian Target Of Rapamycin ◽

Calcineurin Inhibitors ◽

Target Of Rapamycin

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Incidence and risk of treatment-related mortality in patients with renal cell cancer (RCC) and non-RCC treated with mammalian target of rapamycin (mTOR) inhibitors.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.6_suppl.347 ◽

2013 ◽

Vol 31 (6_suppl) ◽

pp. 347-347

Author(s):

Toni K. Choueiri ◽

Youjin Je ◽

Guru Sonpavde ◽

Matt D. Galsky ◽

Marina Kaymakcalan ◽

...

Keyword(s):

Adverse Events ◽

Renal Cell ◽

Fixed Effects ◽

Meta Analysis ◽

Cell Cancer ◽

Mammalian Target Of Rapamycin ◽

Mtor Inhibitors ◽

Target Of Rapamycin ◽

Therapeutic Modality ◽

Increased Risk

347 Background: Inhibition of the mammalian target of rapamycin (mTOR) is an established therapeutic modality for multiple malignancies including renal cell carcinoma (RCC). Agents that target mTOR have been sporadically associated with an increased risk of potentially life-threatening adverse events. We performed an up-to-date meta-analysis to determine the risk of fatal adverse events (FAEs) in cancer patients treated with mTOR inhibitors, including RCC. Methods: MEDLINE/PubMed, conferences and clinicaltrials.gov databases were searched for articles reported from January 1966 to June 2012. Eligible studies were limited to trials of US Food and Drug Administration—approved mTOR inhibitors (everolimus and temsirolimus) that reported on patients with cancer, randomized design, and adequate safety profiles. Data extraction was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Statistical analyses were conducted to calculate the summary incidence, relative risk (RR), and 95% Confidence Intervals (CIs) by using random-effects or fixed-effects models on the basis of the heterogeneity of included studies. Results: In all 2,990 patients from 8 randomized controlled trials (RCTs) were included, 2033 from everolimus trials and 957 from temsirolimus trials. The incidence of FAEs related to mTOR inhibitors use was 3.4% (95% CI, 1.9-6.0) with a RR of 2.33 (95% CI, 1.32 to 4.10; P = .003) compared to control patients. On subgroup analysis, no difference in the rate of FAEs was found between everolimus and temsirolimus or between tumor types (RCC vs. non-RCC). No evidence of publication bias was observed. Conclusions: The use of mTOR inhibitors is associated with an increased risk of FAEs in RCC and non-RCC patients, compared with control patients.

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