The rationale for mTOR inhibition in epithelial ovarian cancer

The AKT/mTOR signaling pathway is frequently overexpressed in human epithelial ovarian cancer and an attractive target for therapy. In vivo mouse models were confirmative for in vitro findings, where the administration of mTOR inhibitors in ovarian cancer xenografts showed antitumoral as well as antiangiogenic effects. Phase I – II trials are now ongoing with mTOR inhibitors in ovarian cancer patients, some in combination with conventional cytotoxic agents. If further development of mTOR inhibition in ovarian cancer is pursued, studying combinations of mTOR inhibitors with other new targeted therapies would be of interest. mTOR inhibitors in the adjuvant setting could have potential, since, for the moment, there is no standard maintenance therapy in ovarian cancer. A crucial challenge will be to identify strong predictive biomarkers. This review highlights the rationale for the use of mTOR inhibitors in ovarian cancer and summarizes the available preclinical findings.     

Results of 4-Year Analysis of Conversion from Calcineurin Inhibitors to mTOR Inhibitors in Renal Transplant Patients: Single-Center Experience

Abstract

In this retrospective study, 83 patients were accepted. Mammalian target of rapamycin (mTOR) group consisting of 37 patients were converted from calcineurin inhibitors (CNI), and the control group included 46 patients (initially CNI-receiving patients). As a control-match of each mTOR inhibitor patient, the succeeding patient with transplantation who continued CNI therapy was chosen. All patients received CNI, MMF, and prednisolone as an immunosuppressive therapy initially. In comparison of two groups, there was no significant difference between sex, donor organ source, donor organ ischemia time, or mismatches. However, mean age between groups was significantly different (mTOR group: 48.3 ± 12, CNI group: 38.6 ± 11, p < 0.001). Decision of conversion to mTOR inhibitors in 30 patients was made by biopsy. The reasons for conversion were determined as CNI nephrotoxicity in 15 patients, chronic allograft nephropathy in 15 patients, malignancy in 6 patients, and renal artery stenosis in 1 patient. Basal glomerular filtration rates (GFRs) were markedly lower in mTOR group than in CNI group (38.8 mL/min vs. 72.7 mL/min). At the end of 48-month follow-ups, GFR increased from 38 mL/min to 54 mL/min in mTOR group; however, it decreased to 53 mL/min from 72 mL/min in CNI group. There was no difference left between the two groups in GFR after 4-year follow-up. Hyperlipidemia was higher in mTOR group. Acute rejection rates were similar. Cytomegalovirus (CMV) disease was more prevalent in CNI group. Graft failure developed due to secondary reasons, causing mortality in both groups. We suggest that conversion to mTOR inhibitors maintains and improves graft functions well.     

Translation initiation: a critical signalling node in cancer

Mammalian target of rapamycin (mTOR) is a master regulator of translation initiation that controls the recruitment of ribosomes to mRNA templates in response to intracellular and extracellular cues. Evidence suggests that mTOR and its direct downstream targets, S6K and eIF4E/4E-BP, play significant roles in oncogenesis, and that inhibiting this pathway holds promise as an anti-proliferative approach. Recent genome-wide analyses of mutations in human cancers indicate that transformed cells activate a handful of processes and signalling pathways that are major contributors to their phenotype. Here we review the current literature implicating mTOR and translation initiation downstream of many of these various signalling pathways and processes usurped in human cancers. This review highlights the widespread activation of mTOR/eIF4E following acquisition of oncogenic lesions and its implication in promoting the transformation phenotype and indicates that targeting the control of translation initiation makes logical sense as a broad-acting therapeutic approach.     

The effects of bolus supplementation of branched-chain amino acids on skeletal muscle mass,strength, and function in patients with rheumatic disorders during glucocorticoid treatment

Objectives: To test the effects of bolus supplementation of branched-chain amino acids (BCAA) on skeletal muscle mass, strength, and function in patients with rheumatic disorders taking glucocorticoid (GC).

Methods: Patients with rheumatic disorders treated with prednisolone (≥10?mg/day) were randomized to ingest additional daily 12?g of BCAA (n?=?9) or not (n?=?9) for 12 weeks. At baseline, and 4, 8, and 12 weeks, they underwent bioelectrical impedance analysis, muscle strength and functional tests, and computed tomography analysis for cross-sectional area of mid-thigh muscle.

Results: Disease activities of the patients were well controlled and daily GC dose was similarly reduced in both groups. Limb muscle mass was recovered in both groups. Whole-body muscle mass and muscle strength and functional mobility were increased only in BCAA (+) group. The effects of BCAA supplementation on recovering skeletal muscle mass were prominent in particular muscles including biceps femoris muscle.

Conclusions: This trial is the first-in-man clinical trial to demonstrate that BCAA supplementation might be safe and, at least in part, improve skeletal muscle mass, strength, and function in patients with rheumatic disorders treated with GC.     

Optimal treatment of poor-risk renal cell carcinoma patients with mTOR inhibitors and anti-VEGFR agents

Poor-risk metastatic renal cell carcinoma (RCC) includes a subgroup of patients with unfavorable prognosis, according to both the Motzer and Heng criteria. Overall, owing to the poor prognosis of these patients, the approach is still a challenge for the first and subsequent lines of treatment, particularly for rare histologies other than clear cell renal cell carcinoma. In this review, we investigated the present treatment option of poor-risk metastatic RCC. Areas covered are data with first and further line of therapy with mTOR inhibitors and other agents but without cytoreductive nephrectomy or rare histologies. The current data on systemic therapy in poor-risk metastatic RCC maintain temsirolimus as the preferred first-line therapy. New agents targeting immune checkpoints are being developed in clinical trials.     

Papel de los nuevos agentes inmunosupresores en el cáncer cutáneo no melanoma en pacientes trasplantados renales

IntroductionNonmelanoma skin cancer (NMSC) is the most common malignancy in patients who have received a solid organ transplant. Multiple factors are involved in the onset of posttransplant NMSC.ObjectivesTo analyze the relationship between new immunosuppressive drugs and the onset of NMSC in renal transplant recipients.MethodThis was a combined retrospective and prospective observational study in which we studied 289 patients who received a kidney transplant between January 1996 and December 2010 at Hospital Universitario Doctor Peset in Valencia, Spain.ResultsSeventy-three patients (25.2%) developed 162 NMSCs over a median follow-up of 72 months. There were no statistically significant differences in the onset of NMSC on comparing different induction therapy strategies involving monoclonal and polyclonal antibodies. NMSCs occurred less frequently in patients treated with mammalian target of rapamycin (mTOR) inhibitors than in those treated with other immunosuppressive regimens, although the differences were not statistically significant. Three of 5 patients with recurrent NMSC who were switched from calcineurin inhibitors to mTOR inhibitors developed additional NMSCs despite the change.ConclusionsInduction therapy with monoclonal and polyclonal antibodies in renal transplant recipients is not associated with an increased risk of NMSC. While mTOR inhibitors are associated with a lower risk of posttransplant NMSC, it remains to be determined whether a switch to these drugs is useful in the management of patients who develop multiple NMSCs.