A mechanistic target of rapamycin inhibitor, everolimus safely ameliorated lupus nephritis in a patient complicated with tuberous sclerosis.

A 26-year-old woman with tuberous sclerosis complex (TSC) received outpatient treatment for the complication of systemic lupus erythematosus (SLE) at our hospital. She visited our hospital with a chief complaint of pitting oedema in bilateral lower legs for 3 days. The urinalysis showed massive proteinuria with a lot of white blood cell casts. The blood tests revealed hypoalbuminaemia, hypercholesterolaemia, hypocomplementaemia, and elevated anti-double-stranded DNA antibody titre. Renal biopsy was not performed because of multiple renal angiomyolipomas, which was one of the features of TSC. She was diagnosed with a nephrotic state due to lupus nephritis. Although she had a standard therapy with high-dose corticosteroid and mycophenolate mofetil and tacrolimus, complete remission had not been achieved leading to a steroid-dependent nephrotic syndrome. During the follow-up, the angiomyolipomas became larger and had a risk of rupture at the age of 29 years. Everolimus, a mechanistic target of rapamycin (mTOR) inhibitor, was started for the treatment of angiomyolipomas, and mycophenolate mofetil and tacrolimus were terminated instead. The activity of lupus nephritis was surprisingly ameliorated, and the amount of corticosteroid successfully tapered. Everolimus has been continued for 6 years without severe side effects. Accumulating evidence suggests that the activated mTOR pathway plays a key role in the pathogenesis of SLE. We reported the long-term efficacy and safety of everolimus for refractory SLE in a patient with TSC for the first time. This case suggests that everolimus can be a promising option for the treatment of lupus nephritis.

Mechanistic Target of Rapamycin (mTOR) Inhibitors.

Mechanistic target of rapamycin (mTOR) inhibitors are macrocyclic lactone antibiotics derived from Streptomyces hygroscopicus that prevent T lymphocyte activation and B cell differentiation. Unlike calcineurin inhibitors (CNIs) that inhibit cytokine production, mTOR inhibitors block the cytokine signal transduction to arrest cells in the G1 to S phase. This class of drugs is commonly used for post-transplantation and cancer management because of its immunosuppressive and antiproliferative properties, respectively. The potential uses of mTOR inhibitors are heavily explored because of their impact on cell growth and proliferation. However, mTOR inhibitors have a broad range of effects that can result in adverse reactions, but side effects can occur with other immunosuppressive agents as well. Thus, the performance of mTOR inhibitors is compared to the outcomes and adverse effects of other immunosuppressive drugs or the combination of other immunosuppressants and mTOR inhibitors. Because mTOR regulates many downstream pathways, mTOR inhibitors can affect these pathways to manage various diseases. Sirolimus (rapamycin) is approved by the Food and Drug Administration (FDA) to treat post-renal transplantation and lymphangioleiomyomatosis (LAM). Everolimus is approved by the FDA to treat postmenopausal advanced hormone receptor-positive, HER2-negative breast cancer in women, progressive neuroendocrine tumors of pancreatic origin (PNET), advanced renal cell carcinoma (RCC), renal angiomyolipoma (AML) and tuberous sclerosis complex (TSC), and subependymal giant cell astrocytoma (SEGA) associated with TSC as well as renal and liver transplantation. Temsirolimus is approved by the FDA to treat advanced RCC. Opportunities to use mTOR inhibitors as therapy for other transplantation, metabolic disease, and cancer management are being researched. mTOR inhibitors are often called proliferation signal inhibitors (PSIs) because of their effects on proliferation pathways.

The Relationship Between Lithium and Cancer Proliferation: A Case-Based Review of the Literature.

BACKGROUND: The incidence and mortality rates of cancer in patients with Bipolar Disorder (BD) is higher compared with the general population. The role of Lithium (Li) in cancer proliferation/inhibition is still a controversial issue in the literature. OBJECTIVE: Based on a clinical case with lithium intake and development of a renal tumor, we aimed to explore the relationship between Li use and tumor proliferation, with regard to the mechanism of action of Li. METHOD: We present evidence of a female patient with bipolar disorder I, who had been on Li for several years, either as monotherapy or in combination with Valproate (VPA). While on Li monotherapy, the patient had undergone unilateral nephrectomy due to a chromophobe cell renal tumor. A literature search was performed using keywords bipolar disorder, medical comorbidity, cancer, renal tumor, lithium, mood stabilizers, valproate and mechanism of action. RESULTS: The limited data on the relationship between Li and cancer proliferation in clinical populations support neither a positive relationship between long-term Li use and increased urinary tract cancers nor an overall cancer risk. Growing evidence identifies effects of Li on cancer proliferation through inhibition of glycogen synthase kinase-3ß (GSK-3ß), modulations of redox status, inflammatory changes, pro-/anti-apoptotic mechanisms, and mitochondrial function changes. CONCLUSION: Despite the presence of contradictory data, a substantial body of evidence mainly from molecular studies points to Li's anti-carcinogenic effects. However, the underlying mechanistic pathways remain unclear. Mitochondrial dysfunction and redox modulations are potential areas for research on the relationship between Li and cancer proliferation.

Multicenter phase 2 trial of sirolimus for tuberous sclerosis: kidney angiomyolipomas and other tumors regress and VEGF- D levels decrease.

BACKGROUND: Tuberous sclerosis (TSC) related tumors are characterized by constitutively activated mTOR signaling due to mutations in TSC1 or TSC2. METHODS: We completed a phase 2 multicenter trial to evaluate the efficacy and tolerability of the mTOR inhibitor, sirolimus, for the treatment of kidney angiomyolipomas. RESULTS: 36 adults with TSC or TSC/LAM were enrolled and started on daily sirolimus. The overall response rate was 44.4% (95% confidence intervals [CI] 28 to 61); 16/36 had a partial response. The remainder had stable disease (47.2%, 17/36), or were unevaluable (8.3%, 3/36). The mean decrease in kidney tumor size (sum of the longest diameters [sum LD]) was 29.9% (95% CI, 22 to 37; n = 28 at week 52). Drug related grade 1-2 toxicities that occurred with a frequency of >20% included: stomatitis, hypertriglyceridemia, hypercholesterolemia, bone marrow suppression (anemia, mild neutropenia, leucopenia), proteinuria, and joint pain. There were three drug related grade 3 events: lymphopenia, headache, weight gain. Kidney angiomyolipomas regrew when sirolimus was discontinued but responses tended to persist if treatment was continued after week 52. We observed regression of brain tumors (SEGAs) in 7/11 cases (26% mean decrease in diameter), regression of liver angiomyolipomas in 4/5 cases (32.1% mean decrease in longest diameter), subjective improvement in facial angiofibromas in 57%, and stable lung function in women with TSC/LAM (n = 15). A correlative biomarker study showed that serum VEGF-D levels are elevated at baseline, decrease with sirolimus treatment, and correlate with kidney angiomyolipoma size (Spearman correlation coefficient 0.54, p = 0.001, at baseline). CONCLUSIONS: Sirolimus treatment for 52 weeks induced regression of kidney angiomyolipomas, SEGAs, and liver angiomyolipomas. Serum VEGF-D may be a useful biomarker for monitoring kidney angiomyolipoma size. Future studies are needed to determine benefits and risks of longer duration treatment in adults and children with TSC. TRIAL REGISTRATION: Clinicaltrials.gov NCT00126672.