Perfect match: mTOR inhibitors and tuberous sclerosis complex.

Tuberous sclerosis complex (TSC) is an autosomal dominant syndrome that presents with diverse and complex clinical features and involves multiple human systems. TSC-related neurological abnormalities and organ dysfunction greatly affect the quality of life and can even result in death in patients with TSC. It is widely accepted that most TSC-related clinical manifestations are associated with hyperactivation of the mammalian target of rapamycin (mTOR) pathway caused by loss­of­function mutations in TSC1 or TSC2. Remarkable progress in basic and translational research has led to encouraging clinical advances. Although mTOR inhibitors (rapamycin/everolimus) demonstrate great potential in TSC management, two major concerns hamper their generalized application. One is the frequent manifestation of adverse events, such as stomatitis, infections, and menstrual disorders; and the other is the poor response in certain patients. Thus, indicators are required to effectively predict the efficacy of mTOR inhibitors. Herein, we have summarized the current utilization of mTOR inhibitors in the treatment of TSC and focused on their efficacy and safety, in an attempt to provide a reference to guide the treatment of TSC.

Low-Dose Everolimus Maintenance Therapy for Renal Angiomyolipoma Associated With Tuberous Sclerosis Complex.

Objective: To assess the safety and efficacy of low-dose everolimus maintenance therapy for tuberous sclerosis complex-related renal angiomyolipoma (TSC-RAML) patients that had previously undergone standard-dose treatment for a minimum of 6 months. Materials and Methods: In total, 24 patients with a definitive TSC diagnosis were enrolled from April 2018 - April 2019 at Xiangya Hospital, Central South University. All patients underwent low-dose everolimus maintenance therapy following standard-dose everolimus induction therapy for a minimum of 6 months. Patients additionally underwent TSC1/TSC2 genetic testing, And they were followed-up at 3, 6, 12, 18, and 24 months. The Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1) criteria were used to monitor patient RAML responses, while adverse events (AEs) were assessed as per the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE, version 4.0). P < 0.05 was the significance level for all analyses, which were performed using SPSS 19.0. Results: TSC1/TSC2 gene mutations were present in all 24 patients, all of whom achieved a significant reduction in TSC-RAML volume within the initial 6-month induction therapy period, and exhibited volume stabilization during the low-dose maintenance therapy treatment period without any instances of TSC-RAML regrowth. Adverse events (AEs) were significantly less severe and less frequent over the course of maintenance therapy relative to standard therapy. Conclusions: Low-dose everolimus maintenance therapy represents an effective approach to achieving TSC-RAML control following a minimum of 6 months of full-dose induction therapy, and may be associated with decreases in everolimus-related AE frequency and severity.

Everolimus versus sirolimus for angiomyolipoma associated with tuberous sclerosis complex: a multi-institutional retrospective study in China.

PURPOSE: To evaluate the efficacy and safety of everolimus and sirolimus in patients with tuberous sclerosis complex-associated angiomyolipomas (TSC-AML). MATERIALS AND METHODS: We performed a multi-institutional retrospective study of TSC-AML patients treated with oral everolimus 10 mg or sirolimus 2 mg per day for at least 3 months. Angiomyolipoma volume was estimated using orthogonal measurements by MRI or CT. Adverse events (AEs) were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events. All analyses were performed using SPSS 19.0 software. RESULTS: Response rates were high in both groups. With the prolonged medication durations, the therapeutic efficacy of both agents became more significant. The TSC-AML volume reduction after 6 and 12 months was more pronounced in patients with everolimus than those with sirolimus. More than half of the patients treated with everolimus had ≥ 50% reduction, and approximately 80% of them had ≥ 30% reduction, which was higher than that in patients treated with sirolimus. Regarding safety, there was no significant difference in the incidence of AEs between the two groups. CONCLUSIONS: Both everolimus and sirolimus are excellent therapeutic options for TSC-AML. However, everolimus has a better therapeutic efficacy than sirolimus, particularly in reducing TSC-AML volume. Everolimus is therefore recommended as the first choice of therapy for TSC-AML.

[Modified serum-guided immunoblotting for differential proteomic study of prostate cancer].

OBJECTIVE: To search for a new method of screening for molecular targets for androgen-dependent prostate cancer. METHODS: We collected tissue samples and paired serum samples from 3 cases of androgen-dependent prostate cancer (ADPC) treated by surgical resection, and included another 3 samples of benign prostatic hyperplasia (BPH) tissue and normal human serum in the control group. The total proteins extracted were separated and transmembrane by two-dimensional gel electrophoresis, followed by hybridization with the sera of the patients with ADPC and those with hormone-independent prostate cancer (HIPC) as the primary antibodies. The differentially expressed proteins were compared by Western blot, analyzed by MALDI-TOF-MS mass spectrography, and verified by RT-PCR and Western blot following bioinformatic identification. RESULTS: This modified method exhibited a significantly better effect in displaying differentially expressed proteins, by which 12 differentially expressed protein spots were identified, including Beclin1, glutathione S-transferase P (GSTP1-1), ZBTB7, dihydrodiol dehydrogenase 2 (DDH), enolase (ENO1), glucose-dependent insulin-releasing peptide receptor (GIPR), Mn-superoxide dismutase (MnSOD), phosphoglycerate mutase 1 (PGAM1), amino-peptidyl-prolyl cistrons isomerase (PPIA), and phospholipid-PE-binding protein (PEBP). The mRNA and protein expressions of Beclin1 were significantly down-regulated in androgen-dependent prostate cancer tissues. CONCLUSION: This modified serum-guided immunoblotting technique has provided a new method for clarifying the molecular mechanisms of the occurrence and progression of HIPC, in which Beclin1-mediated autophagy may play a key role.