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Targeting mTOR Signaling Can Prevent the Progression of FSGS.

ABSTRACT: Mammalian target of rapamycin (mTOR) signaling is involved in a variety of kidney diseases. Clinical trials administering mTOR inhibitors to patients with FSGS, a prototypic podocyte disease, led to conflicting results, ranging from remission to deterioration of kidney function. Here, we combined complex genetic titration of mTOR complex 1 (mTORC1) levels in murine glomerular disease models, pharmacologic studies, and human studies to precisely delineate the role of mTOR in FSGS. mTORC1 target genes were significantly induced in microdissected glomeruli from both patients with FSGS and a murine FSGS model. Furthermore, a mouse model with constitutive mTORC1 activation closely recapitulated human FSGS. Notably, the complete knockout of mTORC1 by induced deletion of both Raptor alleles accelerated the progression of murine FSGS models. However, lowering mTORC1 signaling by deleting just one Raptor allele ameliorated the progression of glomerulosclerosis. Similarly, low-dose treatment with the mTORC1 inhibitor rapamycin efficiently diminished disease progression. Mechanistically, complete pharmacologic inhibition of mTOR in immortalized podocytes shifted the cellular energy metabolism toward reduced rates of oxidative phosphorylation and anaerobic glycolysis, which correlated with increased production of reactive oxygen species. Together, these data suggest that podocyte injury and loss is commonly followed by adaptive mTOR activation. Prolonged mTOR activation, however, results in a metabolic podocyte reprogramming leading to increased cellular stress and dedifferentiation, thus offering a treatment rationale for incomplete mTOR inhibition.

SUBMITTER: Zschiedrich S

PROVIDER: S-EPMC5491276 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Targeting mTOR Signaling Can Prevent the Progression of FSGS.

Zschiedrich Stefan S Bork Tillmann T Liang Wei W Wanner Nicola N Eulenbruch Kristina K Munder Stefan S Hartleben Björn B Kretz Oliver O Gerber Simon S Simons Matias M Viau Amandine A Burtin Martine M Wei Changli C Reiser Jochen J Herbach Nadja N Rastaldi Maria-Pia MP Cohen Clemens D CD Tharaux Pierre-Louis PL Terzi Fabiola F Walz Gerd G Gödel Markus M Huber Tobias B TB

Journal of the American Society of Nephrology : JASN 20170307 7

Mammalian target of rapamycin (mTOR) signaling is involved in a variety of kidney diseases. Clinical trials administering mTOR inhibitors to patients with FSGS, a prototypic podocyte disease, led to conflicting results, ranging from remission to deterioration of kidney function. Here, we combined complex genetic titration of mTOR complex 1 (mTORC1) levels in murine glomerular disease models, pharmacologic studies, and human studies to precisely delineate the role of mTOR in FSGS. mTORC1 target g ...[more]

PMID: 28270414

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Project description:Opinion statementNeuroendocrine tumors (NETs) are a heterogeneous group of malignancies characterized by variable but most often indolent biologic behavior. Well-differentiated NETs can be broadly classified as either carcinoid or pancreatic NET. Although they have similar characteristics on routine histologic evaluation, the 2 tumor subtypes have different biology and respond differently to treatment, with most therapeutic agents demonstrating higher response rates in pancreatic NETs compared with carcinoid. Until recently, systemic treatment options for patients with advanced NETs were limited. However, improvements in our understanding of signaling pathways involved in the pathogenesis, growth, and spread of NETs have translated into an expansion of treatment options. Aberrant signaling through the mechanistic pathway of rapamycin (mTOR) pathway has been implicated in neuroendocrine tumorigenesis. Additionally, altered expression of mTOR pathway components has been observed in NETs and has been associated with clinical outcomes. Targeting the mTOR pathway has emerged as an effective treatment strategy in the management of advanced NETs. In a randomized, placebo-controlled study of patients with advanced pancreatic NET, treatment with the mTOR inhibitor everolimus was associated with improved progression-free survival (PFS). Largely based upon these data, everolimus has been approved in the United States and Europe for the treatment of patients with advanced pancreatic NET. The activity of everolimus remains under investigation in patients with carcinoid tumors. In a randomized study of patients with advanced carcinoid tumors associated with carcinoid syndrome, the addition of everolimus to octreotide was associated with improved PFS compared with octreotide. However, the results did not meet the prespecified level of statistical significance based on central review of radiographic imaging. Results from a randomized study examining the efficacy of everolimus in patients with nonfunctional gastrointestinal and lung NETs are awaited. In addition, further investigation is needed to determine whether primary tumor site or other clinical and molecular factors can impact response to mTOR inhibition. Although everolimus can slow tumor progression, significant tumor reduction is rarely obtained. Targeting multiple signaling pathways is a treatment strategy that may provide better tumor control and overcome resistance mechanisms involved with targeting a single pathway. Results of ongoing and future studies will provide important information regarding the added benefit of combining mTOR inhibitors with other targeted agents, such as VEGF pathway inhibitors, and cytotoxic chemotherapy in the treatment of advanced NETs.

Dataset Information

Targeting mTOR Signaling Can Prevent the Progression of FSGS.

Publications

Targeting mTOR Signaling Can Prevent the Progression of FSGS.

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