sirolimus and Growth-Disorders

PIK3CA-related overgrowth spectrum (PROS) encompasses a range of debilitating conditions defined by asymmetric overgrowth caused by mosaic activating PIK3CA variants. PIK3CA encodes the p110α catalytic subunit of phosphatidylinositol-3-kinase (PI3K), a critical transducer of growth factor signaling. As mTOR mediates the growth-promoting actions of PI3K, we hypothesized that the mTOR inhibitor sirolimus would slow pathological overgrowth.. Thirty-nine participants with PROS and progressive overgrowth were enrolled into open-label studies across three centers, and results were pooled. For the primary outcome, tissue volumes at affected and unaffected sites were measured by dual energy X-ray absorptiometry during 26 weeks of untreated run-in and 26 weeks of sirolimus therapy.. Thirty participants completed the study. Sirolimus led to a change in mean percentage total tissue volume of -7.2% (SD 16.0, p = 0.04) at affected sites, but not at unaffected sites (+1.7%, SD 11.5, p = 0.48) (n = 23 evaluable). Twenty-eight of 39 (72%) participants had ≥1 adverse event related to sirolimus of which 37% were grade 3 or 4 in severity and 7/39 (18%) participants were withdrawn consequently.. This study suggests that low-dose sirolimus can modestly reduce overgrowth, but cautions that the side-effect profile is significant, mandating individualized risk-benefit evaluations for sirolimus treatment in PROS.

Topics: Abnormalities, Multiple; Adolescent; Adult; Aged; Child; Child, Preschool; Class I Phosphatidylinositol 3-Kinases; Female; Growth Disorders; Humans; Male; Middle Aged; Mutation; Phenotype; Phosphatidylinositol 3-Kinases; Sirolimus; TOR Serine-Threonine Kinases

SHORT syndrome is a rare, recognizable syndrome resulting from heterozygous mutations in PIK3R1 encoding a regulatory subunit of phosphoinositide-3-kinase (PI3K). The condition is characterized by short stature, intrauterine growth restriction, lipoatrophy and a facial gestalt involving a triangular face, deep set eyes, low hanging columella and small chin. PIK3R1 mutations in SHORT syndrome result in reduced signaling through the PI3K-AKT-mTOR pathway. We performed whole exome sequencing for an individual with clinical features of SHORT syndrome but negative for PIK3R1 mutation and her parents. A rare de novo variant in PRKCE was identified. The gene encodes PKCε and, as such, the AKT-mTOR pathway function was assessed using phospho-specific antibodies with patient lymphoblasts and following ectopic expression of the mutant in HEK293 cells. Kinase analysis showed that the variant resulted in a partial loss-of-function. Whilst interaction with PDK1 and the mTORC2 complex component SIN1 was preserved in the mutant PKCε, it bound to SIN1 with a higher affinity than wild-type PKCε and the dynamics of mTORC2-dependent priming of mutant PKCε was altered. Further, mutant PKCε caused impaired mTORC2-dependent pAKT-S473 following rapamycin treatment. Reduced pFOXO1-S256 and pS6-S240/244 levels were also observed in the patient LCLs. To date, mutations in PIK3R1 causing impaired PI3K-dependent AKT activation are the only known cause of SHORT syndrome. We identify a SHORT syndrome child with a novel partial loss-of-function defect in PKCε. This variant causes impaired AKT activation via compromised mTORC2 complex function.

Topics: Adaptor Proteins, Signal Transducing; Adolescent; Dwarfism; Female; Growth Disorders; HEK293 Cells; Humans; Hypercalcemia; Mechanistic Target of Rapamycin Complex 2; Metabolic Diseases; Mutation; Nephrocalcinosis; Phosphatidylinositol 3-Kinases; Phosphorylation; Protein Kinase C-epsilon; Proto-Oncogene Proteins c-akt; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Experimental findings indicate that sirolimus (SRL) inhibits longitudinal growth by mechanisms potentially related to its inhibitory effects on both cell proliferation and expression of vascular endothelial growth factor (VEGF). The aim of this study was to investigate the growth pattern of kidney-transplanted children treated with SRL in a multicenter observational clinical study. Height, change in height SD (Δ height) and growth velocity of pediatric patients with renal transplant were calculated at 0, 6, 12, and 24 months after starting SRL. Controls of kidney-transplanted children not treated with SRL were matched by age, gender, renal function, and dose of corticosteroids. Sixty-eight children (34 SRL, 34 controls) were enrolled in the study. Nephrotoxicity was the most frequent indication to start therapy with SRL. SRL exerted an adverse effect on growth as demonstrated by significantly lower (p < 0.05) growth velocity (cm/year) and smaller change in height SD in the SRL group after 6 (4.08 vs. 6.56 and -0.05 vs. 0.14), 12 (4.44 vs. 6.11 and -0.03 vs. 0.28) and 24 (4.53 vs. 6.03 and -0.04 vs. 0.53) months of treatment. This study suggests that SRL therapy may interfere with growth of kidney-transplanted children. This undesirable effect needs to be taken into account when considering a switch to SRL and confirmed in further prospective trials including larger number of patients.

Topics: Child; Female; Graft Rejection; Growth Disorders; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Renal Insufficiency; Retrospective Studies; Sirolimus; Transplantation, Homologous

The TOR protein kinases (TOR1 and TOR2 in yeast; mTOR/FRAP/RAFT1 in mammals) promote cellular proliferation in response to nutrients and growth factors, but their role in development is poorly understood. Here, we show that the Drosophila TOR homolog dTOR is required cell autonomously for normal growth and proliferation during larval development, and for increases in cellular growth caused by activation of the phosphoinositide 3-kinase (PI3K) signaling pathway. As in mammalian cells, the kinase activity of dTOR is required for growth factor-dependent phosphorylation of p70 S6 kinase (p70(S6K)) in vitro, and we demonstrate that overexpression of p70(S6K) in vivo can rescue dTOR mutant animals to viability. Loss of dTOR also results in cellular phenotypes characteristic of amino acid deprivation, including reduced nucleolar size, lipid vesicle aggregation in the larval fat body, and a cell type-specific pattern of cell cycle arrest that can be bypassed by overexpression of the S-phase regulator cyclin E. Our results suggest that dTOR regulates growth during animal development by coupling growth factor signaling to nutrient availability.

Topics: Amino Acid Sequence; Amino Acids; Animals; Cell Cycle; Cell Division; Cell Size; Cyclin E; Drosophila melanogaster; Drosophila Proteins; Energy Metabolism; Gene Targeting; Genes, Insect; Growth Disorders; Humans; Insect Proteins; Larva; Molecular Sequence Data; Phenotype; Phosphatidylinositol 3-Kinases; Phosphorylation; Phosphotransferases (Alcohol Group Acceptor); Protein Kinases; Protein Processing, Post-Translational; Ribosomal Protein S6 Kinases; Sequence Alignment; Sequence Homology, Amino Acid; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases