Pulse mTOR inhibitor treatment effectively controls cyst growth but leads to severe parenchymal and glomerular hypertrophy in rat polycystic kidney disease
ABSTRACT The efficacy of mammalian target of rapamycin (mTOR) inhibitors is currently tested in patients affected by autosomal dominant polycystic kidney disease. Treatment with mTOR inhibitors has been associated with numerous side effects. However, the renal-specific effect of mTOR inhibitor treatment cessation in polycystic kidney disease is currently unknown. Therefore, we compared pulse and continuous everolimus treatment in Han:SPRD rats. Four-week-old male heterozygous polycystic and wild-type rats were administered everolimus or vehicle by gavage feeding for 5 wk, followed by 7 wk without treatment, or continuously for 12 wk. Cessation of everolimus did not result in the appearance of renal cysts up to 7 wk postwithdrawal despite the reemergence of S6 kinase activity coupled with an overall increase in cell proliferation. Pulse everolimus treatment resulted in striking noncystic renal parenchymal enlargement and glomerular hypertrophy that was not associated with compromised kidney function. Both treatment regimens ameliorated kidney function, preserved the glomerular-tubular connection, and reduced proteinuria. Pulse treatment at an early age delays cyst development but leads to striking glomerular and parenchymal hypertrophy. Our data might have an impact when long-term treatment using mTOR inhibitors in patients with autosomal dominant polycystic kidney disease is being considered.
- SourceAvailable from: Albert C M Ong
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- "Rapamycin-based therapeutics effectively decreased cyst growth and preserved renal function in a variety of animal models for PKD [28,29,48]. However, conflicting results were obtained in clinical trials. "
ABSTRACT: The mammalian target of rapamycin (mTOR) signaling pathway is aberrantly activated in polycystic kidney disease (PKD). Emerging evidence suggests that phospholipase D (PLD) and its product phosphatidic acid (PA) regulate mTOR activity. In this study, we assessed in vitro the regulatory function of PLD and PA on the mTOR signaling pathway in PKD. We found that the basal level of PLD activity was elevated in PKD cells. Targeting PLD by small molecule inhibitors reduced cell proliferation and blocked mTOR signaling, whereas exogenous PA stimulated mTOR signaling and abolished the inhibitory effect of PLD on PKD cell proliferation. We also show that blocking PLD activity enhanced the sensitivity of PKD cells to rapamycin and that combining PLD inhibitors and rapamycin synergistically inhibited PKD cell proliferation. Furthermore, we demonstrate that targeting mTOR did not induce autophagy, whereas targeting PLD induced autophagosome formation. Taken together, our findings suggest that deregulated mTOR pathway activation is mediated partly by increased PLD signaling in PKD cells. Targeting PLD isoforms with pharmacological inhibitors may represent a new therapeutic strategy in PKD.PLoS ONE 08/2013; 8(8):e73173. DOI:10.1371/journal.pone.0073173 · 3.23 Impact Factor
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- "mTOR inhibitors are immunosuppressants that target and inhibit mTOR, and thereby exert antiproliferative, antiangiogenetic and tumor-progression blocking capabilities that might serve preventing uncontrolled cholangiocyte cell proliferation. Treatment with mTOR inhibitors dramatically reduced cyst volume in experimental models[11-15]. An observational trial in ADPKD patients who received a kidney transplant observed that sirolimus reduced polycystic liver volumes by 12% compared to an increase of 14% in patients who received standard treatment with tacrolimus. "
ABSTRACT: Polycystic liver disease (PLD) is defined as having more than 20 liver cysts and can present as a severe and disabling condition. Most symptoms are caused by the mass effect of the liver size and include abdominal pain and distension. The somatostatin analogues octreotide and lanreotide have proven to reduce polycystic liver volume. mTOR inhibitors such as everolimus inhibit cell proliferation and might thereby reduce growth of liver cysts. This trial aims to assess the benefit of combination therapy of everolimus and octreotide compared to octreotide monotherapy. In this study we present the structure of the trial and the characteristics of the included patients. This is a randomized open-label clinical trial comparing the effect of 12 months of everolimus and octreotide to octreotide monotherapy in PLD patients. Primary outcome is change in liver volume determined by CT-volumetry. Secondary outcomes are changes in abdominal symptoms and quality of life. Moreover, safety and tolerability of the drugs will be assessed. This trial will compare the relative efficacy of combination therapy with octreotide and everolimus to octreotide monotherapy. Since they apply to different pathways of cystogenesis we expect that combining octreotide and everolimus will result in a cumulative reduction of polycystic liver volume. ClinicalTrials.gov: NCT01157858.Trials 11/2011; 12:246. DOI:10.1186/1745-6215-12-246 · 2.12 Impact Factor
Conference Paper: The product-process-market path: new road maps[Show abstract] [Hide abstract]
ABSTRACT: Global competition is causing management to rethink the way design and production are done. To cut time to market, industry is aiming to shorten both the manufacturing and engineering cycles. New road maps are being developed and experimented with. It is noted that the traditional throw-it-over-the-wall road map has been discarded and the focus has turned to group technology, concurrent engineering, design for manufacture, and design for assembly. Dictaphone Corporation's products aim at the industrial voice recording market, and in late 1990 it formed a team to explore the feasibility of a new product. The team sized up the proposed product's technical feasibility by reviewing Dictaphone's analog/digital technology, PCB (printed circuit board) product process technology, and test requirements. The focus of the case study described is on PCB technology, the PCB being a component of the new product. The concept-design-production path is described. The PCB design-manufacture approach described here provides a road map aimed at product reliability and robustness as well as reduced cycle time, all of which means an improved competitive edge in the market placeTechnology Management : the New International Language; 11/1991