The Long Journey of mTOR Inhibitors and the Long Path That Is Still Ahead
Bibliographic record
Abstract
Rapamycin (sirolimus) was isolated in 1975 from actinomycete Streptomyces hygroscopicus in a soil sample collected during a Canadian expedition to Easter Island (Rapa Nui).1 The target of rapamycin (TOR) was discovered in 1994 in the yeast Saccharomyces,2 is a ubiquitous and highly conserved enzyme complex in a pathway with a key role in physiological homeostasis. Deregulation of its activity is associated with a variety of diseases.3 The first phase I study of ascending doses of sirolimus in stable kidney transplant recipients receiving cyclosporine and prednisone was published in 1996. Subsequent phase II and III clinical trials led to regulatory approval by the Food and Drug Administration in 1999 for the prophylaxis of rejection after kidney transplantation in combination with cyclosporine and steroids. Everolimus followed the same path and was subsequently approved for kidney, heart, and liver transplantation. Sirolimus and everolimus analogs were approved for prevention of intrastent restenosis (pharmacological stents) and for the treatment of some cancers, highlighting the central role of the pathway in disparate disease states. This supplement summarizes recent data and provides critical analysis of the accumulated knowledge of the biological effects of mTOR inhibition. Zaza et al4 describe the effects of mTOR inhibition on protein synthesis, the cell cycle, lipid metabolism, energy metabolism, autophagy, angiogenesis, glucose metabolism, cytoskeleton remodeling, epithelial to mesenchymal transition, and immune cells development and function. The use of mTOR inhibitors in different types of organ transplantation is also reviewed. Flechner provides a critical analysis of randomized clinical trials on different strategies of using mTOR inhibitors after kidney transplantation.5 Nashan6 summarizes data on liver transplants, with the focus on calcineurin inhibitor (CNI) minimization to preserve native renal function. Zuckermann7 discusses recent data on the use of mTOR inhibitors in heart transplantation, under CNI minimization and conversion strategies aiming to preserve renal function and to prevent the development of graft vasculopathy, CMV infection, and malignancy. Berney et al8 discuss both the beneficial and deleterious effects of mTOR inhibitors on β cells and how sirolimus and everolimus-based immunosuppression have impacted on practices and outcomes of pancreas and islet transplantation. More general involvement of inhibition of the mTOR pathway in other diseases is also reviewed. Chan et al9 summarized the current understanding of mTOR signaling pathway under physiological and pathological conditions and recent findings on mTOR inhibitors in the management of kidney diseases. Vergès10 describes the deleterious and complex mechanisms by which mTOR inhibitors impair glucose metabolism by downregulation of the insulin signaling pathway, increasing the risk of diabetes in recipients of organ transplants or in patients with malignancies. De Meyer et al11 debated the net result of anti-atherosclerotic mTOR inhibitor effects versus the known dyslipidemia. Bowman et al12 highlight the role of mTORi in the management of viral infections after solid organ transplant, noting not only the potential role in the management of cytomegalovirus, poliomavirus, herpes virus 8, -related Kaposi sarcoma but also the lack of evidence for use of mTORis in EBV-mediated posttransplant lymphoproliferative disease or hepatitis C virus viral replication. Paoletti13 reviews data on mTOR associated regression of left ventricular hypertrophy in kidney transplant recipients with posttransplant cardiomyopathy. Finally, de Fijter14 details the effects of mTORi on malignancies, suggesting that observed clinical efficacy is a reflection of disease stabilization rather than tumor regression. The efficacy of mTOR inhibitors in all its indications is limited by the complex safety and tolerability profile, the intricate aspects of which have begun to be uncovered using “omics.”15 Preclinical and clinical development of analogs, targeting different binding sites or producing selective inhibition of mTOR complexes (mTORC1 and mTORC2) may help improve the efficacy/toxicity profile of this class of drugs.16
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.004 | 0.005 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.002 | 0.002 |
| Scholarly communication | 0.004 | 0.009 |
| Open science | 0.001 | 0.002 |
| Research integrity | 0.003 | 0.009 |
| Insufficient payload (model declined to judge) | 0.009 | 0.005 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".