Mechanistic target of rapamycin modulation: an emerging therapeutic approach in a wide variety of disease processes

The mechanistic target of rapamycin (mTOR) was first described over 20 years ago 1, 2 and much basic science work since then has shed light both on its multiple functions and its signalling mechanisms. It is found in many tissues including liver, muscle, adipose tissue and brain, where it plays important roles in the regulation of cell survival, proliferation, growth, motility and metabolism. mTOR has been found to be dysregulated in the context of many disease states including some cancers, obesity, diabetes, neurodegenerative diseases and depression. Although inhibitors of mTOR such as rapamycin are already well established in the prevention of transplant rejection, it is only recently that the utility of mTOR modulators has been explored in other conditions. We therefore thought it timely to devote a themed issue of the British Journal of Clinical Pharmacology to the emerging application of mTOR modulation to human disease.

Waldner et al. 3 have revisited the topic of the use of rapamycin and its analogues (rapalogs), collectively known as first generation mTOR inhibitors, for immune suppression, in particular in the context of transplantation. They provide an up to date overview of the area and explore new insights into mTOR function in different cell types. Additionally, they outline how new pharmacological tools, in particular the dual mTOR complex (mTORC) kinase inhibitors (TORKinibs), are both helping to elucidate the detailed role of mTORCs in different cell types and providing a novel potential therapeutic modality for immune suppression and transplant protection. Whether the TORKinibs and other second generation drugs will provide a significant advance over the first generation mTOR inhibitors remains to be seen.

The mTOR inhibitors have, to date, largely established themselves in patients undergoing solid organ transplantation as well as in solid tumour oncology. An emerging field is the use of these agents in patients undergoing allogeneic haematopoietic stem cell transplantation. Lutz and Mielke 4 review this area, and in particular their utility in both prophylaxis and treatment of graft‐vs.‐host disease, as well as the toxicities associated with their use in this context. They rightly emphasise the importance of, and need for, prospective registration trials in order to enable optimisation of dosing as well as to improve pharmacovigilance.

mTOR is known to be aberrantly activated in a number of cancer types. Francipane and Lagasse 5 explore new insights into the role of mTOR signalling in carcinogenesis and cancer biology; and they go on to review the data suggesting that, whereas first generation mTOR inhibitors (rapamycin and rapalogs) have proven ineffective in most cancer trials, the newer mTOR signalling inhibitors (TORKinibs and dual phosphoinositide 3‐kinase/mTOR inhibitors) are showing more promise, especially in cancers bearing stem cell‐like features (and they single out glioblastoma and cancers of the breast, pancreas, colon, prostate and ovary). They argue that these early results provide a compelling rationale for the future clinical development of mTOR‐targeted therapies beyond the classical agents, in the treatment of such cancers. Still on the subject of breast cancer, Steelman et al. 6 review the evidence that rapalogs may enhance the effectiveness of hormonal based therapies in oestrogen receptor positive breast cancer patients whose cancer has progressed in spite of hormonal therapies. They also discuss some of the laboratory evidence in breast cancer cell lines that the newer mTOR signalling inhibitors may enhance the tumour suppressive effects of standard mTOR inhibitors, especially where the tumours exhibit evidence of rapamycin resistance. Lee et al. 7 review the clinical experience with mTOR inhibition in haematological malignancies, concluding that, to date, the first generation mTOR inhibitors have shown disappointing clinical efficacy in most contexts; and, although the second generation inhibitors are now entering clinical trials, early results in combination with preclinical studies suggest that they too are likely to have limited efficacy and may exhibit significant toxicities. However, they go on to review the preclinical evidence that, when used in combination either with each other or with other targeted therapies, or indeed with standard chemotherapy regimes, these agents (whether first or second generation) may provide a useful adjunct in the treatment of B cell malignancies.

An interesting, and unexpected, recent finding is that rapamycin can extend lifespan in a variety of animal models. This may be attributable to the multiple roles played by mTOR signalling in processes involved in ageing, including protein translation, autophagy, stem cell pool turnover, inflammation and cellular senescence. These aspects are reviewed in detail by Evangelisti et al. 8, as well as the finding that rapamycin exhibits the ability to rescue the cellular phenotype in cells from patients with Hutchinson–Gilford progeria syndrome, a genetic disease where the ageing process, whilst vastly accelerated, otherwise appears to mimic most of the traits of physiological ageing. They speculate on the possibilities of mTOR inhibitors being used to prolong life – or perhaps more importantly, to counteract degenerative age‐associated diseases.

In a similar vein, Maiese 9 explores in depth the often dual and opposing roles played by mTOR signalling in the context of neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, Huntington disease, epilepsy, stroke and trauma. He presents the case that modulation of mTOR signalling – activation or inhibition – may present new and useful therapeutic opportunities in these conditions, but that further research to delineate the precise roles of mTOR in these conditions will be an essential prerequisite.

Another important age‐related degenerative disease, this time affecting the cardiovascular system, is atherosclerosis. Kurdi et al. 10 review the role of mTOR signalling in the development and progression of atherosclerosis, and the evidence that mTORC1 inhibition in mouse and rabbit models of atherosclerosis reduces atherosclerotic plaque size and complexity. Indeed, for many years now, insertion of rapalog‐eluting stents into human coronary arteries at the time of percutaneous coronary intervention has been standard and such stents dramatically reduce the rate of restenosis. However, rapalogs when given systemically also induce dyslipidaemia and insulin resistance, both of which are undesirable in the context of atherosclerosis prevention. It may be that using mTOR inhibitors in combination with a statin or with metformin may unleash the full potential of mTOR inhibition in treatment of atherosclerosis; this remains to be seen. Alternatively, intermittent dosing regimens or reduced doses of rapalogs may be a useful way forward.

Major depressive disorder (MDD) is another area where existing therapies have significant limitations and new therapeutic approaches are needed, and this is reviewed by Ignácio et al. 11. Although antidepressants targeting monoamines are widely used in this condition, they are slow in their onset and a large number of patients are refractory to their effects. Preclinical and clinical studies have identified mTOR as an important signalling pathway involved in synaptic plasticity, which is an important component of the pathophysiology of MDD, and also as a key pathway involved in the action of classical antidepressants. Selective modulation of mTOR may be a fruitful avenue for therapy of depression, but may involve significant toxicity; nonetheless, more clinical research is needed to explore the potential utility and place of mTOR modulation in this context.

These papers collectively give a good overview of the largely unexplored potential of therapies, both existing and in the pipeline, that modulate mTOR signalling. Time will tell whether this potential will truly be realised.

Ferro, A. (2016) Mechanistic target of rapamycin modulation: an emerging therapeutic approach in a wide variety of disease processes. Br J Clin Pharmacol, 82: 1156–1157. doi: 10.1111/bcp.13117.