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SUCCESS OF mTOR INHIBITOR IN CLINICS

Introduction: The mTOR Pathway and its clinical importance

In 1994 a protein was discovered that was determined to be a target for the small molecule inhibitor Rapamycin, it was named mTOR [1]. The acronym mTOR stands for the “mammalian Target for Rapamycin” and this protein was demonstrated to be essential for embryonic development, mutated null murine models did not survive in utero [2;3]. Subsequent investigation revealed that the mTOR protein is like the “Grand central station” of multiple regulatory pathways dealing mostly with gene transcription and cell growth. The unique aspect of the mTOR protein is that despite being more related to lipid kinases it also has functions similar to those of the serine/threonine kinase family phosphoinositide 3-kinase related kinases (PIKK) [4]. The mTOR protein contains multiple binding domains that interact with several different ligands that initiate scaffolding processes, adapt other mechanism or regulate mTOR’s activity. mTOR’s activation is more complex in that signals directly from the plasma in relation to either nutritional status or stress conditions can trigger mTOR activation. In addition signals from growth factors, insulin and phorbol 12-myristate 13-acetate (PMA) trigger signaling cascades such as PCK/PLD/mTOR or PI3K/PIP/TSC/Rheb/mTOR that effect the function of mTOR [5]. The pathways effected are EGFR [6;7] or AKT [8], effects are involved in the organization of actin and initiation of the start codon (AUG) in gene transcription [9]. Due to the nature of the activity of mTOR the concept of an mTOR pathway inhibitor was considered an attractive approach to the treatment of various cancers. With the knowledge that mTOR inhibition by rapamycin, the core molecular structure of this molecule could be used to design alternative mTOR kinase inhibitors [10]. Examples of mTOR pathway inhibitors are Rapamycin, chrysorphanic acid, deforolimus, Everolimus and Temsirolimus are just a few of the 20 plus more commonly known molecules. Clinical mTOR selective inhibitors have been used in the treatment of cancer, diabetes, obesity, transplant rejection, glycogen storage diseases and in age related disease.

mTOR inhibitors: FDA approval and clinical status

The determination of the mTOR structure as a complex with a ligand called raptor led to the discovery that the complex was actually a dimer formation of interlocking mTOR and raptor subunits surrounding a central cavity (mTORC1or 2). Inhibitors form complexes with FKBP12 which in turn disrupt the cohesion of the dimer complex mTORC leading to inhibition effects. include Everolimus (

Sirolimus (Rapamycin) is an mTOR antagonist FDA approved in the maintenance treatment after kidney transplants. In addition over fifty clinical trials are currently in progress in a range of disease conditions covering immunotherapy after bone marrow, kidney, liver, pancreases and stem cell transplants. Sirolimus mTOR inhibitor in the treatment of cancer is being investigated for lymphoma, glioblastoma, NSCLC, renal carcinoma, advanced solid tumors, diabetes (focusing on Macular disorders), metastatic cancer and osteosarcoma [11-18]. The range of investigation indicates the possibilities of mTOR inhibitor drugs in the treatment of metabolic and nutritional disorders. Other mTOR inhibitor in clinical trials include Everolimus (with 60 + trials covering breast, prostate, pancreatic, gastric, endometrial, renal colorectal and leukemia’s of various different types) [19-30]; the mTOR agonist Temsirolimus with 60+ trials covering similar cancer type as to Sirolimus and Everolimus [31-41]; the mTOR specific inhibitor Deforolimus with 30 + trials covering, in addition to those all ready mentioned, NSCLC and ovarian [42-44].

With the treatment of cancer nutritional status and individual stress are compromised, mTOR is directly affected by these factors and many others that tumors or treatment itself change. Activity of mTOR function can therefore be different in the various stages of tumor development. The mTOR inhibitor mechanism is difficult to predict and the mechanism of resistance to treatment are difficult to isolate [45-49]. Results of easy to use mTOR activity assay enable researchers to monitor mTOR activtity during treatment and the various stages of tumor development or necrosis. To buy mTOR inhibitors or an mTOR assay kit can be costly and prices vary significantly between suppliers.

References

 

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  23.    Krueger DA, Care MM et al. Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. N Engl J Med 2010; 363(19):1801-1811.

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