mTOR In Cancer Research Articles

Involvement of mTOR signaling in physiopathology and its potential therapeutic interventions

The mammalian target of rapamycin (mTOR) is a master regulator of the cell metabolism which impacts numerous signaling involved in cell proliferation and death and recycling cell constituents to readapt to new physiological or pathological environments. mTOR is constituted by two structural and functional different complexes, mTORC1 and mTORC2. Both can be independently regulated, which has a great impact on the effectiveness of therapeutic interventions in different clinical and experimental situations. Furthermore, mTORC1 interacts with specific chaperones or immunophilins which are intracellular receptors of the immunosuppressive drugs. Low and high molecular weights of immunophilins have different intracellular functions. The present review updates the molecular structure and signaling of mTOR as well as their regulation by immunophilins and upstream and downstream signaling events, highlighting the potential therapeutic intervention of mTOR in cancer, metabolic disturbances, and aging.

Virtual docking screening and quantitative structure-activity relationship studies to explore AKT and PI3K inhibitors acting on mTOR in cancers by theoretical biology and medical modeling.

The mechanistic target of rapamycin (mTOR) coordinates the growth and metabolism of eukaryotic cells with a central role in the regulation of many fundamental cellular processes. It is strongly connected to phosphatidylinositol 3-kinase (PI3K) and AKT signaling. Activation of the PI3K/AKT/mTOR pathway leads to a profound disruption in the control of cell growth and survival, which ultimately leads to competitive growth advantage, metastatic competence, angiogenesis and therapeutic resistance. To explore the common competitive adenosine triphosphate (ATP) inhibitors PI3K/AKT and PI3K/mTOR, we built a 2D mTOR-SAR model that predicted the bioactivity of AKT and PI3K inhibitors towards mTOR. The interaction of the best inhibitors was evaluated by docking analysis and compared to that of the standard AZ8055 and XL388 inhibitors. A mechanistic target of rapamycin-quantitative structure-activity relationship (mTOR-QSAR) model with a correlation coefficient (R2) of 0.80813 and a root mean square error of 0.17756 was obtained, validated and evaluated by a cross-validation leave-one-out method. The best predicted AKT and PI3K inhibitor pIC50 activities were 9.36-9.95 and 9.23-9.87 respectively. After docking and several comparisons, the inhibitors with better predictions showed better affinity and interaction with mTOR compared to AZ8055 and XL388, so we have found that 2 AKT inhibitors and 9 mTOR inhibitors met the Lipinski and Veber criteria and could be future drugs.

The roles and mechanisms of circular RNAs related to mTOR in cancers.

Circular RNAs (circRNAs) are stable molecules with covalently closed structures that have an irreplaceable role in the occurrence, progression, and even treatment of plenty of cancers. Mammalian/mechanistic target of rapamycin (mTOR) is a key regulator in cancers and plays several biological functions, such as proliferation, migration, invasion, autophagy, and apoptosis. All data were collected through PubMed and CNKI, using terms including "circRNA," "mTOR," "caner," "signaling pathway," "biomarker," "diagnosis," "treatment." Articles published in Chinese and English were included. In this review, the expression, function, and mechanism of circRNA-associated mTOR in cancers were described. CircRNA-associated-mTOR can regulate the progression and therapy of a variety of cancers in multiple signaling pathways, such as phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt)/mTOR, mitogen-activated protein kinase (MAPK)/mTOR, and AMP-activated protein kinase (AMPK)/mTOR axis. These cancers including esophageal carcinoma (circLPAR3, ciRS-7), gastric cancer (circNRIP1, hsa_circ_0010882, hsa_circ_0000117, hsa_circ_0072309, and circST3GAL6), colorectal cancer (hsa_circ_0000392, hsa_circ_0084927, hsa_circ_0104631, and circFBXW7), liver cancer (circC16orf62, hsa_circ_100338, hsa_circ_0004001, hsa_circ_0004123, hsa_circ_0075792, hsa_circ_0079299, and hsa_circ_0002130), pancreatic cancer (circ-IARS and circRHOBTB3), renal carcinoma (ciRS-7), bladder cancer (circUBE2K), prostate cancer (circMBOAT2 and circ-ITCH), ovarian cancer (circEEF2, circRAB11FIP1, circMYLK, and circTPCN), endometrial cancer (hsa_circ_0002577 and circWHSC1), lung cancer (circHIPK3, hsa_circ_0001666), thyroid cancer (hsa_circ_0007694 and hsa_circ_0008274), glioma (circGFRA1, circ-MAPK4, circPCMTD1, and hsa_circ_0037251), osteosarcoma (circTCF25), leukemia (circ-PRKDC), and breast cancer (hsa_circ_0000199, circUBAP2, and circWHSC1).

Challenges and Emerging Opportunities for Targeting mTOR in Cancer.

The mechanistic target of rapamycin (mTOR) plays a key role in normal and malignant cell growth. However, pharmacologic targeting of mTOR in cancer has shown little clinical benefit, in spite of aberrant hyperactivation of mTOR in most solid tumors. Here, we discuss possible reasons for the reduced clinical efficacy of mTOR inhibition and highlight lessons learned from recent combination clinical trials and approved indications of mTOR inhibitors in cancer. We also discuss how the emerging systems level understanding of mTOR signaling in cancer can be exploited for the clinical development of novel multimodal precision targeted therapies and immunotherapies aimed at achieving tumor remission.

Link between miRNA‐19b and mTOR signaling pathway in cancer prognosis: from meta‐analysis to mechanism exploration

AIMSPrevious studies came to different conclusions regarding the relationship between miR‐19b and its prognostic value in cancers. Moreover, miR‐19b could affect tumor growth by different pathways mainly targeting PTEN‐PI3K‐AKT which activate mTOR pathway in the downstream. Therefore, we conducted this meta‐analysis to explore the possible correlation between miR‐19b and mTOR in cancers prognosis.Main methodsWe conducted online search and collected a total of 943 articles. According to different authors cross check and our study including/excluding criteria we at end retained 21 articles with 25 studies in this meta‐analysis. Then TCGA data containing miR‐19b level with cancer progression were obtained using OncomiR. Furthermore, Trial Sequential Analysis (TSA) was performed to determine whether the results of our meta‐analysis could be used in clinical applications. After that, articles regarding the mechanism of miR‐19b in various cancers were analyzed and KEGG pathway database was used to find the main regulatory function of miR‐19b in human cancers.Key FindingsOverall hazard ratio results displayed that higher expression of miR‐19b was correlated with shorter overall survival (HRs=1.54, 95%CIs=1.20–1.98) by promoting distant metastasis, but had no relation with disease‐free survival/progression‐free survival (HRs=0.61, 95%CIs=0.31–1.19). TCGA datasets also revealed the tumorigenesis role of miR‐19b. According to TSA results, more evidence are needed to support that miR‐19b had no correlation with DFS/PFS. Exploration of the mechanism revealed the possible link between miR‐19b and mTOR pathway.SignificanceMiR‐19b might play its pro‐cancer role through mTOR pathway and it is likely to be a therapeutic target for cancers.Support or Funding InformationThe study was supported by Zhongnan Hospital of Wuhan University Science and Technology, Innovation and Education Fund [Project cxpy2018067] and Zhongnan Hospital of Wuhan University Science and Technology, Innovation and Education Fund [Project ZNPY2017054].

Targeting mTOR and Metabolism in Cancer: Lessons and Innovations.

Cancer cells support their growth and proliferation by reprogramming their metabolism in order to gain access to nutrients. Despite the heterogeneity in genetic mutations that lead to tumorigenesis, a common alteration in tumors occurs in pathways that upregulate nutrient acquisition. A central signaling pathway that controls metabolic processes is the mTOR pathway. The elucidation of the regulation and functions of mTOR can be traced to the discovery of the natural compound, rapamycin. Studies using rapamycin have unraveled the role of mTOR in the control of cell growth and metabolism. By sensing the intracellular nutrient status, mTOR orchestrates metabolic reprogramming by controlling nutrient uptake and flux through various metabolic pathways. The central role of mTOR in metabolic rewiring makes it a promising target for cancer therapy. Numerous clinical trials are ongoing to evaluate the efficacy of mTOR inhibition for cancer treatment. Rapamycin analogs have been approved to treat specific types of cancer. Since rapamycin does not fully inhibit mTOR activity, new compounds have been engineered to inhibit the catalytic activity of mTOR to more potently block its functions. Despite highly promising pre-clinical studies, early clinical trial results of these second generation mTOR inhibitors revealed increased toxicity and modest antitumor activity. The plasticity of metabolic processes and seemingly enormous capacity of malignant cells to salvage nutrients through various mechanisms make cancer therapy extremely challenging. Therefore, identifying metabolic vulnerabilities in different types of tumors would present opportunities for rational therapeutic strategies. Understanding how the different sources of nutrients are metabolized not just by the growing tumor but also by other cells from the microenvironment, in particular, immune cells, will also facilitate the design of more sophisticated and effective therapeutic regimen. In this review, we discuss the functions of mTOR in cancer metabolism that have been illuminated from pre-clinical studies. We then review key findings from clinical trials that target mTOR and the lessons we have learned from both pre-clinical and clinical studies that could provide insights on innovative therapeutic strategies, including immunotherapy to target mTOR signaling and the metabolic network in cancer.

MTOR: Role in cancer, metastasis and drug resistance.

Mammalian target of rapamycin (mTOR) is a serine/threonine kinase that gets inputs from the amino acids, nutrients, growth factor, and environmental cues to regulate varieties of fundamental cellular processes which include protein synthesis, growth, metabolism, aging, regeneration, autophagy, etc. The mTOR is frequently deregulated in human cancer and activating somatic mutations of mTOR were recently identified in several types of human cancer and hence mTOR is therapeutically targeted. mTOR inhibitors were commonly used as immunosuppressors and currently, it is approved for the treatment of human malignancies. This review briefly focuses on the structure and biological functions of mTOR. It extensively discusses the genetic deregulation of mTOR including amplifications and somatic mutations, mTOR-mediated cell growth promoting signaling, therapeutic targeting of mTOR and the mechanisms of resistance, the role of mTOR in precision medicine and other recent advances in further understanding the role of mTOR in cancer.

Mechanistic/mammalian target of rapamycin: Recent pathological aspects and inhibitors.

The mechanistic/mammalian target of rapamycin (mTOR), also known as the mechanistic target of rapamycin, regulates many normal cell processes such as transcription, cell growth, and autophagy. Overstimulation of mTOR by its ligands, amino acids, sugars, and/or growth factors leads to physiological disorders, including cancer and neurodegenerative diseases. In this study, we reviewed the recent advances regarding the mechanism that involves mTOR in cancer, aging, and neurodegenerative diseases. The chemical and biological properties of recently reported small molecules that function as mTOR kinase inhibitors, including adenosine triphosphate-competitive inhibitors and dual mTOR/PI3K inhibitors, have also been reviewed. We focused on the reports published in the literature from 2012 to 2017.

MTORC2 Deficiency in Myeloid Dendritic Cells Enhances Their Allogeneic Th1 and Th17 Stimulatory Ability after TLR4 Ligation In Vitro and In Vivo.

The mammalian/mechanistic target of rapamycin (mTOR) is a key integrative kinase that functions in two independent complexes, mTOR complex (mTORC) 1 and mTORC2. In contrast to the well-defined role of mTORC1 in dendritic cells (DC), little is known about the function of mTORC2. In this study, to our knowledge, we demonstrate for the first time an enhanced ability of mTORC2-deficient myeloid DC to stimulate and polarize allogeneic T cells. We show that activated bone marrow-derived DC from conditional Rictor(-/-) mice exhibit lower coinhibitory B7-H1 molecule expression independently of the stimulus and enhanced IL-6, TNF-α, IL-12p70, and IL-23 production following TLR4 ligation. Accordingly, TLR4-activated Rictor(-/-) DC display augmented allogeneic T cell stimulatory ability, expanding IFN-γ(+) and IL-17(+), but not IL-10(+) or CD4(+)Foxp3(+) regulatory T cells in vitro. A similar DC profile was obtained by stimulating Dectin-1 (C-type lectin family member) on Rictor(-/-) DC. Using novel CD11c-specific Rictor(-/-) mice, we confirm the alloreactive Th1 and Th17 cell-polarizing ability of endogenous mTORC2-deficient DC after TLR4 ligation in vivo. Furthermore, we demonstrate that proinflammatory cytokines produced by Rictor(-/-) DC after LPS stimulation are key in promoting Th1/Th17 responses. These data establish that mTORC2 activity restrains conventional DC proinflammatory capacity and their ability to polarize T cells following TLR and non-TLR stimulation. Our findings provide new insight into the role of mTORC2 in regulating DC function and may have implications for emerging therapeutic strategies that target mTOR in cancer, infectious diseases, and transplantation.

Therapeutic targeting of the mTOR‐signalling pathway in cancer: benefits and limitations

The mammalian target of rapamycin (mTOR) plays an important role in the regulation of protein translation, cell growth and metabolism. The mTOR protein forms two distinct multi-subunit complexes: mTORC1 and mTORC2. The mTORC1 complex is activated by diverse stimuli, such as growth factors, nutrients, energy and stress signals; and essential signalling pathways, such as PI3K and MAPK, in order to control cell growth, proliferation and survival. mTORC1 also activates S6K1 and 4EBP1, which are involved in mRNA translation. The mTORC2 complex is resistant to rapamycin inhibitory activity and is generally insensitive to nutrient- and energy-dependent signals. It activates PKC-α and Akt and regulates the actin cytoskeleton. Deregulation of the mTOR-signalling pathway (PI3K amplification/mutation, PTEN loss of function, Akt overexpression, and S6K1, 4EBP1 and eIF4E overexpression) is common in cancer, and alterations in components of the mTOR pathway have a major role in tumour progression. Therefore, mTOR is an appealing therapeutic target in many tumours. Here we summarize the upstream regulators and downstream effectors of the mTORC1 and mTORC2 pathways, the role of mTOR in cancer, and the potential therapeutic values and issues related to the novel agents targeting the mTOR-signalling pathway.

The mTOR signalling pathway in human cancer.

The conserved serine/threonine kinase mTOR (the mammalian target of rapamycin), a downstream effector of the PI3K/AKT pathway, forms two distinct multiprotein complexes: mTORC1 and mTORC2. mTORC1 is sensitive to rapamycin, activates S6K1 and 4EBP1, which are involved in mRNA translation. It is activated by diverse stimuli, such as growth factors, nutrients, energy and stress signals, and essential signalling pathways, such as PI3K, MAPK and AMPK, in order to control cell growth, proliferation and survival. mTORC2 is considered resistant to rapamycin and is generally insensitive to nutrients and energy signals. It activates PKC-α and AKT and regulates the actin cytoskeleton. Deregulation of multiple elements of the mTOR pathway (PI3K amplification/mutation, PTEN loss of function, AKT overexpression, and S6K1, 4EBP1 and eIF4E overexpression) has been reported in many types of cancers, particularly in melanoma, where alterations in major components of the mTOR pathway were reported to have significant effects on tumour progression. Therefore, mTOR is an appealing therapeutic target and mTOR inhibitors, including the rapamycin analogues deforolimus, everolimus and temsirolimus, are submitted to clinical trials for treating multiple cancers, alone or in combination with inhibitors of other pathways. Importantly, temsirolimus and everolimus were recently approved by the FDA for the treatment of renal cell carcinoma, PNET and giant cell astrocytoma. Small molecules that inhibit mTOR kinase activity and dual PI3K-mTOR inhibitors are also being developed. In this review, we aim to survey relevant research, the molecular mechanisms of signalling, including upstream activation and downstream effectors, and the role of mTOR in cancer, mainly in melanoma.

11C]GSK2126458 and [18F]GSK2126458, the first radiosynthesis of new potential PET agents for imaging of PI3K and mTOR in cancers

GSK2126458 is a highly potent inhibitor of phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) with low picomolar to subnanomolar activity. [11C]GSK2126458 and [18F]GSK2126458, new potential PET agents for imaging of PI3K and mTOR in cancer, were first designed and synthesized in 40–50% and 20–30% decay corrected radiochemical yield, and 370–740 and 37–222GBq/μmol specific activity at end of bombardment (EOB), respectively.

Targeting the Mammalian Target of Rapamycin (mTOR) in Cancer Therapy: Lessons from Past and Future Perspectives

Over the last decade, extensive studies have been made to understand the role played by the mammalian target of rapamycin (mTOR) in cancer. Knowledge in this field has been gained from discoveries in basic research as well as from observations made in patients treated with allosteric mTOR inhibitors such as rapamycin. Despite promising preclinical studies, targeting mTOR in cancer therapy has shown limited clinical benefits so far. However, recent findings have revealed the complexity of the functions of mTOR in cancer and have helped develop new strategies to improve the anticancer efficacy of mTOR inhibitors. In particular, a complex network between mTOR and other signaling pathways has been identified that influences the anticancer efficacy of mTOR inhibitors. In addition, an emerging role of mTOR in the tumor microenvironment has been suggested. In this review, we confront the major findings that have been made in the past, both in experimental settings as well as in clinical trials. We further review the strategies that have been designed to further improve the efficacy of therapies targeting mTOR.

Next-generation mTOR inhibitors in clinical oncology: how pathway complexity informs therapeutic strategy

Mammalian target of rapamycin (mTOR) is a PI3K-related kinase that regulates cell growth, proliferation, and survival via mTOR complex 1 (mTORC1) and mTORC2. The mTOR pathway is often aberrantly activated in cancers. While hypoxia, nutrient deprivation, and DNA damage restrain mTORC1 activity, multiple genetic events constitutively activate mTOR in cancers. Here we provide a brief overview of the signaling pathways up- and downstream of mTORC1 and -2, and discuss the insights into therapeutic anticancer targets - both those that have been tried in the clinic with limited success and those currently under clinical development - that knowledge of these pathways gives us.

Targeting mTOR in cancer: renal cell is just a beginning

The mammalian target of rapamycin (mTOR) is a key regulator of cell growth and proliferation. The mTOR pathway integrates signals from nutrients, energy status and extracellular growth factors to regulate many processes, including cell cycle progression, angiogenesis, ribosome biogenesis, and metabolism. Growth factors such as insulin-like growth factor, epidermal growth factor and vascular endothelial growth factor bind to and activate their corresponding tyrosine kinase receptors (TKR) located on the cell surface, to induce signal transduction to the nucleus. TKR induces intracellular signaling cascades via the phosphorylation of the phosphatidylinositol 3-kinase, which in turn phosphorylates Akt. Of particular interest among the Akt targets is the downstream effect on mTOR, which is responsible for protein synthesis of molecules necessary for nutrient uptake, angiogenesis, ribosome biogenesis, cell growth, and proliferation. Growing evidence suggests that mTOR deregulation is associated with many types of human cancer. The importance of mTOR signaling in tumor biology is now widely accepted. Consequently, a number of agents that selectively target mTOR are being developed for cancer treatment and currently temsirolimus and everolimus are approved for the treatment of advanced renal cell cancer. However, the therapeutic benefit of mTOR inhibitors in the clinic may vary depending on the activation state of the different components of the mTOR pathway in a given case. Therefore it seems clear that predicting sensitivity to rapamycins in different cancers will likely require assessing multiple molecular markers related to mTOR signaling pathway, such as phosphatase and tensin homolog (PTEN), phospho-Akt, cytoplasmic p27, and phospho-S6 kinase.

Abstract 2634: Combination of HSP90 and mTOR inhibition promotes pancreatic cancer growth inhibition

Abstract The molecular determinants of resistance to mTOR targeted therapies remain unspecified. Genomic analysis has demonstrated that a number of gene families promoting intracellular signal transduction are overexpressed in mTOR resistant human pancreas explant xenografts. Heat shock proteins serve as molecular chaperone for many of the proteins implicated in the analysis. As such, it was hypothesized that proximal intracellular signal transduction inhibition with a HSP90 inhibitor could overcome inherent pancreas cancer resistance to mTOR inhibitors. Fourteen human pancreatic cell lines have been analyzed with respect to their proliferative capacity upon exposure to RAD001 (mTOR inhibitor) and AUY922 (HSP90 inhibitor), both as single agents and in combination. In vitro analysis with CalcuSyn® software demonstrates synergistic antiproliferative effects of these two drugs. For example, combination index (CI) values ranging from 0.01 to 0.5 were observed when the mTOR resistant cell line PANC02.03 was treated with the combination of RAD001 and AUY922. In vivo treatment of the L3.6 xenograft model with AUY922 and RAD001 resulted in preferential tumor growth inhibition of the combination relative to either drug alone. These effects were associated with the inhibition of the pI3K/AKT/mTOR and the ERK pathways. In summary, proximal signal transduction inhibition by a HSP90 may overcome inherent pancreas cancer mTOR inhibitor resistance. Future work is designed to extend these finding and to determine the specific pathways that are necessary for the observed growth inhibition. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2634.

The mTOR Signaling Network: Insights from Its Role During Embryonic Development

Target of Rapamycin (TOR) signaling, originally discovered as the pathway affected by an antifungal macrolide, exemplifies the potential of medicinal chemistry as a discovery tool. Three decades from its identification, signaling involving the TOR kinase has evolved into a complex network with a crucial role in vertebrate growth control. Specifically, it integrates signals to coordinate cell growth (i.e., enhanced mass and size) and cell cycle progression with sufficiency of nutrients, energy, and growth factors. In this review, we discuss multiple aspects of TOR signaling, including cellular regulators and mediators, human diseases related to TOR dysregulation such as cancer, and signaling nodes in the pathway amenable to targeted drug inhibition. The functions and mechanisms of TOR during embryonic development highlight the dynamic role of TOR signaling and reveal additional functions beyond cell growth control. Embryonic TOR signaling has differential tissue-specific and temporal effects, and is involved in organogenesis, sexual differentiation, and epithelial-to-mesenchymal transition signaling. Molecular mechanisms that may contribute to embryonic-specific TOR functions are also examined here. Finally, this review discusses the complex signaling of mTOR in cancer and the development of mTOR inhibitors for cancer therapy.

Mammalian target of rapamycin (mTOR) pathway signalling in lymphomas

The mammalian target of rapamycin mTOR is a central element in an evolutionary conserved signalling pathway that regulates cell growth, survival and proliferation, orchestrating signals originating from growth factors, nutrients or particular stress stimuli. Two important modulators of mTOR activity are the AKT and ERK/MAPK signalling pathways. Many studies have shown that mTOR plays an important role in the biology of malignant cells, including deregulation of the cell cycle, inactivation of apoptotic machinery and resistance to chemotherapeutic agents. The development of several mTOR inhibitors, in addition to rapamycin, has facilitated studies of the role of mTOR in cancer, and verified the antitumour effect of mTOR inhibition in many types of neoplasms, including lymphomas. Clinical trials of rapamycin derivatives in lymphoma patients are already in development and there are encouraging preliminary results, such as the substantial response of a subset of mantle cell lymphoma patients to the rapamycin analogue temsirolimus. Based on results obtained from in vitro and in vivo studies of the mTOR pathway in lymphomas, it seems that better understanding of mTOR regulation will reveal aspects of lymphomagenesis and contribute to the development of more powerful, targeted therapies for lymphoma patients.

MTOR signaling in human cancer

Inhibitors of mTOR, the mammalian target of rapamycin, have been extensively studied in clinical trials for cancer treatment. Results have been promising, mostly in certain lymphomas, but in solid tumours the results have been generally less encouraging. However, recent results, particularly in renal cell carcinoma, have provided renewed interest in the role of mTOR inhibitors in solid tumours. A rational, and potentially more successful, development of these agents (i.e., RAD001, temsirolimus and AP23573) likely relies in a deeper knowledge of mTOR signalling in cancer, both at the preclinical and clinical levels. These would allow a better selection of patients more likely to respond to the use of biologically active doses of the agents and the development of mechanistically based combinations with other agents. The goal of this review is to provide an update on the complex signalling of mTOR in cancer and on the biological effects of mTOR inhibitors in cancer cells.

MTOR and cancer therapy

Proteins regulating the mammalian target of rapamycin (mTOR), as well as some of the targets of the mTOR kinase, are overexpressed or mutated in cancer. Rapamycin, the naturally occurring inhibitor of mTOR, along with a number of recently developed rapamycin analogs (rapalogs) consisting of synthetically derived compounds containing minor chemical modifications to the parent structure, inhibit the growth of cell lines derived from multiple tumor types in vitro, and tumor models in vivo. Results from clinical trials indicate that the rapalogs may be useful for the treatment of subsets of certain types of cancer. The sporadic responses from the initial clinical trials, based on the hypothesis of general translation inhibition of cancer cells are now beginning to be understood owing to a more complete understanding of the dynamics of mTOR regulation and the function of mTOR in the tumor microenvironment. This review will summarize the preclinical and clinical data and recent discoveries of the function of mTOR in cancer and growth regulation.