Biochemical correlates of mTOR inhibition by the rapamycin ester CCI-779 and tumor growth inhibition (original) (raw)
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The role of mTOR in the management of solid tumors: An overview
Cancer Treatment Reviews, 2009
Mammalian target of rapamycin (mTOR) is a key protein kinase controlling signal transduction from various growth factors and upstream proteins to the level of mRNA and ribosome with a regulatory effect on cell cycle progression, cellular proliferation and growth. TOR genes were discovered rather serendipitously while investigating the cause of resistance to immunosuppressant rapamycin in yeast. In normal cells, mTOR controls brilliantly the load of signals from its effectors resulting in a normal cell function. On the contrary, in various diseases and mainly in cancer this balance is lost due to mutations or overactivation of upstream pathways leading to a persistent proliferation and tumor growth. What makes mTOR attractive to researchers seems to be its key position which is on the crossroad of various signal pathways (Ras, PI3K/Akt, TSC, NF-κB) towards mRNA, ribosome, protein synthesis and translation of significant molecules, the uncontrolled production of which may lead to tumor proliferation and growth. Inhibition of mTOR by rapamycin (a natural product) or its analogs aims to prevent the deleterious effects of the abnormal signaling, regardless at which point of the signal pathway has the abnormality launched. Here, we will review the physiological functions of mTOR, its association to carcinogenesis and the latest evidence regarding the use of mTOR inhibitors in cancer treatment as well as future trends and aims of research.
THE BIOLOGICAL ROLE OF mTOR IN THE PATHOGENESIS AND MANAGEMENT OF SOLID TUMORS: AN OVERVIEW
The mammalian target of rapamycin (mTOR) constitutes an integrator of multiple signals and a master programmer of pivotal cellular functions such as cell growth and proliferation. Due to its complex function, it plays a substantial role in homeostasis at molecular, cellular, tissue and organism level and its aberrant activation is implicated in tumorigenesis and tumor progression. mTOR signaling depends on a number of upstream regulators such as PI3K and Akt, and a number of downstream effectors such as p70 S6 kinase 1 (S6K1) and 4E-BP1. The mTOR pathway seems to be a promising pathway in anticancer treatment and mTOR inhibitors constitute a currently emerging and evaluated class of antitumor agents. Nonetheless, the complexity and multifactorial regulation of this signal transduction pathway make it difficult to determine pivotal parameters such as the optimal therapeutic schedules and the appropriate criteria for the selection of patients most likely to respond, which will enable medical oncologists to proceed to the appropriate use of these agents in clinical setting. The complete dissection of both mTOR signaling and the adjacent pathways will enable experts to develop and implement multi-targeted treatment, which appears to be the most promising approach, due to the persistent and dynamic interaction between different signaling pathways. Under such circumstances, we will be capable of exploiting mTOR signaling and maximizing the benefit of patients. In the present review, we are discussing the regulation of the mTOR signaling, pointing out its implication in the pathogenesis of solid tumors as well as its encouraging therapeutic potential.
Targeting Tumorigenesis: Development and Use of MTOR Inhibitors In Cancer Therapy
J Hematol Oncol, 2009
The mammalian target of rapamycin (mTOR) is an intracellular serine/threonine protein kinase positioned at a central point in a variety of cellular signaling cascades. The established involvement of mTOR activity in the cellular processes that contribute to the development and progression of cancer has identified mTOR as a major link in tumorigenesis. Consequently, inhibitors of mTOR, including temsirolimus, everolimus, and ridaforolimus (formerly deforolimus) have been developed and assessed for their safety and efficacy in patients with cancer. Temsirolimus is an intravenously administered agent approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) for the treatment of advanced renal cell carcinoma (RCC). Everolimus is an oral agent that has recently obtained US FDA and EMEA approval for the treatment of advanced RCC after failure of treatment with sunitinib or sorafenib. Ridaforolimus is not yet approved for any indication. The use of mTOR inhibitors, either alone or in combination with other anticancer agents, has the potential to provide anticancer activity in numerous tumor types. Cancer types in which these agents are under evaluation include neuroendocrine tumors, breast cancer, leukemia, lymphoma, hepatocellular carcinoma, gastric cancer, pancreatic cancer, sarcoma, endometrial cancer, and non-small-cell lung cancer. The results of ongoing clinical trials with mTOR inhibitors, as single agents and in combination regimens, will better define their activity in cancer.
Inhibition of mTOR suppresses experimental liver tumours
Anticancer Research, 2005
Sirolimus, and its antiproliferative capacity, was studied in vivo in three different syngenic rat tumours in the liver. Sirolimus is an inhibitor of the cytosolic mTOR-kinase, associated with the phosphoinositide-3-kinase/Akt pathway. After one week of daily sirolimus treatment, initiated on the day of tumour-cell inoculation, a dose-response relationship was shown at doses between 0.01 mg/kg/day and 1 mg/kg/day, decreasing tumour weight from 0.5±0.1g in control rats (n=9) to 0.09±0.04g for sirolimus 1 mg/kg (n=9). Treating established liver adenocarcinoma (n=15), sirolimus halved the tumour weight (1.4±0.2g vs 0.7±01g, p=0.005). Trough concentration in blood was 6.4±0.2 ng/ml after five days of daily treatment with 1 mg/kg sirolimus intraperitoneally. At this dose, there was no decrease in food consumption or rat weight, but decrease in weight of spleen, and increase in weight of liver (p<0.01). The three tumours studied, an nitrosoguanidin-induced adenocarcinoma, a Leydic cell sarcoma and a hepatoma, all responded, establishing sirolimus as a promising anticancer drug.
The Therapeutic Potential of mTOR Inhibitors in Breast Cancer
British journal of clinical pharmacology, 2016
Rapamycin and modified rapamycins (rapalogs) have been used to prevent allograft rejection after organ transplant for over 15 years. The mechanistic target of rapamycin (mTOR) has been determined to be a key component of the mTORC1 complex which consists of the serine/threonine kinase TOR and at least five other proteins which are involved in regulating its activity. Some of the best characterized substrates of mTORC1 are proteins which are key kinases involved in the regulation of cell growth (e.g., p70S6K) and protein translation (e.g., 4E-BP1). These proteins may in some cases serve as indicators to sensitivity to rapamycin-related therapies. Dysregulation of mTORC1 activity frequently occurs due to mutations at or amplifications of upstream growth factor receptors (e.g., human epidermal growth factor receptor-2, HER2) as well as kinases (e.g., PI3K) and phosphatases (e.g., PTEN) critical in the regulation of cell growth. More recently, it has been shown that certain rapalogs may...
Escaping mTOR inhibition for cancer therapy: Tumor suppressor functions of mTOR
Molecular & Cellular Oncology, 2017
A master promoter of cell growth, mammalian target of rapamycin (mTOR) is upregulated in a large percentage of cancer cells. Still, targeting mTOR using rapamycin has a limited outcome in patients. Our recent results highlight the additional role of mTOR as a tumor suppressor, explaining these modest results in the clinic.
Oncotarget, 2020
The mechanistic target of rapamycin (mTOR) is a PI3K-related kinase that regulates cell growth, proliferation and survival in response to the availability of energy sources and growth factors. Cancer development and progression is often associated with constitutive activation of the mTOR pathway, thus justifying mTOR inhibition as a promising approach to cancer treatment and prevention. However, development of previous rapamycin analogues has been complicated by their induction of adverse side effects and variable efficacy. Since mTOR pathway regulation involves multiple feedback mechanisms that may be differentially activated depending on the degree of mTOR inhibition, we investigated whether rapamycin dosing could be adjusted to achieve chemopreventive efficacy without side effects. Thus, we tested the efficacy of two doses of a novel, highly bioavailable nanoformulation of rapamycin, Rapatar, in a mouse prostate cancer model (male mice with prostate epitheliumspecific Pten-knockout). We found that the highest efficacy was achieved by the lowest dose of Rapatar used in the study. While both doses tested were equally effective in suppressing proliferation of prostate epithelial cells, higher dose resulted in activation of feedback circuits that reduced the drug's tumor preventive efficacy. These results demonstrate that low doses of highly bioavailable mTOR inhibitor, Rapatar, may provide safe and effective cancer prevention.