INHIBITING mTOR IN CANCER THERAPY

by Selleckchem | Aug 14 2012

SIGNALLING VIA mTOR:
mTOR is serine/threonine kinase protein and stands for “mammalian target of Rapamycin”. It also known as FRAP1 i.e., FK506-binding protein 12 - rapamycin associated protein-1. It as encoded by a gene known as FRAP1.mTOR is known to be involved in controlling various cellular processes for example; cell growth, survival, proliferation, transcriptional regulation and migration of proteins. mTOR regulatory proteins function in these processes by responding to the energy and nutrient status of the cell. As mTOR is involved in lots of cellular processes regarding its growth proliferation and survival, it can provide a target in cancer therapy; therefore, mTORc1 inhibitors have been designed that can control the cancer progression and development by inhibiting the functions mTOR performs [1]. Inhibiting mTOR signaling pathway thus controls the tumor growth and limits tumorigenesis [2].

MECHANISM OF ACTION:
Different molecules are designed and practiced in order to look for effective mTOR inhibition. Relevant doses are adjusted for the inhibitor at clinical level [3]. mTOR agonists or antagonists are used for understanding mTOR pathway and devising strategy for it inhibition. Various mTOR assays e.g., homogenous flourogenic assays are there that are used for assessing the expression and activity level of target molecule in different systems. Kits can also be used for the sake of convenience and increased sensitivity for mTOR activity assay. Rapamycin; a protein kinase inhibitor, also used for naming this complex system of enzymes is an example of such mTOR inhibitors [4]. Doctors or researchers can buy these mTOR inhibitors for the purpose of preclinical assessments of the drugs. CCI-779 when used against human models of pancreatic xenografts and breast cancer gave a strong inhibition [5-6]. RAD001 was observed to inhibit p21 for inhibition of mTOR pathway and results in apoptosis of the cell [7]. Ku-0063794 is a recently studied mTOR inhibitor [8].

CLINICAL TRIALS OF mTOR INHIBITORS:
mTOR inhibitors have been used against many different types of cancers in order to assesss the activity in preclinical trials which further encouraged its clinical trials [9]. RAD001 or Everolimus when used in clinical trial phase I in patients of breast carcinoma in advanced stage gave promising especially when used in combination with Letrozole [10]. The drug was also found to be effective singly when used for treating RCC i.e., renal cell carcinoma in clinical trials phase II [11]. Another drug i.e., CCI-779 or Temsirolimus gave efficient results when used against locally advanced or metastatic breast cancer [12]. Some recently discovered FRAP1 inhibitor include WAY-600, WYE-687 and WYE-354 which are pyrazolopyrimidine i.e., an ATP competitor. Some clinical and preclinical studies regarding these inhibitors are yet to be completed [13]. Combinatorial therapy can also be applied on these inhibitors for example NVP-BEZ235 [14] with other mTOR inhibiting drugs or some other inhibitors. That gave quite efficient synergistic results. Use of RTK inhibitor with Rapamycin is one of the examples of such anti cancer therapy in prostate cancer [15].

REFERNCES:
1. Guertin DA, S.D., The pharmacology of mTOR inhibition. Science Signaling, 2009.
2. Carraway H, H.M., Mammalian target of rapamycin (mTOR) antagonists. Breast Cancer Res, 2004.
3. Yip CK, e.a., Structure of the Human mTOR Complex I and Its Implications for Rapamycin Inhibition. Molecular Cell, 2010.
4. Huang S, e.a., Rapamycins: mechanism of action and cellular resistance. Cancer Biol Ther, 2003.
5. Ito D, e.a., In vivo antitumor effect of the mTOR inhibitor CCI-779 and gemcitabine in xenograft models of human pancreatic cancer. International Journal of Cancer, 2006.
6. Yu K, e.a., mTOR, a novel target in breast cancer: the effect of CCI-779, an mTOR inhibitor, in preclinical models of breast cancer. Endocr Relat Cancer, 2001.
7. Beuvink I, e.a., The mTOR Inhibitor RAD001 Sensitizes Tumor Cells to DNA-Damaged Induced Apoptosis through Inhibition of p21 Translation. Cell, 2005.
8. Martínez JM, e.a., Ku-0063794 is a specific inhibitor of the mammalian target of rapamycin (mTOR). Biochem J., 2009.
9. Huang S, H.P., Targeting mTOR signaling for cancer therapy. Current Opinion in Pharmacology, 2003.
10. Awada A, e.a., The oral mTOR inhibitor RAD001 (everolimus) in combination with letrozole in patients with advanced breast cancer: Results of a phase I study with pharmacokinetics. European Journal of Cancer, 2008.
11. Amato RJ, e.a., A phase 2 study with a daily regimen of the oral mTOR inhibitor RAD001 (everolimus) in patients with metastatic clear cell renal cell cancer. Cancer, 2009.
12. Chan S, e.a., Phase II Study of Temsirolimus (CCI-779), a Novel Inhibitor of mTOR, in Heavily Pretreated Patients With Locally Advanced or Metastatic Breast Cancer Journal of Clinical Oncology, 2005.
13. Yu K, e.a., Biochemical, Cellular, and In vivo Activity of Novel ATP-Competitive and Selective Inhibitors of the Mammalian Target of Rapamycin Cancer Res, 2009.
14. Serra V, e.a., NVP-BEZ235, a Dual PI3K/mTOR Inhibitor, Prevents PI3K Signaling and Inhibits the Growth of Cancer Cells with Activating PI3K Mutations Cancer RS, 2008.
15. Masiello D, e.a., Combining an mTOR Antagonist and Receptor Tyrosine Kinase Inhibitors for the Treatment of Prostate Cancer. Cancer Bio and Ther, 2007.

Cat.No.	Product Name	Information
S1120	Everolimus	Everolimus is an mTOR inhibitor of FKBP12 with IC50 of 1.6-2.4 nM in a cell-free assay. Everolimus induces cell apoptosis and autophagy and inhibits tumor cells proliferation.
S1226	KU-0063794	KU-0063794 is a potent and highly specific dual-mTOR inhibitor of mTORC1 and mTORC2 with IC50 of ~10 nM in cell-free assays; no effect on PI3Ks.
S1044	Temsirolimus	Temsirolimus is a specific mTOR inhibitor with IC50 of 1.76 μM in a cell-free assay. Temsirolimus induces autophagy and apoptosis.
S1009	Dactolisib (BEZ235)	Dactolisib (BEZ235, NVP-BEZ235) is a dual ATP-competitive PI3K and mTOR inhibitor for p110α/γ/δ/β and mTOR(p70S6K) with IC50 of 4 nM /5 nM /7 nM /75 nM /6 nM in cell-free assays, respectively. Inhibits ATR with IC50 of 21 nM in 3T3^TopBP1-ER cell. Dactolisib induces autophagy and suppresses HIV-1 replication. Phase 2.