Mammalian target of rapamycin inhibitors

Del Bufalo D, Ciuffreda L, TriscinogUo D, Desideri M, Cognetti F, Zupi G Milella M. (2006) Antiangiogenic potential of the mammalian target of rapamycin inhibitor temsirohmus. Cancer Res 66 5549-5554. 

Mita MM, Mita AC, Chu QS, Rowinsky EK, Eetterly GJ, Goldston M, Patnaik A, Mathews L, Ricart AD, Mays T, Knowles H, Rivera VM, Kreisberg J, Bedrosian CL, Tolcher AW. (2008) Phase Itrial of the novel mammalian target of rapamycin inhibitor deforolimus (AP23573 MK-8669)... 

Pantuck AJ, Thomas G, Belldegrun AS, Figlin RA. Mammalian target of rapamycin inhibitors in renal cell carcinoma current status and future applications. Semin Oncol. 2006 33 607. 

Monoclonal and polyclonal antibodies directed at reactive T cells are important adjunct therapies and provide a unique opportunity to target specifically immune-reactive cells. Finally, newer small molecules and antibodies have expanded the arsenal of immunosuppressives. In particular, mTOR (mammalian target of rapamycin) inhibitors (sirolimus, everolimus) and anti-CD25 (interleukin [IL]-2 receptor) antibodies (basiliximab, daclizumab) target growth factor pathways, substantially limiting clonal expansion and potentially promoting tolerance. 

Shi Y, Yan H, Frost P, Gera J, Lichtenstein A. Mammalian target of rapamycin inhibitors activate the AKT kinase in multiple myeloma cells by up-regulating the insulin-like growth factor receptor/insulin receptor substrate 1/phosphatidyl-inositol 3-kinase cascade. Mol Cancer Ther 2005 4 1533-1540... 

Temsirolimus is an mTOR (mammalian target of rapamycin) inhibitor. mTOR has multiple downstream targets, including cell translational machinery. Temsirolimus demonstrated clinical efficacy with significantly increased survival of renal cancer patients. In a clinical trial, 626 patients were randomized to one of three arms interferon alfa (IFN) alone ( = 207) temsirolimus 25 mg alone n = 209) or the combination of temsirolimus 15 mg and IFN ( = 210 Hudes et al. 2007). Temsirolimus was associated with a statistically significant improvement in overall survival when compared with IFN. The median OS was 10.9 months on the temsirolimus arm and 7.3 months on the IFN arm. Progression-free survival was 5.5 months on the temsirolimus arm and 3.1 months on the IFN arm. The combination of temsirolimus 15 mg and IFN did not increase survival over temsirolimus alone but was associated with increased toxicity. 

Balagula Y, Rosen A, Tan BH, Busam KJ, Pulitzer MP, Motzer RJ, et al. Clinical and histopathologic characteristics of rash in cancer patients treated with mammalian target of rapamycin inhibitors. Cancer October 15,2012 118(20) 5078-83. PubMed PMID 22437824. Epub 2012/03/23. eng. 

Gomez-Fernandez C, Garden BC, Wu S, Feldman DR, Lacouture ME. The risk of skin rash and stomatitis with the mammalian target of rapamycin inhibitor temsirolimus a systematic review of the literature and meta-analysis. Eur J Cancer February 2012 48(3) 340-6. PubMed PMID 22206873. Epub 2011/12/31. eng. 

Rapamycin is an immunosuppressive diug and an inhibitor of S6K1 (also known as p70S6-kinase) which phosphorylates ribosomal S6 protein. S6K1 is activated in response to insulin via activation of Akt. Rapamycin binds to a specific target protein (mTOR, mammalian target of rapamycin) which is functionally located downstream of Akt, but upstream... 

Figure 7.1 Major signaling pathways relevant to this chapter. Simplified schematic diagram of the major signaling pathways which impinge on mRNA translation I. The phosphatidylinositide 3-kinase (PI 3-kinase) pathway II/III. MAP kinases, especially the classical MAP kinase (ERK) pathway and the p38 MAP kinase pathway IV. The mammalian target of rapamycin (mTOR) pathway. Strictly, this diagram shows the rapamycin-sensitive events linked to mTORCl. Selected inhibitors and their sites of action are shown. A numberof components and cross-connections have been omitted for clarity.

Brunn, G.J., Williams, J., Sabers, C., Weiderrecht, G., Lawrence, J. C., and Abraham, R. T. (1996). Direct inhibition of the signaling functions of the mammalian target of rapamycin by the phosphoinositide 3-kinase inhibitors, wortmannin and LY294002. EMBOJ. 15, 5256-5267. 

Everolimus (40 Afinitor Novartis, 2009), a rapamycin analog, is the 42-0-(2-hydroxyethyl) derivative of sirolimus (34), and is marketed as an immunosuppressant by Novartis under the tradename Afinitor for use in advanced renal cell carcinoma.In March 2009, the FDA approved everolimus (40) for use against advanced renal cell carcinoma after failure of treatment with sunitinib or sorafenib. The drug works similarly to sirolimus as an inhibitor of mTOR (mammalian target of rapamycin), a serine-threonine kinase, downstream of the PI3K/AKT pathway. Everolimus (40) binds to an intracellular protein, EKBP-12, resulting in an inhibitory... 

Another approach to the management of IM resistance is to combine agents that are individually active against CML but have differing mechanisms of action that may allow either additive or synergistic effects in a non-cross-resistant marmer. This approach has been extensively studied in the literature and will not be reviewed in detail here. An excellent discussion of combination therapy is foimd in the reviews by Hochhaus and La Rosee (52,85). Some combination approaches have utilized famesyl transferase inhibition such as lonafamib in combination with IM, inhibitors of the mammalian target of rapamycin (mTOR) in combination with IM and combining mycophenolic acid, an inhibitor of the JAK-STAT pathway. 

Other options being pursued include the use of temsi-rolimus (CCI-779), a selective inhibitor of the mammalian target of rapamycin. Partial responses were noted in 7% of patients, and minor responses in 26%. The median survival rate was 15 months. The notable activity of the drug in patients with poor prognostic features prompted a phase 3 trial.43, 442... 

Cyclosporine A (CSA), sirolimus, and tacrolimus are commonly used immunosuppressive drugs. Cyclosporine and tacrolimus are calcineurin inhibitors, whereas sirolimus is a mammalian target of rapamycin (mTOR) inhibitor. Calcineurin inhibitors bind to immunophilins, and drug-immunophilin complexes inhibit calcineurin activity, which in turn prevents nuclear translocation of the nuclear factor of activated T cells (NFAT) (1,2). This results in inhibition of activation and proliferation of CD4 and CDS lymphocytes by inhibiting IL-2 production. The mTOR protein is a... 

In a retrospective study, 46 metastatic RCC patients treated with mammalian target of rapamycin (mTOR) inhibitors (21 treated with temsirolimus and 25 with everolimus), computed tomographic (CT) evidence of pneumonitis... 

Sirolimus (rapamycin) (Vezina et al. 1975) is widely used to prevent rejection in organ transplant. It is especially usefiil in kidney transplants because, different from cyclosporine and tacrolimus, it is not a calcineurin inhibitor and therefore is less toxic to the kidney. Sirolimus inhibits T-cell and B-cell activation. It binds to the immunophilin FKproteinl2, and this binary complex inactivates a serine-threonine kinase (mTOR) termed the mammalian target of rapamycin (Huang et al. 2003). The final effect is the arrest at phase G1 of cell cycle progression. This effect occurs not only in T cell and B cells, but it has been observed in many tumor cell lines. Semisynthetic derivatives of rapamycin, suitable for i.v. administration, have been developed as antitumor agents. Temsirolimus was approved by FDA in 2007 for advanced kidney cancer treatment (Hudes 2009). Everolimus was also approved for kidney cancer treatment in 2009 and for organ rejection prophylaxis in 2010. At present, phase III clinical trials are under way in a variety of tumors (Dansey 2006). 

Sirohmus is a macrocychc lactone produced by the bacteria Streptomyces hygroscopious. Like the calcineurin inhibitors cyclosporine and tacrolimus its mechanism of action involves formation of a complex with an immunophiUn, in this case, FKBP-12. Unlike cyclosporine and tacrolimus, sirohmus does not affect calcineurin activity but binds to and inhibits the mammalian kinase, target of rapamycin (mTOR.). mTOR is a key enzyme in cell-cycle progression. When inhibited this kinase blocks cell cycle progression at the G1 to S phase transition (Dumont and Su, 1996 Sehgal, 2003). 

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