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TEMSIROLIMUS

Introduction: mTOR inhibitiors

The mTOR kinase is part of the same pathway as AKT and PI3K, this signaling pathway is a tyrosine kinase sub family of the super protein kinase family. The PI3K/AKT/mTOR signaling cascade is involved in a variety of cellular functions such as migration, growth, protein synthesis, survival and proliferation.[1] PI3K and AKT inhibitors have all been reported as having significant potential as treatments against disorders involving cell growth [2], mTOR is part of the same pathway and theoretically would make a potential target for inhibition. It has also been reported that mutations in the mTOr signaling have been implicated in cardiovascular disease, cancer and disorders of the metabolism.[1] Rapamycin was the first mTOR inhibitor to be released but was quickly followed by a 2nd generation analogue Sirolimus. Temsirolimus is a 3rd generation molecule designed to be an improvement over rapamycin and Sirolimus. Temsirolimus has demonstrated potential in the treatment of renal carcinomas [3], NSCLC [4] and malignant glioma [5].

Temsirolimus: Properties and Availability

In recent years many the structure of rapamycin has been derivatized into many series of molecules which have been screened for similar activity. Out of this screening came Everolimus and now Temsirolimus. Like Rapamycin the Temsirolimus structure is cyclic in nature and consisting of a series of diene and trione segments, a side chain substitution gives this molecules its biological activity. Since the structure of Temsirolimus is so similar to rapamycin and Everolimus so too is its physical properties, Temsirolimus solubility in DMSO and ethanol can be achieved up to a maximum of 200 mg/ml but in water Temsirolimus is basically insoluble above 10-15 µM concentrations. Temsirolimus stability is fairly good, it is stable at -20°C for the standard 2 years in its powdered form, while no mention is made of instability in solution it is recommended that this chemical is stored as aliquots at -20°C to minimize freeze/thawing. Temsirolimus cost for a 25 mg vial can range from a Temsirolumus price of $146 up to $1359 depending on the Temsirolimus supplier. Researchers can buy Temsirolimus in a variety of purities that often do not match the price charged.

Temsirolimus: Preclinical and clinical Investigations

The Temsirolimus mechanism has been determined to be inhibition via the mTOR pathway leading to the reduction of VEGF levels and in HIF-1a levels in tumor cells. HIF-1a is a regulatory protein that is not degraded in renal cancer causing unrestrained tumor growth. MTOR up regulation increases the negative effects seen with HIF-1a hence inhibition of mTOR aids in the regulation of this protein [6-9]. In addition to renal cancer Temsirolimus has been investigated with regard to small cell lung cancer [10-12], hepatocellular carcinoma[13] and refractory multiple myeloma[14]. In xenograph models Temsirolimus demonstrated activity against malignant glioma [15] while in prostate cells Temsirolimus demonstrated ability to reverse resistance to standard therapy (doxorubicin) [16;17]. In breast cancer Temsirolimus demonstrate modest abilities in tumors with loss of PTEN function but was limited in other xenographs [18].

Temsirolimus: Clinical status

In 2007 after fast track investigations Temsirolimus was approved for the treatment of renal cell carcinoma. Further Temsirolimus clinical trials at the phase 1 and phase 2 level have been reported in various other diseases with differing degrees of success. In pediatric high-grade glioma Temsirolimus as a single agent did not meet study criteria but did achieve a degree of stable disease. It was not considered effective but warranted further consideration in combination with other therapeutic agents.[19] In combination with Sorafenib in metastatic melanoma significant toxicity was reported with no beneficial response for the patient [20]. In acute myeloid leukemia a response rate of 75% was seen among older patients suggesting this form of treatment in this disease is clinically effective [21] Only modest effect was seen in ovarian cancer [22], but in advance solid tumor patients combinations with carboplatin / paclitaxel  showed a 46% partial response and 49% stable disease [23]. Phase 1 and 2 trial reports are being published in 2012 and Temsirolimus’s role in clinical treatment of disease will be define more completely in the near future.

References

   1.   Dowling RJ, Topisirovic I et al. Dissecting the role of mTOR: lessons from mTOR inhibitors. Biochim Biophys Acta 2010; 1804(3):433-439.

   2.   Dos SC, Recher C et al. [The PI3K/Akt/mTOR pathway: a new therapeutic target in the treatment of acute myeloid leukemia]. Bull Cancer 2006; 93(5):445-447.

   3.   Mackenzie MJ, Rini BI et al. Temsirolimus in VEGF-refractory metastatic renal cell carcinoma. Ann Oncol 2011; 22(1):145-148.

   4.   Wu C, Wangpaichitr M et al. Overcoming cisplatin resistance by mTOR inhibitor in lung cancer. Mol Cancer 2005; 4(1):25.

   5.   Stupp R, Hegi ME et al. Chemoradiotherapy in malignant glioma: standard of care and future directions. J Clin Oncol 2007; 25(26):4127-4136.

   6.   Elit L. CCI-779 Wyeth. Curr Opin Investig Drugs 2002; 3(8):1249-1253.

   7.   Temsirolimus: CCI 779, CCI-779, cell cycle inhibitor-779. Drugs R D 2004; 5(6):363-367.

   8.   Eto M, Naito S. Molecular targeting therapy for renal cell carcinoma. Int J Clin Oncol 2006; 11(3):209-213.

   9.   Feldman DR, Motzer RJ. Novel targets and therapies for metastatic renal cell carcinoma. Oncology (Williston Park) 2006; 20(14):1745-1753.

10.   Sher T, Dy GK et al. Small cell lung cancer. Mayo Clin Proc 2008; 83(3):355-367.

11.   Shor B, Zhang WG et al. A new pharmacologic action of CCI-779 involves FKBP12-independent inhibition of mTOR kinase activity and profound repression of global protein synthesis. Cancer Res 2008; 68(8):2934-2943.

12.   Wangpaichitr M, Wu C et al. Inhibition of mTOR restores cisplatin sensitivity through down-regulation of growth and anti-apoptotic proteins. Eur J Pharmacol 2008; 591(1-3):124-127.

13.   Piguet AC, Semela D et al. Inhibition of mTOR in combination with doxorubicin in an experimental model of hepatocellular carcinoma. J Hepatol 2008; 49(1):78-87.

14.   Farag SS, Zhang S et al. Phase II trial of temsirolimus in patients with relapsed or refractory multiple myeloma. Leuk Res 2009; 33(11):1475-1480.

15.   Geoerger B, Kerr K et al. Antitumor activity of the rapamycin analog CCI-779 in human primitive neuroectodermal tumor/medulloblastoma models as single agent and in combination chemotherapy. Cancer Res 2001; 61(4):1527-1532.

16.   Grunwald V, DeGraffenried L et al. Inhibitors of mTOR reverse doxorubicin resistance conferred by PTEN status in prostate cancer cells. Cancer Res 2002; 62(21):6141-6145.

17.   Wu L, Birle DC et al. Effects of the mammalian target of rapamycin inhibitor CCI-779 used alone or with chemotherapy on human prostate cancer cells and xenografts. Cancer Res 2005; 65(7):2825-2831.

18.   Yu K, Toral-Barza L et al. 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; 8(3):249-258.

19.   Geoerger B, Kieran MW et al. Phase II trial of temsirolimus in children with high-grade glioma, neuroblastoma and rhabdomyosarcoma. Eur J Cancer 2012; 48(2):253-262.

20.   Davies MA, Fox PS et al. Phase I study of the combination of sorafenib and temsirolimus in patients with metastatic melanoma. Clin Cancer Res 2012.

21.   Amadori S, Stasi R et al. Temsirolimus, an mTOR inhibitor, in combination with lower-dose clofarabine as salvage therapy for older patients with acute myeloid leukaemia: results of a phase II GIMEMA study (AML-1107). Br J Haematol 2012; 156(2):205-212.

22.   Behbakht K, Sill MW et al. Phase II trial of the mTOR inhibitor, temsirolimus and evaluation of circulating tumor cells and tumor biomarkers in persistent and recurrent epithelial ovarian and primary peritoneal malignancies: a Gynecologic Oncology Group study. Gynecol Oncol 2011; 123(1):19-26.

23.   Kollmannsberger C, Hirte H et al. Temsirolimus in combination with carboplatin and paclitaxel in patients with advanced solid tumors: a NCIC-CTG, phase I, open-label dose-escalation study (IND 179). Ann Oncol 2012; 23(1):238-244.