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 2^nd generation analogue Sirolimus. Temsirolimus is a 3^rd 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

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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.

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