Temsirolimus: a long-lived antineoplastic drug


Temsirolimus was developed by Hara Wyeth Pharmaceuticals and was approved for listing by FDA in May 2007 for the treatment of renal cell carcinoma. The drug is the first antineoplastic drug to act on mTOR. Renal cell carcinoma is a common form of cancer, accounting for about 2% of all cancers, and the 5-year survival rate for advanced renal cell carcinoma is only 5-10%.

The discovery of temsirolimus

mTOR protein, the target of temsirolimus, is a very important protein, which is the center of mammalian metabolic regulation and participates in the physiological activities of a variety of cells and tissues, and plays an extremely important role in cell growth, differentiation, metastasis, and survival. It is a hot target in tumor treatment. Temsirolimus is a semi-synthetic compound from rapamycin. Rapamycin is a natural product isolated from a soil bacterium and has been approved for sale by FDA because of its immunosuppressive effect. mTOR regulates cell differentiation by activating p70S6K1 and 4EBP1 proteins, and after inhibition, cell division stops at G1 and S phases. This indicates that rapamycin and its analogs have potential antitumor activity. Based on this mechanism, rapamycin is used in anti-tumor research, and a series of derivatives are obtained and their antitumor activity is tested.

The clinical trial of temsirolimus

Temsirolimus is an intravenous mTOR inhibitor that has been approved for the treatment of advanced renal cell carcinoma. Because the deletion of LKB1 activates the mTOR pathway, therapeutic drugs can be used to treat tumors with STK11 changes by inhibiting the mTOR pathway. Temsirolimus is conducting clinical trials on a variety of tumor types. A phase I clinical trial of temsirolimus combined with topotecan in the treatment of gynecological tumors has shown acceptable safety. That is the evaluation of dose-limited myelosuppression in female patients who have not been treated with radiotherapy. A phase II clinical study of temsirolimus in the treatment of recurrent or metastatic cervical cancer reported that the drug was partially effective in 3 percent of patients and no progression was found in 57.6 percent of patients with stable tumors. During the treatment, the patients were only accompanied by mild to moderate side effects but did not exceed grade three. In phase I clinical study of temsirolimus combined with carboplatin and paclitaxel, 18 patients with head and neck squamous cell carcinoma had a partial response rate of 22 percent. However, a phase II clinical trial of temsirolimus combined with erlotinib in the treatment of head and neck squamous cell carcinoma was terminated prematurely due to poor tolerance. A phase I clinical trial of temsirolimus and bevacizumab combined with liposomal doxorubicin in the treatment of advanced solid tumors showed that the combination of the three drugs was well tolerated, 21% of the patients survived for more than 6 months without progression, and 21% of the patients showed partial or complete remission.

Future

The mechanism of Tamsilimus and rapamycin is similar, both of which bind to FKBP and mTOR to form complex. And people interest in mTOR is not limited to anti-tumor. As a conservative target, mTOR, has a “code” to make people live longer, while temsirolimus, as its inhibitor, has a “code” to make people live longer. Based on our knowledge of it, and as the focus of research of anti-aging drug, perhaps a few years later, temsirolimus will radiate a stronger vitality.

References

1. Hudes, G., Carducci, M., Tomczak, P., Dutcher, J., Figlin, R., Kapoor, A., … & Kovacevic, Z. (2007). Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. New England Journal of Medicine356(22), 2271-2281.

2. Chang, S. S. (2019). Re: Safety and Efficacy of Temsirolimus as Second Line Treatment for Patients with Recurrent Bladder Cancer. The Journal of urology, 10109701JU000055464194059ef.