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Temsirolimus
1Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins, Baltimore, Maryland 21231-1000, USA.
Abstract:
Temsirolimus (CCI-779), a small molecule inhibitor of mTOR protein, is a water-soluble synthetic rapamycin ester that has been developed in both oral and intravenous (i.v.) formulations. PI3k/Akt/mTOR pathway activation is implicated in the pathogenesis of many cancers. Inhibition of mTOR protein abrogates pathway-mediated cellular transcription and translation, leading to cell cycle arrest, antiangiogenesis and apoptosis. The drug has significant in vitro antitumor effect against a number of cancer cell lines and has demonstrated in vivo cytostatic activity in xenograft models. Flat dosing of 25 mg, 75 mg and 250 mg i.v. weekly were selected for tumor-specific phase I trials. Biological activity was observed at all these doses. However, the frequency and intensity of the toxicities increased at higher doses and more high-dose patients had to reduce the dose or discontinue the drug. Notable temsirolimus-related toxicities include rash, mucostomatitis, diarrhea, hyperlipidemia, hyperglycemia and thrombocytopenia. Temsirolimus is farther along in clinical development than any other mTOR inhibitor in its class and has demonstrated significant activity in patients with poor-risk clear-cell renal cell carcinoma. Patients receiving temsirolimus alone achieved longer survival than those receiving interferon alone or temsirolimus plus interferon in a randomized phase III trial. Predictive biomarkers for clinical efficacy are undetermined and remain under investigation.
Insights
Temsirolimus, an mTOR inhibitor, shows anti-cancer effects by stopping cell growth and blood vessel formation. While effective, higher doses increase toxicities, impacting treatment tolerance in patients.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- The PI3k/Akt/mTOR pathway is crucial in cancer development.
- Temsirolimus is a synthetic rapamycin ester inhibiting the mTOR protein.
- mTOR inhibition leads to cell cycle arrest, antiangiogenesis, and apoptosis.
Purpose of the Study:
- To evaluate the antitumor effects and toxicity of temsirolimus.
- To determine optimal dosing for phase I trials.
- To assess temsirolimus's efficacy in advanced cancers.
Main Methods:
- In vitro studies on cancer cell lines.
- In vivo xenograft models.
- Phase I trials with flat intravenous dosing (25, 75, 250 mg weekly).
- Phase III randomized trial comparing temsirolimus, interferon, or combination therapy.
Main Results:
- Temsirolimus demonstrated significant in vitro antitumor activity and in vivo cytostatic effects.
- Biological activity was observed across all tested doses.
- Increased doses correlated with higher frequency and intensity of toxicities (rash, mucositis, diarrhea, hyperlipidemia, hyperglycemia, thrombocytopenia).
- Temsirolimus monotherapy improved survival in poor-risk clear-cell renal cell carcinoma patients compared to interferon alone in a Phase III trial.
Conclusions:
- Temsirolimus exhibits significant anti-cancer activity through mTOR inhibition.
- Dose escalation leads to increased toxicity, necessitating careful management.
- Temsirolimus offers a survival benefit in specific patient populations, particularly clear-cell renal cell carcinoma.
- Further research is needed to identify predictive biomarkers for temsirolimus efficacy.
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