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Targeting mTOR in renal cell carcinoma

Targeting mTOR in renal cell carcinoma The mammalian target of rapamycin (mTOR) is clearly an important therapeutic target for advanced renal cell carcinoma (RCC), although its mechanisms of activation are not completely understood. In first‐line treatment of patients who have both advanced RCC and multiple risk factors for short survival, temsirolimus improves overall survival (OS) compared with interferon. In patients whose tumors have progressed after sunitinib and/or sorafenib therapy, everolimus improves progression‐free survival compared with placebo. Beyond the initial phase 3 studies demonstrating efficacy, many important questions remain in the clinical application of mTOR inhibition and in developing other inhibitors of PI3K/Akt/mTOR signaling. Important objectives of current and future clinical investigations include a more detailed description of the molecular pathology of RCC and identification of potential biomarkers that are predictive of tumor sensitivity to PI3K/Akt/mTOR targeted therapies. This information may identify other groups of RCC patients that are likely to benefit from inhibition of this signaling pathway. Additional questions concern mechanisms by which tumors become resistant to mTOR inhibitor therapy and how such resistance can be defeated. Possible mechanisms include the loss of feedback inhibition of insulin receptor substate/PI3K signaling resulting from the inhibition of mTOR complex 1 by rapamycin analogs and the activating phosphorylation of Akt by mTOR complex 2. Laboratory studies indicate that these resistance mechanisms could be countered by using other targeted agents in combination with mTOR inhibitors. Cancer 2009;115(10 suppl):2313‐20. © 2009 American Cancer Society. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Cancer Wiley

Targeting mTOR in renal cell carcinoma

Hudes, Gary R.
Cancer , Volume 115 (S10) – Mar 15, 2010
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References (48)

Publisher
Wiley
Copyright
"Copyright © 2009 Wiley Subscription Services, Inc., A Wiley Company"
ISSN
0008-543X
eISSN
1097-0142
DOI
10.1002/cncr.24239
pmid
19402072
Publisher site
See Article on Publisher Site

Abstract

The mammalian target of rapamycin (mTOR) is clearly an important therapeutic target for advanced renal cell carcinoma (RCC), although its mechanisms of activation are not completely understood. In first‐line treatment of patients who have both advanced RCC and multiple risk factors for short survival, temsirolimus improves overall survival (OS) compared with interferon. In patients whose tumors have progressed after sunitinib and/or sorafenib therapy, everolimus improves progression‐free survival compared with placebo. Beyond the initial phase 3 studies demonstrating efficacy, many important questions remain in the clinical application of mTOR inhibition and in developing other inhibitors of PI3K/Akt/mTOR signaling. Important objectives of current and future clinical investigations include a more detailed description of the molecular pathology of RCC and identification of potential biomarkers that are predictive of tumor sensitivity to PI3K/Akt/mTOR targeted therapies. This information may identify other groups of RCC patients that are likely to benefit from inhibition of this signaling pathway. Additional questions concern mechanisms by which tumors become resistant to mTOR inhibitor therapy and how such resistance can be defeated. Possible mechanisms include the loss of feedback inhibition of insulin receptor substate/PI3K signaling resulting from the inhibition of mTOR complex 1 by rapamycin analogs and the activating phosphorylation of Akt by mTOR complex 2. Laboratory studies indicate that these resistance mechanisms could be countered by using other targeted agents in combination with mTOR inhibitors. Cancer 2009;115(10 suppl):2313‐20. © 2009 American Cancer Society.

Journal

Cancer – Wiley

Published: Mar 15, 2010

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