Future directions in the treatment of hormone-sensitive advanced breast cancer: the RAD001 (Everolimus)-letrozole clinical program.
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Lane, Heidi and Lebwohl, David (2006) Future directions in the treatment of hormone-sensitive advanced breast cancer: the RAD001 (Everolimus)-letrozole clinical program. Seminars in Oncology, 33 (2 Suppl 7). S18-S25. ISSN 0093-7754
Abstract
Therapeutics that interfere with estrogen receptor function (antiestrogens, eg, tamoxifen; aromatase inhibitors, eg, letrozole) have contributed to a dramatic reduction in breast cancer mortality; however, not all estrogen-receptor-positive breast cancers respond. The mammalian target-of-rapamycin (mTOR) is emerging as an important target molecule in the treatment of breast cancer. Furthermore, activation of growth-factor signaling pathways that involve mTOR may contribute to both the failure of endocrine therapy as well as the development of resistance. RAD001 (everolimus) is a potent, orally bioavailable inhibitor of the mTOR pathway. Preclinical data show that RAD001 effectively inhibits the proliferation and growth of a number of cancer cell lines in vitro and a range of tumor types in experimental animal models of cancer. Moreover, RAD001 exhibits an antiangiogenic activity, which may also contribute to its anticancer activity. The aromatase inhibitor letrozole is a potent endocrine therapy for breast cancer that acts to inhibit the aromatization of androgens, thereby reducing plasma and tumor estrogen levels. Combining RAD001 with letrozole is a rational approach to the treatment of advanced breast cancer, offering the potential for inhibition of tumor cell growth/proliferation and angiogenesis while at the same time potentially preventing the development of letrozole resistance. Preclinical data, derived from aromatase-expressing, estrogen-receptor-positive breast tumor models, suggest a synergistic interaction between RAD001 and letrozole that results in more profound effects on proliferation and the induction of tumor cell death. Importantly, early clinical data show no pharmacokinetic interaction or increase in toxicity with combined treatment, as compared with treatment with RAD001 alone, and there is evidence of antitumor activity. Enrollment into phase II studies is presently underway.
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| Additional Information: | author can archive post-print (ie final draft post-refereeing); Publisher's version/PDF cannot be used |
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| Date Deposited: | 14 Dec 2009 14:00 |
| Last Modified: | 14 Dec 2009 14:00 |
| URI: | https://oak.novartis.com/id/eprint/403 |