Everolimus: targeted therapy on the horizon for the treatment of breast cancer.

Abstract

The mammalian target of rapamycin (mTOR) is a signaling kinase of the phosphatidylinositol 3-kinase/protein kinase B (also known as Akt) signaling pathway that mediates cell growth and metabolism. Dysregulation of the mTOR pathway creates a favorable environment for the development and progression of many cancers, including breast cancer, and is associated with the development of resistance to endocrine therapy and to the anti-human epidermal growth factor receptor-2 (HER2) monoclonal antibody trastuzumab. Therefore, the addition of mTOR inhibitors to conventional breast cancer therapy has the potential to enhance therapeutic efficacy and/or overcome innate or acquired resistance. Everolimus, an mTOR inhibitor with demonstrated preclinical activity against breast cancer cell lines, has been shown to reverse Akt-induced resistance to hormonal therapy and trastuzumab. Phase I-II clinical trials have demonstrated that everolimus has promising clinical activity in women with HER2-positive, HER2-negative, and estrogen receptor-positive breast cancer when combined with HER2-targeted therapy, cytotoxic chemotherapy, and hormonal therapy, respectively. Everolimus is generally well tolerated; hematologic abnormalities and stomatitis are most common adverse events when this drug is combined with cytotoxic chemotherapy. Based on these promising results, everolimus is currently under evaluation in a series of phase III Breast Cancer Trials of Oral Everolimus (BOLERO) trials of women with HER2-positive and estrogen receptor-positive breast cancer. Results of these trials will help to establish the role of everolimus in the treatment of clinically important breast cancer subtypes.

• Authors: Chad M Barnett
• Journal: Pharmacotherapy (Pharmacotherapy) Vol. 32 Issue 4 Pg. 383-96 (Apr 2012) ISSN: 1875-9114 [Electronic] United States
• PMID: 22461124 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)
• Copyright: © 2012 Pharmacotherapy Publications, Inc.

Chemical References

• Immunosuppressive Agents
• Receptors, Estrogen
• Everolimus
• MTOR protein, human
• ERBB2 protein, human
• Receptor, ErbB-2
• TOR Serine-Threonine Kinases
• Sirolimus

Topics

• Breast Neoplasms (drug therapy, genetics)
• Clinical Trials as Topic
• Clinical Trials, Phase III as Topic
• Drug Interactions
• Everolimus
• Female
• Humans
• Immunosuppressive Agents (pharmacokinetics, pharmacology, therapeutic use)
• Receptor, ErbB-2 (genetics)
• Receptors, Estrogen (genetics)
• Sirolimus (adverse effects, analogs & derivatives, pharmacokinetics, pharmacology, therapeutic use)
• TOR Serine-Threonine Kinases (antagonists & inhibitors)