Evaluation of the pharmacokinetics of ixabepilone for the treatment of breast cancer.

INTRODUCTION: Chemotherapeutic agents, such as anthracyclines, taxanes and fluoropyrimidines, have significantly improved the outcome of breast cancer patients. However, mechanisms of resistance limit the effectiveness of these drugs. The microtubule-stabilizing agent ixabepilone has been approved for treatment of metastatic breast cancer (MBC) patients resistant or refractory to taxanes, anthracycline and capecitabine. AREAS COVERED: In this review, we summarized data on pharmacodynamics, pharmacokinetics, preclinical and clinical studies of ixabepilone in breast cancer. This article was compiled through searches on ixabepilone up to March 2015 in the PubMed and the clinicaltrials.gov databases; the FDA and European Medicine Agency (EMA) websites; and the ASCO and AACR proceedings. EXPERT OPINION: Ixabepilone is a well-tolerated and effective drug in MBC at the approved dose. The most important challenges that ongoing clinical trials are still addressing are: the optimal dosing schedule that might improve the risk/benefit ratio, the clinical efficacy of ixabepilone in early breast cancer, the efficacy in triple-negative breast cancer (TNBC) patients and the identification of biomarkers predictive of response.

The RAS/RAF/MEK/ERK and the PI3K/AKT signalling pathways: role in cancer pathogenesis and implications for therapeutic approaches.

INTRODUCTION: The RAS/RAF/MAP kinase-ERK kinase (MEK)/extracellular-signal-regulated kinase (ERK) (MAPK) and the PI3K/AKT/mammalian target of rapamycin (mTOR) (PI3K) pathways are frequently deregulated in human cancer as a result of genetic alterations in their components or upstream activation of cell-surface receptors. These signalling cascades are regulated by complex feedback and cross-talk mechanisms. AREAS COVERED: In this review the key components of the MAPK and AKT pathways and their molecular alterations are described. The complex interactions between these signalling cascades are also analysed. EXPERT OPINION: The observation that the MAPK and the PI3K pathways are often deregulated in human cancer makes the components of these signalling cascades interesting targets for therapeutic intervention. Recently, the presence of compensatory loops that activate one pathway following the blockade of the other signalling cascade has been demonstrated. Therefore, the blockade of both pathways with combinations of signalling inhibitors might result in a more efficient anti-tumor effect as compared with a single agent. In addition, the MAPK and PI3K pathways are activated by mutations that coexist or can be mutually exclusive. In this regard, a large-scale characterization of the cancer genome might offer personalized cancer genomic information, which may improve the anti-tumor efficacy of signalling inhibitors.

Pharmacokinetic evaluation of zoledronic acid.

INTRODUCTION: Increased bone resorption is associated with several diseases, including osteoporosis, bone metastases and Paget's disease of bone. Zoledronic acid (ZA) is the most potent of the clinically available bisphosphonates. In addition to its antiresorptive activity, there has been increasing evidence to suggest that it also has anticancer properties. AREAS COVERED: This article is complied through PubMed and Medline databases searches on ZA. In this review, the authors summarize the current knowledge (up to December 2010) on the pharmacodynamic and pharmacokinetic properties of ZA. EXPERT OPINION: ZA is a well-tolerated and effective drug in the management of metabolic as well as cancer-related bone disease. Clinical benefits in cancer patients include improvement in bone pain, reduction in skeletal events and delay of time to first skeletal event. However, novel indications for this drug are emerging from clinical studies in early breast cancer. Recent findings suggest that the addition of ZA to endocrine therapy can significantly prevent bone loss in premenopausal patients. Increasing evidence also indicates a potential anticancer activity of ZA, although this property needs to be further explored.