Asbestos Cancer Update 2008

 The epothilones and their analogs constitute a novel class of antineoplastic agents, produced by the myxobacterium Sorangium cellulosum. These antimicrotubule agents act in a similar manner to taxanes, stabilizing microtubules and resulting in arrested tumor cell division and apoptosis. Unlike taxanes, however, epothilones and their analogs are macrolide antibiotics, with a distinct tubulin binding mode and reduced susceptibility to a range of common tumor resistance mechanisms that limit the effectiveness of taxanes and anthracyclines. While natural epothilones A and B show potent antineoplastic activity in vitro, these effects were not seen in preclinical in vivo models due to their poor metabolic stability and unfavorable pharmacokinetics. A range of epothilone analogs was synthesized, therefore, with the aim of identifying those with more favorable characteristics. Here, we describe the preclinical characterization and selection of ixabepilone, a semi-synthetic epothilone B analog, among many other epothilone analogs. Ixabepilone demonstrated superior preclinical characteristics, including high metabolic stability, low plasma protein binding and low susceptibility to multidrug resistance protein-mediated efflux, all of which were predictive of potent in vivo cell-killing activity. Ixabepilone also demonstrated in vivo antitumor activity in a range of human tumor models, several of which displayed resistance to commonly used agents such as anthracyclines and taxanes. These favorable preclinical characteristics have since translated to the clinic. Ixabepilone has shown promising phase II clinical efficacy and acceptable tolerability in a wide range of cancers, including heavily pretreated and drug-resistant tumors. Based on these results, a randomized phase III trial was conducted in anthracycline-pretreated or resistant and taxane-resistant metastatic breast cancer to evaluate ixabepilone in combination with capecitabine. Ixabepilone combination therapy showed significantly superior progression-free survival and tumor responses over capecitabine alone.

PURPOSE: The epothilones are effective antitumor medications for patients with breast cancer, including patients who have been previously treated with or are resistant to anthracyclines or the taxanes. SUMMARY: With the best currently available therapies, the median survival time for patients with metastatic breast cancer is only 2-3 years, and many patients develop resistance to taxanes or other chemotherapy drugs. The epothilones are a novel class of antitumor medications, similar to the taxanes in some respects, but that also possess several advantages. Like taxanes, epothilones are believed to produce antitumor effects by binding to and stabilizing intracellular microtubules, which are essential in DNA replication and cell division.

Several in vitro and animal studies have shown that the epothilones are more potent microtubule stabilizers than the taxanes, they are effective against cancer cell lines with high levels of drug resistance, and they induce the regression of taxane-resistant human tumors. Preclinical studies also have demonstrated synergistic increases in tumor cell killing when the epothilones are combined with other antitumor medications. Epothilone B (patupilone) has been evaluated in a series of phase I and II clinical trials, which demonstrated disease stabilization or objective responses in patients with a variety of cancers, including ovarian, prostate, breast, colon, stomach, and kidney cancers. This agent is currently being evaluated in phase III clinical trials. A second epothilone, ixabepilone, was recently approved by the FDA for the treatment of metastatic breast cancer. Ixabepilone was evaluated as monotherapy for the treatment of breast cancer in phase II clinical trials of previously untreated patients and in taxane-experienced and taxane-resistant disease. A phase III clinical trial demonstrated that the combination of ixabepilone and capecitabine was superior to capecitabine alone in heavily pretreated, taxane-resistant patients. CONCLUSION: Ongoing clinical trials will continue to define the role of the epothilones in cancer therapy.

The search for novel chemotherapeutic agents in the treatment of breast cancer with lower susceptibility to resistance mechanisms than current agents has led to the discovery of the epothilones and their analogues. Epothilones stabilize microtubules in a manner similar to taxanes but are structurally distinct. Ixabepilone, an epothilone B analogue, having demonstrated high antimicrotubule activity in preclinical studies, has shown notable efficacy in phase II trials in patients with early-stage and metastatic breast cancer. Of particular note, single-agent ixabepilone is effective in tumors resistant to anthracyclines, taxanes, and capecitabine, for which there is currently no recommended therapy. Different mechanisms of action and the non-overlapping toxicities of ixabepilone with other agents provide the rationale for ixabepilone in combination as a valid therapeutic approach. Phase II results assessing ixabepilone in combination with capecitabine in anthracycline- and taxane-pretreated patients are promising. The investigation of ixabepilone in the neoadjuvant setting has also revealed potential biomarkers to predict ixabepilone response. Ixabepilone has demonstrated activity in patients with tumors that are estrogen receptor-, progesterone receptor-, and HER2-negative. The safety profile throughout the trials has been manageable, with peripheral neuropathy as one of the more notable adverse events, which has been mostly reversible. A phase III trial comparing ixabepilone plus capecitabine versus capecitabine alone demonstrated significant prolongation of median progression-free survival and reduction in relapse risk. Additionally, other members of the epothilone family, such as patupilone, ZK-EPO, BMS-310705, and KOS-862, have demonstrated efficacy against breast cancer in phase I clinical trials. Ongoing phase II/III trials continue to assess ixabepilone and other members of the epothilone family in breast cancer, particularly in combination regimens, as being valid treatment options in multidrug-resistant breast cancer.

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