Preclinical discovery of ixabepilone, a highly active antineoplastic agent

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.     

The epothilones: new therapeutic agents for castration-resistant prostate cancer

The management of castration-resistant prostate cancer (CRPC) presents a clinical challenge because of limitations in efficacy and durability with currently available therapeutics. The epothilones represent a novel class of anticancer therapy that stabilizes microtubules, causing cell death and tumor regression in preclinical models. The structure of the tubulin-binding site for epothilones is distinct from that of the taxanes. Moreover, preclinical studies suggest nonoverlapping mechanisms of resistance between epothilones and taxanes. In early-phase studies in patients with CRPC, treatment with ixabepilone, a semisynthetic analog of epothilone B, induced objective responses and prostate-specific antigen declines in men previously progressing on docetaxel-based regimens. Clinical activity has been observed in nonrandomized trials for patients with CRPC using ixabepilone in the first- and second-line settings as a single agent and in combination with estramustine. Patupilone and sagopilone were also shown to have promising efficacy in phase II clinical trials of patients with CRPC. All three epothilones appear to be well tolerated, with modest rates of neutropenia and peripheral neuropathy. The lack of crossresistance between epothilones and taxanes may allow sequencing of these agents. Evaluating epothilones in phase III comparative trials would provide much-needed insight into their potential place in the management of patients with CRPC.     

Efficacy and safety of ixabepilone, a novel epothilone analogue

The epothilones and their analogues are a new class of anticancer agents derived from the fermentation of myxobacterium Sorangium cellulosum. These compounds have some similarities to taxanes in targeting and stabilizing microtubules, but they also have important differences. Among the epothilone family, ixabepilone has emerged to be a semisynthetic epothilone analogue of interest. Ixabepilone has demonstrated consistent preclinical activity and seems active against various taxane-sensible and taxane-resistant cell lines, including those with overexpression of multidrug resistance and with mutations in the beta-tubulin gene. The interest of this ixabepilone has been confirmed clinically. Phase II clinical studies have demonstrated high activity in patients with taxane-resistant metastatic breast cancer and in patients with other chemotherapy-resistant tumor types.     

Targeting the microtubules in breast cancer beyond taxanes: the epothilones

Microtubule-targeting agents such as the taxanes are highly active against breast cancer and have become a cornerstone in the treatment of patients with early and advanced breast cancer. The natural epothilones and their analogs are a novel class of microtubule-stabilizing agents that bind tubulin and result in apoptotic cell death. Among this family of compounds, patupilone, ixabepilone, BMS-310705, ZK-EPO, and KOS-862 are in clinical development. Extensive preclinical studies have shown that epothilones are working through partially nonoverlapping mechanisms of action with taxanes. In the clinic, epothilones have been found in a series of phase I and phase II studies to be active even in patients who had recently progressed to taxanes. The toxicity profile of these agents consists mostly of sensory neuropathy, sometimes reversible. Neoadjuvant studies with epothilones have been conducted and a number of phase III studies in advanced breast cancer are either under way or have been recently completed. The results of these studies are eagerly awaited and it is anticipated that epothilones may become an important treatment option in patients with breast cancer.     

Clinical experience with epothilones in patients with breast cancer

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.     

Epothilones: clinical update and future directions

Epothilones are cytotoxic compounds that function in a similar fashion to paclitaxel and show promise for the treatment of a variety of cancers by inducing microtubule bundling and apoptotic cell death. However, their mechanism of microtubule binding is different from that of paclitaxel, which makes epothilones an attractive drug class for patients with taxane-resistant malignancies. As taxane resistance remains a significant barrier in the treatment of a variety of cancers, it is important to understand epothilones and their indications. Several epothilone compounds, including ixabepilone (BMS-247550, aza-epothilone B, Ixempra), patupilone (EPO906, epothilone B), KOS-862 (desoxyepothilone B, epothilone D), BMS-310705, ZK-EPO (ZK-219477), nd KOS-1584, have been testedf or the treatment of a variety of solid tumor types. Recently, ixabepilone became the first epothilone to be approved by the US Food and Drug Administration, for the treatment of metastatic or locally advanced breast cancer as monotherapy or in combination with capecitabine (Xeloda) after other treatments have failed. This article reviews recent findings from clinical trials of epothilones and discusses future directions for the use of these agents in cancer therapy, with a focus on the two most-studied epothilones to date: ixabepilone and patupilone.     

Ixabepilone, first in a new class of antineoplastic agents: the natural epothilones and their analogues

Although targeted therapies are becoming increasingly important in oncology, cytotoxic agents are likely to remain a valuable element in the treatment paradigm of cancer. However, resistance to chemotherapy is a major obstacle to the successful treatment of cancer. Therefore, there is a need for novel antineoplastic agents that are able to overcome mechanisms of tumor resistance. Drugs that target microtubules, including paclitaxel and docetaxel, are among the most commonly prescribed anticancer therapies. However, the utility of taxane-based therapies is limited by difficulties with formulation, administration, and resistance induced by P-glycoprotein. The epothilones and their analogues are a novel class of antimicrotubule agents that has demonstrated antitumor activity in the setting of resistance. These antimicrotubule agents are structurally unrelated to the taxanes, with a distinct beta-tubulin-binding mode. Ixabepilone is a rationally designed, semisynthetic analogue of natural epothilone B, which displays reduced susceptibility to a range of common tumor resistance mechanisms. Promising phase II activity and a manageable safety profile with ixabepilone have been seen in a wide range of tumor types, including heavily pretreated/resistant and early-stage breast cancer. Moreover, encouraging phase III results with ixabepilone and capecitabine for patients with breast cancer have recently been presented. Clinical trials are also planned for ixabepilone in combination with targeted agents, such as trastuzumab and bevacizumab. Ixabepilone is likely to be the first available drug in its class, with the potential to bring clinical benefit to patients with a wide range of malignancies.     

Clinical Development of Ixabepilone and Other Epothilones in Patients with Advanced Solid Tumors

Chemotherapy efficacy in patients with solid tumors is influenced by primary and acquired multidrug resistance (MDR). Epothilones represent a novel class of microtubule inhibitors with lower susceptibility to drug resistance and efficacy in taxane‐resistant tumors. While other epothilones are currently under investigation, ixabepilone is the first epothilone B analogue approved by the U.S. Food and Drug Administration. Ixabepilone has been shown to have preclinical activity in chemotherapy‐sensitive and chemotherapy‐resistant tumor models, and synergistic antitumor activity with other chemotherapeutic and targeted agents. Single‐agent ixabepilone has demonstrated clinical activity in multiple solid tumors including advanced breast, lung, prostate, pancreatic, renal cell, and ovarian cancers. Most notably, efficacy has been demonstrated in patients with metastatic breast cancer (MBC) progressing after treatment with anthracyclines and taxanes. A phase III trial in anthracycline‐ and taxane‐resistant MBC showed superior disease control with ixabepilone plus capecitabine versus capecitabine monotherapy, resulting in its approval. Ixabepilone is also active in chemotherapy‐naïve and taxane‐resistant hormone‐refractory prostate cancer and platinum‐resistant non‐small cell lung cancer. Neutropenia and peripheral sensory neuropathy are the most common adverse events associated with treatment. This review discusses the challenges of MDR and the data that support the use of epothilones in this setting, focusing on ixabepilone.     

Treatment beyond taxanes,emerging new cytotoxic agents

Until recently, taxanes were considered the first choice of therapy for patients with metastatic breast cancer (MBC). However, the clinical utility of the taxanes is limited in some patients by the emergence of drug resistance. Moreover, these agents are increasingly used as adjuvant therapy, increasing the population of patients with prior exposure once the disease has metastasised. Current approved treatment options after prior taxane therapy include capecitabine, liposomal doxorubicin and nab-paclitaxel – as single agents and/or in combination. Vinorelbine and gemcitabine may also be used. Most recently, the epothilones, a novel group of microtubule-stabilising agents, have shown promising activity in patients with MBC, including those resistant to taxanes and other cytotoxic drugs. Currently, three epothilone B synthetic derivatives, ixabepilone (BMS-247550), patupilone (EPO906), and sagopilone (ZK-EPO) are in development. This article will examine the latest data for these next-generation cytotoxics in the treatment of MBC.     

Ixabepilone: a novel antineoplastic agent with low susceptibility to multiple tumor resistance mechanisms

Tumor resistance to chemotherapeutic agents ultimately leads to treatment failure in the majority of cancer patients. The identification of new agents that are less susceptible to mechanisms of tumor resistance could, therefore, bring significant clinical benefits to patients with advanced cancer. One new drug class of great interest in this respect is the epothilones and their analogues, which are microtubule inhibitors with low susceptibility to several mechanisms of drug resistance. Ixabepilone is an analogue of natural epothilone B with activity against a wide range of tumor types, including drug-resistant tumors. This is consistent with the preclinical activity of ixabepilone against human cancer cell lines resistant to taxanes and other agents. Taxane resistance in these cells may be acquired or primary and results from several mechanisms, such as overexpression of multidrug-resistance proteins and the betaIII-tubulin isoform. Ixabepilone has demonstrated efficacy as monotherapy or in combination with capecitabine in anthracycline- and taxane-pretreated/resistant metastatic breast cancer (MBC), and has recently been approved for use in resistant/refractory MBC. Other epothilones, such as patupilone, KOS-1584, and ZK-EPO, are also being evaluated in drug-resistant cancers. Ixabepilone represents a new treatment option for MBC patients with cancers resistant to available chemotherapeutic agents.     

Epothilones: a novel class of microtubule-stabilizing drugs for the treatment of cancer

Microtubule-targeted anticancer drugs are effective in treating various cancers but are limited in use due to development of resistance and unacceptable toxicities. The epothilones are a novel class of microtubule-stabilizing anticancer drugs and may have a role in treating taxane-resistant cancers. Revised and updated data from several clinical studies for ixabepilone were recently published and subsequently resulted in ixabepilone becoming the first epothilone approved as monotherapy or in combination for treatment of locally advanced or metastatic breast cancer. BMS-310705, patupilone, KOS-862, KOS-1584 and ZK-EPO are epothilones that have been developed. Although peripheral sensory neuropathy and neutropenia are the dose-limiting toxicities for ixabepilone, these dose-limiting toxicities are ixabepilone specific. This review will discuss the current preclinical, clinical pharmacokinetic and pharmacodynamic, efficacy and toxicity data of the epothilones.     

Epothilones in development for non--small-cell lung cancer: novel anti-tubulin agents with the potential to overcome taxane resistance

Progress in the treatment of non-small-cell lung cancer (NSCLC) will require the introduction of new agents as well as better use of existing therapies. Targeted therapies are likely to have a profound effect on the treatment of NSCLC after identification of patients who are most likely to benefit. The epothilones are novel anti-tubulin agents derived from Sorangium cellulosum. β III tubulin overexpression has been implicated as a mechanism of anti-tubulin resistance that can be overcome by epothilones. Several epothilones have advanced to clinical trials; ixabepilone (BMS247550, aza-epothilone B, Bristol-Myers Squibb, New York, NY), patupilone (EPO906, Novartis, Basel, Switzerland) and sagopilone (ZK-EPO, ZK-219477, Schering AG, Berlin-Wedding, Germany) are currently in active development. Several of the epothilones, most notably ixabepilone, have demonstrated activity in lung cancer in phase I and II trials, including taxane-resistant patients. Although a phase II study failed to show superior outcome in patients with β III tubulin overexpression, other aspects of the epothilones argue for their continued development.     

Epothilones in breast cancer: current status and future directions

Taxanes have become fundamental in the treatment of early and advanced breast cancer. However, tumors vary in their sensitivity to these agents; resistance can be acquired or de novo resistance can occur. Epothilones and associated analogs are novel microtubule-stabilizing agents that induce apoptosis and promote cell death. There is now a growing body of clinical data describing the efficacy of epothilones in breast cancer patients who have progressed on taxanes and anthracyclines. This culminated with US FDA approval in October 2007 of ixabepilone (Ixempra, Brystol Myers Squibb, NJ, USA) either as single agent or in combination with capecitabine for the treatment of breast cancer, which has progressed after prior therapies. The results of ongoing and future randomized clinical trials will further define how epothilones, in particular ixabepilone, will be integrated into the management of early and metastatic breast cancer. In parallel, the search for biomarkers predictive of sensitivity to epothilones continues in an attempt to tailor these therapies to patients with greater accuracy.     

New taxanes and epothilone derivatives in clinical trials

This review describes the experimental and clinical properties of new taxanes and epothilones. Six new taxanes are currently in clinical trials: BMS 184476, BMS 188797, BMS 275183, IDN 5109/BAY 598862, RPR 109881A et RPR 116258 All these derivatives share the same feature which is a decreased recognition by Pgp-170, the product of the MDR1 gene. This confers innovative properties such as in vitro and in vivo activities on tumors expressing the Pgp-170, activity by the oral route. Identification of other families of molecules bearing the same mechanism of action as taxol has been a goal pursued by many groups. The discovery of epothilones led to the pharmaceutical development of two molecules: EPO 906 (which corresponds to the natural compound epothilone B) and BMS 247550. Phase I clinical trials have established that all these investigational drugs (taxanes and epothilones) can be safely administered in patients, the limiting toxicity being most of the time febrile neutropenia. Many tumor responses have been noted.     

The epothilones: translating from the laboratory to the clinic.

The epothilones are macrolide compounds that have been shown to stabilize microtubules. The epothilones are strong promoters of tubulin polymerization in vitro and have significant antitumor activity against human cancer cells that are taxane resistant, express the multidrug resistance gene MDR-1 (ABCB1), and have acquired tubulin mutations. Several epothilones have been evaluated in clinical trials in a variety of tumor types. Ixabepilone (aza-epothilone B) has significant antitumor activity in breast cancer resistant to an anthracycline and a taxane, and has been approved by the U.S. Food and Drug Administration for the treatment of patients with metastatic or locally advanced breast cancer. There have been sustained efforts to develop pharmacodynamic markers to monitor the pharmacologic effect of the epothilones on tumors and normal tissues. The development of predictive markers for epothilone chemotherapy is highly desired to provide more tailored therapy for patients with cancer.     

Epothilones in breast cancer: current status and future directions

Taxanes have become fundamental in the treatment of early and advanced breast cancer. However, tumors vary in their sensitivity to these agents; resistance can be acquired or de novo resistance can occur. Epothilones and associated analogs are novel microtubule-stabilizing agents that induce apoptosis and promote cell death. There is now a growing body of clinical data describing the efficacy of epothilones in breast cancer patients who have progressed on taxanes and anthracyclines. This culminated with US FDA approval in October 2007 of ixabepilone (Ixempra?, Brystol Myers Squibb, NJ, USA) either as single agent or in combination with capecitabine for the treatment of breast cancer, which has progressed after prior therapies. The results of ongoing and future randomized clinical trials will further define how epothilones, in particular ixabepilone, will be integrated into the management of early and metastatic breast cancer. In parallel, the search for biomarkers predictive of sensitivity to epothilones continues in an attempt to tailor these therapies to patients with greater accuracy.     

Epothilones in the treatment of ovarian cancer

Epothilones are a new group of microtubule-stabilizing agents that have demonstrated antitumor activity in taxane-resistant models. Taxanes remain some of the most active cytotoxic agents in current cancer therapy. Primary or acquired resistance to taxanes in tumor cells partly prevents their long-term efficacy. Certain side effects, such as myelosupression or irreversible neuropathy, can also limit prolonged taxane administration. Epothilone B (EPO906; patupilone), a natural compound, and its semisynthetic derivative, ixabepilone (BMS-247550), differ in their pharmacokinetic and toxicity profiles. Ovarian cancer patients frequently relapse after first-line treatment based on platinum-taxane doublets. Therefore, epothilones might represent a therapeutic alternative in this setting. Patupilone and ixabepilone have undergone parallel clinical development, but their future role in ovarian cancer therapeutics remains ill defined.     

Preclinical efficacy spectrum and pharmacokinetics of ixabepilone

Purpose  Ixabepilone, a semisynthetic analog of natural epothilone B, was developed for use in cancer treatment. This study extends previous findings regarding the efficacy of ixabepilone and its low susceptibility to tumor resistance mechanisms and describes the pharmacokinetics of this new antineoplastic agent. Methods  The cytotoxicity of ixabepilone was assessed in vitro in breast, lung, and colon tumor cell lines and in vivo in human xenografts in mice. Antitumor activities of ixabepilone and taxanes were compared in multidrug-resistant models in vivo. Differential drug uptake of ixabepilone and paclitaxel was assessed in a P-glycoprotein (P-gp)-resistant colon cancer model in vitro. The pharmacokinetic profile of ixabepilone was established in mice and humans. Results  Ixabepilone demonstrated potent cytotoxicity in a broad range of human cancer cell lines in vitro and in a wide range of xenografts in vivo. Ixabepilone was ~3-fold more potent than docetaxel in the paclitaxel-resistant Pat-21 xenograft model (resistant due to overexpression of βIII-tubulin and a lack of βII-tubulin). Ixabepilone activity against P-gp-overexpressing breast and colon cancer was confirmed in in vivo models. Cellular uptake of ixabepilone, but not paclitaxel, was established in a P-gp-overexpressing model. The pharmacokinetics of ixabepilone was characterized by rapid tissue distribution and extensive tissue binding. Conclusions  Cytotoxicity studies against a range of tumor types in vitro and in vivo demonstrate that ixabepilone has potent and broad-spectrum antineoplastic activity. This is accompanied by favorable pharmacokinetics. Ixabepilone has reduced susceptibility to resistance due to P-gp overexpression, tubulin mutations, and alterations in β-tubulin isotype expression.     

Current perspectives of epothilones in breast cancer

Taxanes have been broadly used in the treatment of breast cancer. However, the majority of initially responsive breast cancer patients eventually develop resistance to taxanes (acquired resistance) and a non-negligible percentage of patients are primarily resistant to these agents (de novo resistance). Additionally, taxanes require pre-medication and may cause important side effects such as febrile neutropenia and neuropathy. Hence, new agents with better efficacy and/or a better toxicity profile and/or are easier to administer need to be developed. Epothilones are a novel class of microtubule-targeting agents sharing a similar mechanism of action to the taxanes and having a more potent antiproliferative activity in various tumour cells lines, particularly in cases of taxane-resistant breast cancer. This review will focus on clinical development of epothilones in breast cancer, particularly ixabepilone which is in the late stages of development, their potential impact in clinical practice, advantages and limitations.     

新型抗肿瘤药埃坡霉素的临床研究进展

埃坡霉素（epothilones）是一类非紫杉烷类促微管蛋白聚合剂,其作用机制与紫杉醇相似,但结构完全不同,临床前研究结果显示其细胞毒活性较紫杉醇强,对紫杉类耐药的细胞株和小鼠肿瘤移植模型显示出较强的抗肿瘤活性。近来合成或半合成了很多埃坡霉素类似物,目前已进入临床抗肿瘤治疗研究的埃坡霉素类似物主要有ixabepilone、patupilone、BMS-310705、ZK—EPO、KOS-862及KOS-1584。现有的临床研究结果提示部分接受过紫杉类药物治疗的晚期乳腺癌、卵巢癌、膀胱癌或非小细胞肺癌患者埃坡霉素治疗有效。本文就埃坡霉素的化学结构,作用机制、药理活性及毒副作用等临床研究的进展进行了回顾和综述。