Microtubule-Stabilizing Agent: Halichondrin B Analog (E7389)

Abstract

The American Cancer Society projected that, in 2006, more than 212,000 cases of invasive breast cancer would be diagnosed and that more than 40,000 women would die of breast cancer-related causes.1 Advances in screening, adjuvant therapy, and the integration of novel therapies, such as trastuzumab, have improved patient outcomes. Despite these advances, it is estimated that between 20% and 85% of women with earlystage breast cancer will have distant metastases within 5 years of initial diagnosis. Furthermore, an additional 6% to 10% will have stage IV disease as the initial diagnosis of breast cancer.2 Therefore, the management of metastatic and refractory breast cancer remains a challenge for the medical oncologist. Despite the plethora of novel non-cytotoxic agents, cytotoxic chemotherapy continues to play an integral role in the management of advanced breast cancer. Available chemotherapeutics provide statistically significant advantages in terms of tumor response and time to progression. Whether agents are used alone or in combination, typical response rates are in the range of 25% to 55%. Response durations of 8-14 months are common, and most patients have palliation of symptoms associated with objective responses.2,3-5 There is no clear consensus for the superiority of any particular agent or regimen in the first-line metastatic setting or for the efficacy of a particular regimen in the second-line and subsequent therapies. Complete and durable responses in the setting of advanced disease are rare. As a result, only modest, incremental improvements in overall survival have been reported. Nonetheless, with the use of modern chemotherapeutics, overall survival for patients with metastatic breast cancer has improved. These patients now have a median survival duration of about 4 years compared with 18-24 months 10 years ago.6-8 Unfortunately, this improvement is sometimes accompanied by increased and substantial toxicity. Although our management of metastatic disease is clearly better than it was a decade ago, our ability to manage metastatic breast cancer as a chronic condition has been modest at best. Effective, well-tolerated new drugs are needed to control advanced, relapsed, or refractory breast cancer. One such drug currently being investigated is E7389—a derivative of halichondrin B. The anticancer and anti-microtubule activities of halichondrin B are well documented; however, the sea sponge from which this agent is derived, Halichondria okadai, is extremely rare. As a result, the pharmaceutical production and clinical applicability of this agent has been problematic.9,10 E7389 is a structurally simplified synthetic analog of halichondrin B that can be more easily manufactured. It contains the biologically active macrocyclic moiety of its parent compound. Preclinical models have demonstrated that E7389 has anti-microtubule activity identical to that of halichondrin B.11