Eribulin, known as Halaven, is a chemotherapy medication approved for treating advanced cancers, including metastatic breast cancer after previous therapies, and unresectable liposarcoma. It is a synthetic version of halichondrin B, a natural compound found in the marine sponge, Halichondria okadai.
Targeting the Cellular Skeleton
Cells possess an internal framework called the cytoskeleton, which includes structures known as microtubules. These microtubules function like cellular scaffolding or railway tracks, providing shape and facilitating internal transport within the cell. Microtubules are particularly important during cell division, a process called mitosis.
During mitosis, microtubules assemble to form the mitotic spindle, a temporary structure that is responsible for accurately separating duplicated chromosomes. The mitotic spindle ensures that each new daughter cell receives a complete set of genetic material. Microtubules are dynamic, constantly growing (polymerizing) and shrinking (depolymerizing) at their ends.
Eribulin’s primary mechanism involves binding to the “plus ends” of these growing microtubules. This binding inhibits their ability to lengthen, halting the polymerization process. By preventing microtubule growth, eribulin disrupts the proper formation of the mitotic spindle.
This disruption causes cancer cells to become stuck in the G2/M phase of the cell cycle, a stage where they prepare for and attempt cell division. The prolonged inability to divide properly triggers apoptosis, the cell’s programmed self-destruction. This action is akin to stopping construction on one end of a bridge while the other end is still being dismantled, leading to an unstable and non-functional structure.
A Unique Method of Microtubule Disruption
Eribulin’s interaction with microtubules sets it apart from other drugs that target these structures. Taxanes, for example, stabilize microtubules, preventing their shortening. Vinca alkaloids prevent the assembly of tubulin proteins, the building blocks of microtubules.
Eribulin’s unique action specifically inhibits microtubule growth at the plus ends without significantly affecting their shortening at the minus ends. It binds to a distinct site on tubulin, differing from the binding sites of vinca alkaloids or taxanes. This selective interference with microtubule dynamics is a hallmark of eribulin’s mechanism.
Eribulin also causes tubulin proteins to accumulate into non-functional aggregates. This process, known as tubulin sequestration, reduces the pool of free tubulin. By trapping these building blocks, eribulin starves the cell of components needed to maintain its microtubule network.
Effects Beyond Direct Cell Killing
Eribulin’s influence extends beyond directly inducing cell death, affecting the broader tumor microenvironment. Preclinical studies have shown that eribulin can induce vascular remodeling within tumors. This process involves changes to the tumor’s blood vessels, potentially improving blood flow and oxygen delivery to the tumor tissue.
Increased oxygenation within the tumor, a state known as reduced hypoxia, can make cancer cells more responsive to other therapies, including chemotherapy and radiation. This vascular normalization effect might enhance the effectiveness of subsequent treatments by improving their delivery to the tumor.
Eribulin also demonstrates an ability to reverse the epithelial-to-mesenchymal transition (EMT). EMT is a biological process where cancer cells acquire characteristics that make them more mobile and invasive, contributing to metastasis. By promoting a shift back to an epithelial phenotype, eribulin may reduce the cancer’s capacity to spread to distant sites.
Clinical Relevance of the Mechanism
Understanding eribulin’s mechanism provides insight into its clinical profile, including common side effects. Since microtubules are involved in the transport of materials within nerve cells, disrupting them can lead to peripheral neuropathy.
This side effect manifests as numbness, tingling, or pain, particularly in the hands and feet. Peripheral neuropathy has been a common reason for treatment discontinuation in some patients receiving eribulin.
Bone marrow cells are among the most rapidly dividing cells. As eribulin interferes with cell division, these rapidly proliferating cells are particularly susceptible to its effects. This explains the occurrence of neutropenia, a reduction in neutrophils, which can increase the risk of infection.