Eribulin, sold under the brand name Halaven among others, is an

anti-cancer medication Chemotherapy (often abbreviated chemo, sometimes CTX and CTx) is the type of cancer treatment that uses one or more anti-cancer drugs ( chemotherapeutic agents or alkylating agents) in a standard regimen. Chemotherapy may be given with a cu ...

used to treat

breast cancer Breast cancer is a cancer that develops from breast tissue. Signs of breast cancer may include a Breast lump, lump in the breast, a change in breast shape, dimpling of the skin, Milk-rejection sign, milk rejection, fluid coming from the nipp ...

and

liposarcoma Liposarcomas are the most common subtype of soft tissue sarcomas, accounting for at least 20% of all sarcomas in adults. Soft tissue sarcomas are rare neoplasms with over 150 different histological subtypes or forms. Liposarcomas arise from the ...

. The most common side effects include fatigue, nausea, hair loss (alopecia), constipation, certain nerve damage causing weakness or numbness in the hands and feet (peripheral neuropathy), abdominal pain and fever (pyrexia). Eribulin may also cause low levels of infection-fighting white blood cells (neutropenia) or decreased levels of potassium or calcium. Eribulin was approved for medical use in the United States in November 2010, the European Union in March 2011, and Canada in December 2011. It is available as a

generic medication A generic drug is a pharmaceutical drug that contains the same chemical substance as a drug that was originally protected by chemical patents. Generic drugs are allowed for sale after the patents on the original drugs expire. Because the active ch ...

Medical uses

Eribulin is

indicated In medicine, an indication is a valid reason to use a certain test, medication, procedure, or surgery. There can be multiple indications to use a procedure or medication. An indication can commonly be confused with the term diagnosis. A diagnosis ...

for the treatment of people with locally advanced or metastatic breast cancer, and for the treatment of adults with unresectable liposarcoma.

Adverse effects

Serious side effects may include anaemia; decrease in white blood cell count, which can increase the risk of serious infections that could lead to death; hair loss; cancer-related fatigue; numbness, tingling or burning in the hands and feet (neuropathy); harm to a developing fetus; as well as changes in heartbeat (QTc prolongation), that may also lead to death.

Structure and mechanism

Eribulin is a fully synthetic macrocyclic

ketone In organic chemistry, a ketone is an organic compound with the structure , where R and R' can be a variety of carbon-containing substituents. Ketones contain a carbonyl group (a carbon-oxygen double bond C=O). The simplest ketone is acetone ( ...

analog of the marine

natural product A natural product is a natural compound or substance produced by a living organism—that is, found in nature. In the broadest sense, natural products include any substance produced by life. Natural products can also be prepared by chemical s ...

halichondrin B, the parent molecule being a naturally occurring, potent mitotic inhibitor with a unique

mechanism of action In pharmacology, the term mechanism of action (MOA) refers to the specific biochemical Drug interaction, interaction through which a Medication, drug substance produces its pharmacological effect. A mechanism of action usually includes mention o ...

. The parent molecule was originally found in the

sponge Sponges or sea sponges are primarily marine invertebrates of the animal phylum Porifera (; meaning 'pore bearer'), a basal clade and a sister taxon of the diploblasts. They are sessile filter feeders that are bound to the seabed, and a ...

'' Halichondria okadai''. Eribulin is a mechanistically unique inhibitor of microtubule dynamics, binding predominantly to a small number of high affinity sites at the plus ends of existing microtubules. Eribulin has both cytotoxic and non-cytotoxic mechanisms of action. Its cytotoxic effects are related to its antimitotic activities, wherein

apoptosis Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...

of cancer cells is induced following prolonged and irreversible mitotic blockade. In addition to its cytotoxic, antimitotic-based mechanisms, preclinical studies in human breast cancer models have shown that eribulin also exerts complex effects on the biology of surviving cancer cells and residual tumors that appear unrelated to its antimitotic effects. These non-mitotic mechanisms include vascular remodeling that leads to increased tumor perfusion and mitigation of tumor hypoxia, phenotypic changes consistent with reversal of epithelial-mesenchymal transition (EMT), and decreased capacity for migration and invasion leading to reduced metastatic capacity as measured in a preclinical experimental metastasis model. In other studies, eribulin treatment of

leiomyosarcoma A leiomyosarcoma (LMS) is a rare malignant (cancerous) smooth muscle tumor. The word is . The stomach, bladder, uterus, blood vessels, and Gastrointestinal tract, intestines are examples of hollow organs made up of smooth muscles where LMS can be ...

and

cells leads to increased expression of

smooth muscle Smooth muscle is one of the three major types of vertebrate muscle tissue, the others being skeletal and cardiac muscle. It can also be found in invertebrates and is controlled by the autonomic nervous system. It is non- striated, so-called bec ...

and

adipocyte Adipocytes, also known as lipocytes and fat cells, are the cell (biology), cells that primarily compose adipose tissue, specialized in storing energy as fat. Adipocytes are derived from mesenchymal stem cells which give rise to adipocytes through ...

differentiation antigens, respectively. Taxane-resistant cancers are often unresponsive to eribulin. A recent study found that this resistance is due to expression of multidrug resistance protein 1 (MDR1). Fluorescently labeled eribulin has been used to study the

pharmacokinetics Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to describing how the body affects a specific su ...

and

pharmacodynamics Pharmacodynamics (PD) is the study of the biochemistry, biochemical and physiology, physiologic effects of drugs (especially pharmaceutical drugs). The effects can include those manifested within animals (including humans), microorganisms, or comb ...

at single cell level ''in vivo''. The synthesis of eribulin was first published in 2001; a new synthetic route to the drug was published in 2009.

Research

Eribulin is being investigated for use in a variety of solid tumors, including

non-small cell lung cancer Non-small-cell lung cancer (NSCLC), or non-small-cell lung carcinoma, is any type of epithelial lung cancer other than small-cell lung cancer (SCLC). NSCLC accounts for about 85% of all lung cancers. As a class, NSCLCs are relatively insensitiv ...

prostate cancer Prostate cancer is the neoplasm, uncontrolled growth of cells in the prostate, a gland in the male reproductive system below the bladder. Abnormal growth of the prostate tissue is usually detected through Screening (medicine), screening tests, ...

brain cancer A brain tumor (sometimes referred to as brain cancer) occurs when a group of cells within the brain turn cancerous and grow out of control, creating a mass. There are two main types of tumors: malignant (cancerous) tumors and benign (non-cance ...

cervical cancer Cervical cancer is a cancer arising from the cervix or in any layer of the wall of the cervix. It is due to the abnormal growth of cells that can invade or spread to other parts of the body. Early on, typically no symptoms are seen. Later sympt ...

, urothelial cancer,

melanoma Melanoma is the most dangerous type of skin cancer; it develops from the melanin-producing cells known as melanocytes. It typically occurs in the skin, but may rarely occur in the mouth, intestines, or eye (uveal melanoma). In very rare case ...

, solitary fibrous tumors, and various

sarcoma A sarcoma is a rare type of cancer that arises from cells of mesenchymal origin. Originating from mesenchymal cells means that sarcomas are cancers of connective tissues such as bone, cartilage, muscle, fat, or vascular tissues. Sarcom ...

s. Two eribulin based products are in the research and development phase; a liposomal formulation and antibody drug combination therapy, both are for the treatment of solid tumors. The liposomal formulation of eribulin, E7389 liposomal, is in Phase I clinical trials. Preliminary ''in vivo'' experiments show a decrease in C(max) and a longer half-life with the liposomal formulation. The drug antibody eribulin combination therapy is a joint venture between Eisai and Merck. The clinical trials combine eribulin and pembrolizumab, a PD-1 inhibitor, for the treatment of breast cancer and other advanced cancers.

References

{{Authority control Antineoplastic drugs Macrocycles Orphan drugs Tetrahydropyrans Tetrahydrofurans Methoxy compounds Amines