2 Cancer Meds May be Promising Combo Treatment for Cushing’s Disease

A combination of bexarotene and lapatinib, two approved anti-cancer medications, may hold promise in treating Cushing’s disease, according to a recent study.

The study, “Bexarotene combined with lapatinib for the treatment of Cushing’s disease: evidence based on drug repositioning and experimental confirmation,” was published in the journal Signal Transduction and Targeted Therapy.

Cushing’s syndrome is caused by the excessive production of the glucocorticoid hormone cortisol by the adrenal glands, which sit on top of the kidneys.

This syndrome can be triggered by over-production of the adrenocorticotropic hormone (ACTH) driven by a tumor in the pituitary gland, a medical condition known as Cushing’s disease.

Recent studies have identified a transcription factor — a protein that is able to control the activity of certain genes — called Nur77 as a promising therapeutic target for Cushing’s disease. Nur77 can control the activity of POMC, the gene that provides instructions to make proopiomelanocortin, ACTH’s precursor.

A compound able to prevent Nurr77 from activating POMC and the production of proopiomelanocortin might be able to prevent ACTH from being produced.

According to researchers, a compound with this mechanism of action, given alongside a second medication that helps to normalize ACTH levels over the short term, could be a promising combination for patients with Cushing’s disease.

Researchers with the Chinese Academy of Medical Science and Peking Union Medical College tested if a combination of bexarotene and lapatinib, approved in the U.S. to treat different types of cancer, held potential as a treatment.

Bexarotene (sold under the brand name Targretin) is approved to treat cutaneous T-cell lymphoma. Bexarotene is an agonist of RXR-alpha, another transcription factor that is known to interact with Nur77 and drive it away from the cell’s nucleus, where Nur77 would normally activate POMC to produce proopiomelanocortin.

Due to its ability to potentiate RXR-alpha’s interaction with Nur77, bexarotene was selected to be tested as a medication that might be repurposed for Cushing’s disease.

They also selected lapatinib (brand name Tykerb), approved to treat advanced forms of hormone-driven breast cancer, due to its ability to block the PI3K-AKT pathway, which controls cancer cell growth and survival. By inhibiting this signaling pathway, lapatinib can potentially prevent tumor cells in the pituitary gland from expanding.

When investigators tested the combination of these therapies in mouse pituitary tumor cells cultured in a lab dish, they found  these cells lost their ability to grow and produce ACTH.

They also confirmed ACTH production was prevented through bexarotene’s effect of promoting the association of RXR-alpha with Nur77, which lowered the production of proopiomelanocortin.

The same benefits were seen when researchers treated mice with implanted tumor cells with this bexarotene-lapatinib mix.

“[O]ur present study revealed a novel combination therapy of BEXA/LAPA [bexarotene-lapatinib] through a Nurr77-dependent mechanism via drug repositioning and experimental confirmation, which provides new ideas for CD [Cushing’s disease] treatment,” the researchers concluded.