HDAC6 Inhibitor QTX125 Slows Mantle Cell Lymphoma Progression, Preclinical Study Shows

HDAC6 Inhibitor QTX125 Slows Mantle Cell Lymphoma Progression, Preclinical Study Shows

A new epigenetic therapy that prevents DNA modifications is able to slow down the growth of mantle cell lymphoma and induce cancer cell death, a study in mice and lab-grown cells shows.

The compound, called QTX125, is an inhibitor of an enzyme known as histone deacetylase 6 (HDAC6) that showed better effectiveness than the same kind of currently available therapies.

The study, “In vitro and in vivo activity of a new small-molecule inhibitor of HDAC6 in mantle cell lymphoma,” was published in the journal Haematologica.

Cancer cells are masters at taking advantage of biological mechanisms that help them survive. One strategy they use is modifying their genetic and metabolic profiles, by taking control of some key molecules that regulate these processes.

HDAC6 is an enzyme that adds chemical molecules to DNA, determining which genes are and aren’t expressed at a given time in a cell. The protein is involved in many human diseases, and promotes cancer initiation, development, and spread in multiple tumor types.

Thus, some HDAC6 inhibitors, such as rocilinostat (ACY-1215), are already in clinical trials for both blood and solid cancers.

Researchers have now developed QTX125, a new small molecule designed to specifically target and inhibit HDAC6, while keeping the activity of other HDAC enzymes intact.

Authors examined the anti-tumor activity of QTX125 in 48 human cancer cell lines, covering the most prevalent cancer types — including breast, prostate, and ovarian cancer, melanoma, chronic myelogenous leukemia, multiple myeloma, and Hodgkin’s lymphoma.

QTX125 was particularly effective in lymphomas, including Burkitt’s cell lymphoma, follicular lymphoma, and mantle cell lymphoma.

Treatment of mantle cell lymphoma now consists of a combination of chemotherapy and Rituxan (rituximab) — called R-CHOP. No targeted therapies exist specifically for this kind of lymphoma. Because of this, the researchers assessed QTX125 as a potential treatment for this blood cancer.

QTX125 promoted cell death in a dose-dependent manner, meaning that the higher the dose, the more cancer cells died. Interestingly, the compound was better at inhibiting HDAC6 than any other HDAC6 inhibitors in development, and acted only on cancer cells, leaving healthy blood cells unharmed.

QTX125’s effectiveness was evaluated in mice implanted with mantle cell lymphoma cells. It was significantly better than the chemotherapy cyclophosphamide at reducing tumor growth and progression, the investigators found.

“What makes us especially happy in this case is the possible use of the drug in clinical trials for next year,” Manel Esteller, senior author of the study, said in a press release. Esteller is the director of the Epigenetics and Cancer Biology Program at the Bellvitge Biomedical Research Institute, ICREA researcher, and a professor of genetics at the University of Barcelona.

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