Histone deacetylase (HDAC) inhibitors are anti-cancer agents that block the function of an enzyme called HDAC, allowing the expression of genes that are involved in cell division and ultimately slowing down the spread of cancer.

The U.S. Food and Drug Administration (FDA) has so far approved four HDAC inhibitors for the treatment of cancer. These include romidepsin, Zolinza (vorinostat), and belinostat (PXD101) for T-cell lymphomas such as cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphoma (PTCL). Farydak (panobinostat) has been approved for myeloma.

How do HDAC inhibitors work?

DNA inside the body’s cells is not “free-floating,” but is tightly coiled and condensed into structures called chromatin with the help of proteins called histones. Histones also control the access of enzymes to the DNA for genes to be made into proteins.

HDACs are enzymes that help “turn off” gene expression by removing acetyl groups from histone proteins — hence the term deacetylases. Treatment with HDAC inhibitors blocks the activity of HDAC enzymes and allows the genes to be “turned on” or made into protein. Inhibiting the activity of HDAC enzymes can turn on tumor suppressor genes to help control cell division and slow down cancer progression.

HDAC inhibitors in clinical trials for myeloma

A Phase 3 clinical trial (NCT01023308) called PANORAMA-1 studied the use of Farydak. The therapy was used in combination with a proteasome inhibitor such as Velcade (bortezomib) and dexamethasone in people with relapsed or refractory multiple myeloma (RRMM) who have already received two prior treatments of Velcade and immunomodulatory treatments such as Revlimid (lenalidomide). The results showed that individuals who received Farydak lived longer than the control group, with a shrinkage in cancer size in about 59% of the patients.

Romidepsin also was tested in people with RRMM in a Phase 2 clinical trial (NCT00066638). Although romidepsin alone did not achieve the desired response, several patients showed stabilization of M-protein production — an abnormal protein produced by myeloma cells — and improvement in bone pain and hypercalcemia symptoms. Hypercalcemia is a condition in which calcium levels in the blood are above normal.

Zolinza in combination with Velcade was found to be well-tolerated and effective in RRMM patients in a Phase 2 clinical trial (NCT00773838). In a Phase 1 trial (NCT00729118), Zolinza had been found to improve transplant response and prolong survival when added to Revlimid maintenance therapy in myeloma patients who had undergone autologous hematopoietic stem cell transplant (AHSCT). A Phase 3 clinical trial (NCT00773747) of Zolinza in combination with Velcade to treat myeloma patients was completed in 2015. The results did not show clinical relevance in terms of progression-free survival when compared with healthy people (controls).

Belinostat was evaluated in combination with dexamethasone in a Phase 2 clinical trial (NCT00131261) in advanced myeloma patients who failed at least two prior therapies. A Phase 2 trial (NCT00431340) to study the safety and efficacy of belinostat in individuals with RRMM was terminated due to dose-limiting toxicity.

Due to clinically insignificant results in clinical trials, belinostat and Zolinza are no longer being considered as suitable HDAC inhibitors for myeloma.

Experimental HDAC inhibitors

Two other HDAC inhibitors are currently being tested in clinical trials for myeloma in combination with other treatments. These are ricolinostat (ACY-1215), which is being assessed in two Phase 1/2 clinical trials — NCT01583283 and NCT01997840 — and citarinostat (ACY-241), being evaluated in a Phase 1 clinical trial (NCT02886065). The citarinostat trial is currently recruiting participants in the U.S. with smoldering multiple myeloma.

 

Last updated: Feb. 11, 2020

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Özge has a MSc. in Molecular Genetics from the University of Leicester and a PhD in Developmental Biology from Queen Mary University of London. She worked as a Post-doctoral Research Associate at the University of Leicester for six years in the field of Behavioural Neurology before moving into science communication. She worked as the Research Communication Officer at a London based charity for almost two years.