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Exploiting HDAC Inhibition

Cancer and Metabolic Diseases Represent Promising Applications

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Histone deacetylases (HDACs) are emerging as exciting new targets for drug development, particularly for cancer and metabolic diseases. Because they exert control over gene tranion and cell-cycle progression, they represent a novel approach for epigenetic therapeutic intervention.

The first such agent was approved by the FDA in 2006 (suberoylanilide hydroxamic acid or SAHA, vorinostat) for the treatment of advanced cutaneous T-cell lymphoma. The rapid approval of SAHA helped accelerate the study of this innovative area. Currently, only one other HDAC is approved in the same indication, although a number of other inhibitors are now in development.

There are many proposed consequences of HDAC inhibition that range from induction of apoptosis, inhibition of DNA repair, upregulation of tumor suppressors, and others. This is further complicated because the HDAC family consists of at least 18 members divided phylogenetically into four classes.

CHI’s conference “HDAC Inhibitors” will showcase updates on new therapeutics and emerging methodologies, as well as discussing where the field is headed.

“There are already some links identified between the presence of specific isoforms of HDAC enzymes and specific forms of cancer,” notes Bernd Hentsch, Ph.D., chief development officer at 4SC (“For example, ed HDAC enzymes are frequently found to be overexpressed in specific types of cancer as compared to normal tissue, such as the HDAC1 protein in hepatocellular carcinoma (HCC) or HDAC2 in colorectal tumors.

“In fact, this overexpression, as exemplified in the case of HCC and HDAC1, can be directly linked to a poorer prognosis. Even though this would imply that targeting such individual HDAC enzymes could be the way to go, the development of an HDAC inhibitor with a wider spectrum could provide broader applicability or even stronger clinical activity.”

The race to identify the most promising approach is still being run, notes Dr. Hentsch. “The field is currently trying to understand whether it would be more advantageous to target individual HDAC proteins or pursue a broader (pan) inhibitory approach. It is clear that if one strikes more HDAC enzymes at a time, such a drug may cover more malignancies or may even offer a more efficacious therapy. On the other hand, the fine-tuned balance between HDAC inhibitor ivity and toxicity is still unclear at present.”

The company is developing its own lead HDAC inhibitory product, resminostat. “This is a novel pan-HDAC inhibitor undergoing Phase II evaluation as an oral mono or combination therapy for treating advanced HCC and relapsed or refractory Hodgkin lymphoma,” Dr. Henstch says. “We are also due to commence a Phase II trial to investigate resminostat as a second-line treatment for KRAS-mutated colorectal carcinoma patients in combination with standard chemotherapy. To broaden our HDAC portfolio, we are advancing a ive HDAC into a Phase I this year.”

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