Ultimately, advancing more HDAC inhibitors into viable therapeutics will require a more in-depth understanding, not only of the basic science of HDACs, but also their pharmacology, suggests Sriram Balasubramanian, Ph.D., senior director, translational research at Pharmacyclics.
“We are finding that HDAC inhibitors work well for hematological malignancies such as lymphomas, leukemias, and multiple myeloma, but only partially for solid tumors, which represent the majority of cancers. So, a basic question is ‘how do we get them to work here?’ It is likely that HDAC inhibitors may function best in combination with other therapies. But, to answer these questions, we will need to elucidate basic mechanisms of how HDACs function. As that pool of knowledge grows, we will be better able to determine how to combine HDAC inhibitor therapy with other strategies.”
Dr. Balasubramanian says another challenge is dealing with toxicity issues. “It is estimated that anywhere from 4–20 percent of the transcriptome can be altered as a result of using a single pan-HDAC inhibitor such as SAHA. Additionally, tens to hundreds of proteins may become acetylated after treatment with a pan-inhibitor. On the plus side, it appears that normal cells are more resistant to the apoptotic effects of HDAC inhibition. This may partly explain how clinical efficacy can be achieved at the tolerated doses.”
Since all of the HDAC inhibitors currently marketed or in clinical development inhibit multiple isoforms, broader applications of HDAC inhibitors will require a more sophisticated understanding of how each isoform works.
“There is clearly a role of specific isoforms in certain types of cancer, as well as in other diseases. But because of their similarity, it can be difficult to make selective compounds. This has been a real struggle in the field. Even with high-throughput screening, the progress has been limited by the structural information available,” Dr. Balasubramanian explains.
“Since the binding pockets of different isoforms can be quite similar, high-resolution crystal structures are needed. HDAC isoforms have been hard to crystallize individually, partly because they are usually found in complexes and with few exceptions, not as single entities. What is needed is more structure-guided rational design and computational chemistry.”
The exciting prospect of HDAC inhibitor therapeutics is clearly on the radar. Resolving specificity and toxicity issues should help launch even more candidates into clinical trials.