A real histone deacetylase inhibitor finally approved for cancer

SAHA, or suberoylanilide hydroxamic acid, was recently granted orphan drug approval by the US FDA for skin lesions resulting from cutaneous T-cell lymphoma.

SAHA (vorinostat, Zolinza) will be marketed by Merck as they acquired in 2004 Aton Pharma, who had been developing the compound. (This free Nature Biotechnology article, while dated, gives background on the acquisition and the then-development of other similar compounds.) Merck's press release is farily detailed and available in PDF format.

I'm somewhat surprised that more has not been made of this approval since histone deacetylase inhibitors have been touted for cancer and as differentiation agents since the mid 1970s, beginning with sodium butyrate, sodium phenylbutyrate, and other short chain fatty acids. The problem with these compounds, like many other natural products (butyrate is produced in our guts as a product of fiber fermentation), is that they fail to acheive concentrations in blood necessary to exert anticancer effects that are seen in cell culture. In fact, the old antiepilepsy and antimanic drug, valproic acid, can also act as a histone deacetylase inhibitor.

Believe it or not, we still really don't know how these agents work. Yes, we know a multitude of their cellular effects, but we don't know how they act in treating cancer. Inhibiting histone deacetylases, or HDACs, is known to activate gene transcription that may in turn repress some other genes, but only a subset of genes are responsive. The collective result of these effects is growth arrest, cellular differentiation, and/or programmed cell death. HDAC inhibitors often synergize with other cytotoxic chemotherapeutics. However, there is far more finesse in this system than we understand currently. Moreover, there are other, non-histone targets of protein acetylation that may play a role in the action of these compounds.

Two major fungal natural products, trichostatin A (also known commonly as TSA) and trapoxin, have been major laboratory tools in the study of this area of gene transcription and cancer biology. Stuart Schreiber's group used an affinity matrix with trapoxin to isolate biochemically the first histone deacetylase. Despite their nanomolar potency, these compounds were found to be too broadly toxic to be employed as anticancer drugs.

As I said earlier, the butyrates were so low in potency that grams of the compounds had to be infused intravenously to attain reasonable plasma levels. Butyrate itself only has a plasma half-life of 6 min. Phenylbutyrate was little longer lived and there are isolated cases of its use in leukemia and disorders of glutamine metabolism. So, the hydroxamic acids were developed and this approval of SAHA should open the door to finding out just how effective this new class of anticancer drugs will be.

One should always take note anytime a new chemotherapeutic drug is approved that acts via a novel mechanism. Combination chemotherapy is based on using drugs with non-overlapping mechanisms of action. Hence, I applaud the approval of SAHA and eagerly await results of its more broad application against other human cancers.