HDAC Inhibitors: Much to Learn About Effective Therapy

Shabason and colleagues’ review of the development of histone deacetylase (HDAC) inhibitors as treatment for cancers is timely, with an emphasis on therapeutic strategies combining HDAC inhibitors and radiation therapy. As the authors indicate, vorinostat (Zolinza)-originally known as suberoylanilide hydroxamic acid, or SAHA-was the first of the HDAC inhibitors approved by the US Food and Drug Administration (FDA) for clinical use in the treatment of cutaneous T-cell lymphoma (CTCL).[1] In November 2009, a second HDAC inhibitor-romidepsin (Istodax)-received FDA approval for the treatment of CTCL. Currently there is a great deal of competition in the HDAC inhibitor field, as several new and, hopefully, more effective compounds are being developed and entering clinical trials.[2]

Incomplete Understanding

It is clear that we do not have a complete understanding of the biologic activities of the 11 zinc-dependent HDAC enzymes, one or more of which are the targets of the inhibitors under development.[3] We know that these enzymes have both histone and nonhistone protein targets. Indeed, the HDACs are more properly referred to as lysine deacetylases, since class IIa HDACs 4, 5, 7 and 9 and class IIb HDAC6 appear to primarily target nonhistone proteins. The targets of the HDAC inhibitors are proteins that regulate gene expression, cell proliferation, cell migration, and cell death as well as have a role in angiogenesis and immune responses.[3]

Preclinical studies indicate that HDAC inhibitors can induce cancer cell death by targeting one or more cellular pathways. Normal cells are relatively resistant to HDAC inhibitor–induced cell death. This may be owing to the fact that cancer cells have multiple genetic defects and, unlike normal cells, do not have the capacity to reverse the adverse effects of HDAC inhibitors. A rather important question in this field is whether pan HDAC inhibitors such as vorinostat, which inhibits class I HDACs and class IIb HDAC6, are potentially more effective therapeutic agents than HDAC isoform selective inhibitors. The development of HDAC isoform selective inhibitors for clinical use has proved to be challenging and has not yet been achieved,[4,5]

HDAC inhibitors have shown antitumor activity across a broad variety of hematologic and solid tumors in both preclinical studies and clinical trials, but only a portion of patients with a given diagnosis have a therapeutic response.[2,3] As the authors emphasize, a very important issue is the need to identify markers of potential response or resistance to HDAC inhibitors. The accumulation of acetylated histones in peripheral mononuclear cells has been used as a guide to effective dosing, but this biologic effect of the HDAC inhibitor does not correlate with clinical response.[6] The use of HR23B as a marker of sensitivity of hematologic malignancies is important to evaluate. A systematic analysis of potential markers, such as levels of pro- and antiapoptotic proteins in circulating tumor cells, may be a path to identifying diagnostic indicators of clinical value in patients with solid tumors.

Conclusions

Shabason and colleagues review the results of clinical trials, as well as extensive preclinical studies, that indicate that HDAC inhibitors may be most useful in combination with other anticancer agents such as radiotherapy and cytotoxic or targeted drugs.[2,3,7] We have a good deal more to learn about the most effective therapeutic strategies for the use of HDAC inhibitors. The sequence of administration of HDAC inhibitors and other anticancer agents, optimal dosing, and schedule of drug administration remain challenging issues in developing more effective therapeutic strategies. HDAC inhibitors are a promising new group of targeted anticancer agents, particularly in combination therapy, with potential application for the treatment of hematologic and solid neoplasms.

Financial Disclosure: Merck Pharmaceuticals licensed SAHA and related compounds from MSKCC/Columbia University through acquisition of Aton Pharma, a biotech startup, in 2004. Dr. Marks was a founder of Aton and has a continuing financial potential royalty interest in Merck’s development of SAHA.

References:

References

1. Marks PA, Breslow R: Dimethyl sulfoxide to vorinostat: Development of this histone deacetylase inhibitor as an anticancer drug. Nat Biotechnol 25:84-90, 2007.

2. Ma X, Ezzeldin HH, Diasio RB: Histone deacetylase inhibitors: Current status and overview of recent clinical trials. Drugs 69:1911-1934, 2009.

3. Xu WS, Parmigiani RB, Marks PA: Histone deacetylase inhibitors: Molecular mechanisms of action. Oncogene 26:5541-5552, 2007.

4. Wang H, Dymock BW: New patented histone deacetylase inhibitors. Expert Opin Ther Pat 19:1727-1757, 2009.

5. Suzuki T: Explorative study on isoform-selective histone deacetylase inhibitors. Chem Pharm Bull (Tokyo) 57:897-906, 2009.

6. Kelly WK, O’Connor OA, Krug LM, et al: Phase I study of an oral histone deacetylase inhibitor, suberoylanilide hydroxamic acid, in patients with advanced cancer. J Clin Oncol 23:3923-3931, 2005.

7. Frew AJ, Johnstone RW, Bolden JE: Enhancing the apoptotic and therapeutic effects of HDAC inhibitors. Cancer Lett 280(2):125-133, 2009.