HDIs and oncology’s great hope

Ricky Johnstone

The US Food and Drug Administration has already approved the first HDI, Merck’s Vorinostat, as a treatment for cutaneous T-cell lymphoma. Several other HDIs are in late-phase clinical trials.

But Dr Ricky Johnstone, head of the Gene Regulation Laboratory at the Peter MacCallum Cancer Research Institute’s Cancer Immunology Division, says unlocking HDIs’ full potential requires a detailed understanding of how they work, alone or in combination with current chemotherapy agents like cis-platins, taxols, and monoclonal antibodies.

Histone acetylation and deacetylation are opposing epigenetic processes with central roles in regulating gene activity. Acetylation activates genes by modifying chromatin.

Histone acetyltransferase enzymes (HATs) attach acetyl groups to lysine residues on histone proteins. The acetylated histone spools relax their hold on the DNA wound around them, allowing transcription factors to access the promoters of genes at that chromosomal locus.

Acetylated regions of chromosomes have a puffy appearance. The cell shuts down activated loci by synthesising histone deacetylase enzymes, which move into chromatin and remove the acetyl molecules from the histone spools. The deacetylated histones bind strongly to the DNA coiled around them, rendering gene promoters inaccessible to transcription complexes.

Johnstone and his colleagues are using knockout-mutant mice to explore how HDIs induce apoptosis and how cancerous cells escape cell-cycle and apoptotic checks to proliferate and survive.

RNA interference has gone from a laboratory curiosity to a powerful tool for exploring gene networks in cell culture. Short interfering RNAs (siRNAs) now make it a relatively simple matter to knock down the activity of genes of interest in normal and cancerous cell lines.

HDIs originally came to attention for their ability to induce cellular differentiation in tumour cells, but more recently have caused excitement for their potential to treat neurological disorders involving gene-transcription defects, including motor neuron disease.

Researchers from California’s Scripps Institute reported in a paper in PNAS in October that the HDI 4b ameliorates the symptoms of Huntington’s disease in transgenic mice expressing a pathological form of the human huntingtin gene, as well as restoring a more normal pattern of huntingtin expression.

It is the capacity of HDIs to augment the tumour-killing power of conventional cancer-killing agents that excites oncology researchers. As monotherapies, HDIs show their greatest potential for treating blood cancers.

Johnstone says they are very effective for the treatment of cutaneous T-cell lymphoma. While they are not quite as potent as current chemotherapeutics, they are considerably less toxic. But used in combination with more familiar therapies, they appear to work synergistically to force cancerous cells to differentiate and undergo apoptosis – programmed cell death.

Ultimately, says Johnstone, their efficacy will probably hinge on genotyping patients’ cancers to determine their vulnerability to particular combinations of HDIs and other cell-killing agents.

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