Future research strategies for glucocorticoid therapy

Why do some people contact diseases while others stay healthy? This is a central question in medicine. Similarly, why some individuals recover quickly using drug treatments while others do not is a fundamental question in pharmacology. Individual differences in susceptibility to disease and drug efficacy are believed to originate from both environmental and genetic factors. Here, I will briefly discuss these two factors by highlighting the research on the glucocorticoid receptor (GR), which is an important drug target.

Since the discovery of the inflammation‑suppressing effect of glucocorticoids by Philip Hench in the 1950s, numerous drugs, such as dexamethasone and prednisone, have been developed that target the GR. Recent research on genetic and environmental factors affecting GR signalling indicate that these factors will shape the future of personalised glucocorticoid therapy.

Genetic factors

Insight into the structure of the human genome, completed in 2001, revealed that millions of small genetic polymorphisms exist between individuals. Today, these polymorphisms are called single nucleotide polymorphisms (SNPs) and are believed to account for 80% of the genetic variability in humans. SNPs also form the genetic components of the variability in individuals’ susceptibility to diseases and response to therapeutics.

On average, one SNP is present in 500 bp (base pairs). With a length of approximately 300000 bp, about 600 SNPs will be present in the human GR gene. Several SNPs corresponding with functional domains of the human GR protein and mRNA have already been identified, and follow‑up studies have shown that these are associated with the GR’s sensitivity to cortisol.^1-3 Therefore, mutations in the human GR gene may cause glucocorticoid resistance. Other mutations affect the stability of the GR mRNA and are associated with increased susceptibility to rheumatoid arthritis.⁴ Further studies showed association with increased body mass index and increased abdominal obesity.⁵

The effect of SNPs on GR signalling is likely to be much more complex because GR activation is mediated by a protein complex that consists of numerous proteins, such as heat shock proteins. SNPs in these proteins may also affect cortisol‑based drug efficacy. Indeed, SNPs in FKBP5, a protein involved in GR signalling, have been associated with remission in antidepressant treatment.⁶

In light of all this research, determining the patient SNP profile of drug targets may have a predictive value for drug efficacy and could form part of the future of personalised medicine.

Environmental factors

It has been known for decades that GR signaling is negatively affected by environmental factors, such as traumatic stress in early life, chronic stress in adulthood and aging.^7-9 Interestingly, all these factors are associated with reduced GR protein levels, which indicate that individual fluctuation in the amount of drug targets is of relevance for disease and drug therapy. Subsequent research into the mechanisms of reduced GR protein levels highlighted epigenetic programming as an important feature.^10,11

More recently, cell‑specific microRNAs, a group of small non-coding RNAs, have been identified as regulators of GR protein levels.¹² Together with classical gene promoter regulation, a complex picture emerges for GR protein expression. Insight into this regulation in patients may be of relevance for individual cortisol-based treatment.

Future research strategies

So, with the above in mind, what are the future research strategies in personalised medicine? These strategies are already being seen today; every day, studies are appearing that report disease‑associated SNPs as important drug targets. Numerous studies focusing on expression regulation of drug targets are also being conducted.

One future research strategy could be to use ‘humanised’ animal models. Human drug-target genes bearing disease‑associated SNPs can be introduced in animal models and drug efficacy can be measured. For diagnostic purposes, DNA chips with all drug‑target related SNPs can also be developed and such tools may aid the development of tailor‑made therapies. Similarly, biochemical kits can be designed that identify protein levels, the epigenetic state and microRNAs relevant for drug targets to explore novel and innovative therapeutic avenues.

The discovery of microRNAs and RNA‑interference technology holds great promise for developing novel therapeutics that may lead to a new generation of highly specific nucleic acid-based drugs. To deliver such drugs, however, novel carrier tools, such as polymers, nanoparticles and peptide-conjugates, will also be required.

References
1. G.P. Chrousos, et al., J. Clin. Invest. 69, 1261-1269 (1982).
2. M. Ruiz, et al., Clin. Endocrinol. 55, 363-371 (2001).
3. A. Vottero, et al., J. Clin. Endocrinol. Metab. 87, 2658-2667 (2002).
4. E.R. Emery, et al., J. Rheumatol. 28, 2383-2388 (2001).
5. E.F. van Rossum and S.W. Lamberts, Recent Prog. Horm. Res. 59, 333-357 (2004).
6. E.B. Binder, et al., Nat. Genet. 36, 1319-1325 (2004).
7. I.C. Weaver, et al., Ann. N. Y. Acad. Sci. 1024, 182-212 (2004).
8. K. Mizoguchi, Neuroscience 159, 259-270 (2009).
9. R.M. Sapolsky and B.S. McEwen, Endocrinology 114, 287-292 (1984).
10. P.O. McGowan, et al., Nat. Neurosci. 12, 342-348 (2009).
11. I.C. Weaver, et al., Nat. Neurosci. 7, 847-854 (2004).
12. E. Vreugdenhil, et al., Endocrinology 150, 2220-2228 (2009).

Based on a contribution by Erno Vreugdenhil, Associate Professor at the Leiden/Amsterdam Center for Drug Research, University Leiden (The Netherlands).