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Feature

TherapeuticAdvances: 19th September 2002

Posted on: 27 Sep 02

Summary

This week’s TherapeuticAdvances focuses on emerging indications for histone deacetylase modulators including breast cancer and asthma. In addition we feature premature ejaculation, an indication that
sept 19th

LeadDiscovery.co.uk is a company founded by industrial researchers for the drug development sector. Our panel of pharmaceutical scientists produces TherapeuticAdvances, a twice-monthly bulletin of cutting edge scientific research with therapeutic potential. Selected research is fully analyzed in DiscoveryDossiers. These dossiers can be produced for institutions as due diligence reports or to boost technology transfer/partnering activity. Alternatively, dossiers can be purchased as overviews to support target identification or development efforts.

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An overview of TherapeuticAdvances

19th September 2002

A free and unabridged version of TherapeuticAdvances is available at http://www.leaddiscovery.co.uk/TherapeuticAdvances%20Archive/190902/index.html

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This week’s TherapeuticAdvances focuses on emerging indications for histone deacetylase modulators including breast cancer and asthma. In addition we feature premature ejaculation, an indication that may equal erectile dysfunction in blockbuster potential. Crossing into cardiovascular disease we report on the resurgence of angiotensin II receptor ligands …and finally, "Focus on CNS Disease" reports on advances in schizophrenia research.

In this weeks edition:

  • Histone deacetylase research opens the way to new treatments of breast cancer and asthma [more]
  • Sexual health: From erectile  dysfunction to female arousal disorder and premature ejaculation [more]
  • The resurgence of angiotensin II receptor ligands [more]
  • Breakthroughs in schizophrenia [more]

 Histone deacetylase research opens the way to new treatments of breast cancer and asthma

Modern day medicine is dominated by therapies that modify the activity of proteins linked to disease however altering the expression of these proteins represents an alternative therapeutic approach. Greater understanding of transcription and, in particular the role of chromatin plasticity in this process has driven greater understanding of the histone deacetylases (HDAC) and their therapeutic potential (Click here to access our recent report on this field). HDAC inhibitors can regulate the transcription of specific disease causing proteins. This week’s "Focus on Oncology" highlights the tumor suppressor maspin, the expression of which is lost in breast cancer leading to angiogenesis, invasive activity and metastasis. We report on data describing the hyperacetylation of the promoter region of the gene expressing maspin in breast cancer. We further report how reversing this using the HDAC inhibitor, trichostatin A, causes the re-expression of maspin, a finding that may lead to the development of successful metastatic breast cancer treatments. Although cancer has sat at the cutting edge of HDAC research, the therapeutic benefit of HDAC modulators is by no means restricted to neoplastic disease. This is well demonstrated by a second study featured in the current edition of TherapeuticAdvances. Asthma is a very common condition, affecting 155 million people worldwide. Targeting inflammatory mediators represents a well-accepted strategy for the treatment of asthma, however the complexity and the multiplicity of the immune system suggests that it may be beneficial to modulate the expression of multiple cytokines. Field-leaders at the National Heart and Lung Institute in London have examined the expression and activity of HDACs in bronchial biopsies from normal subjects and subjects with asthma. These authors report that subjects with asthma had reduced HDAC enzymatic activity and reduced HDAC1 and HDAC2 protein expression. These changes were reversed by inhaled steroids and were suggested to underlie the increased expression of multiple inflammatory genes in asthma. This study therefore suggests that molecules able to modify histone acetylation may be able to control conditions such as asthma as well as cancer. The body of published HDAC data is growing exponentially and over one new report is appearing each day. This new study demonstrates how the field is now starting to contribute to indications other than cancer and deserves careful monitoring by all in the drug development sector. [For further details all featured projects log on to TherapeuticAdvances]

Sexual health: From erectile  dysfunction to female arousal disorder and premature ejaculation

A second field that has been gaining considerable attention in the pharmaceutical industry is sexual health. This field exploded in 1998 when Pfizer launched Viagra, which then proceeded to become and overnight blockbuster. The rest of the pharmaceutical industry rapidly reacted, at first with the development of second-generation phosphodiesterase inhibitors and more recently with the investigation of other targets for erectile dysfunction or indeed alternative sexual health indications. Female sexual dysfunction remains an unmet indication with blockbuster potential (see our recent report "Male and female sexual dysfunction: Blockbuster indication for multiple pharmacological targets"). In our current edition of TherapeuticAdvances we focus on a large study that firmly establishes erectile dysfunction as a complication of diabetes. Likewise, in our newly launched "Lifestyles" section, which is dedicated to "quality of life" issues, we focus on a further male sexual health indication, premature ejaculation. Like erectile dysfunction, this condition represents a major market, and indeed in the age-range of 18-59 years old, premature ejaculation represents the predominant sexual dysfunction, affecting 28.5% of men. Today, there is no approved medical therapy for the treatment of premature ejaculation and successful pharmaceutical development in this field may therefore reap immense rewards. This appears to be changing and University of Cincinnati researchers who have identified the neural circuitry responsible for ejaculation have provided a platform for the identification of therapeutic candidates. Far from being a satisfied field, sexual dysfunction appears to remain a gold-mine for the pharmaceutical industry and development of treatments for conditions such as female sexual health and premature ejaculation are likely to demonstrate this in the near future. [For further details all featured projects log on to TherapeuticAdvances]

The resurgence of angiotensin II receptor ligands

Angiotensin II is one target that is addressed in our recent sexual dysfunction dossier. Anti-hypertensive angiotensin II receptor antagonists have recently come of age. Most examples of this therapeutic class have already entered the clinic and those that have reached the market are cutting into the market previously occupied by ACE inhibitors. Current global sales are around $2 million and continue to increase by about 35% per year. Identification of additional indications for angiotensin II receptor antagonists is appealing since this will further boost sales. This resurgent field is therefore encroaching on a number of different fields, such as sexual dysfunction and, as described in a second LeadDiscovery report, anxiety, depression and Alzheimer's disease (Click here for further details). Perhaps better known however are data showing that this class is able to limit atherosclerosis. These data are particularly important since atherosclerosis and hypertension are both risk factors for myocardial infarction and the use of angiotensin II receptor antagonists may therefore be of greater benefit than previously thought. Add to this data reported in our previous edition of TherapeuticAdvances (click here) describing the therapeutic effects that this class has in limiting the damage caused by myocardial infarction and it soon becomes apparent that the renin-angiotensin system is likely to be the subject of renewed R&D attention. [For further details all featured projects log on to TherapeuticAdvances]

Breakthroughs in schizophrenia

Our overview of TherapeuticAdvances concludes with mention of research highlighted in our "Advances from Industry" section which is, this week, dedicated to schizophrenia. Approximately 1% of Americans develop this disease and together, patients occupy about 25% of all hospital beds costing the US health care system US $19 billion per year. A lack of understanding of the etiology of schizophrenia has impeded the development of therapeutic candidates however researchers at DeCODE Genetics may have taken a step forward in our understanding and treatment of this disease. Neuregulin 1 is expressed at central nervous system synapses and has a clear role in the expression and activation of neurotransmitter receptors, including glutamate receptors that are implicated in schizophrenia. Mutant mice heterozygous for either neuregulin 1 or its receptor, ErbB4, show a behavioral phenotype that overlaps with mouse models for schizophrenia. Furthermore, DeCODE researchers also report that this ligand-receptor system may be the molecular target for clozapine, an atypical antipsychotic drug used to treat schizophrenia. TherapeuticAdvances is dedicated to highlighting new targets for the drug development sector and we hope that neuregulin 1 emerges as one particular target that will underlie treatments of this serious and unmet therapeutic area. [For further details all featured projects log on to TherapeuticAdvances]

Please remember that you can learn more about the publications mentioned above by logging on to TherapeuticAdvances. This is completely free and without obligation, so why not click the link and pay us a visit. In addition please note that we are currently featuring 2 new reports:

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Dr Jon Goldhill, LeadDiscovery

Last updated on: 27/08/2010 11:40:18

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