Responsive DNA accessibility to epigenetic drug helps indicate the right treatment for prostate cancer patients

Study published in Cell Reports shows that the accessibility of DNA varies from patient to patient, and may act as a fingerprint for prostate cancer progression.

Studying the specific characteristics of such DNA accessibility could make it possible to understand which of the epigenetics treatments already used in clinical trials for other cancers are best suited to prostate cancer patients.

Prostate cancer is the most common male cancer in the USA and Europe. Whilst diagnostics tools exist, detecting the severity and stage of prostate cancer can be extremely difficult.

Researchers at NCMM have discovered a way that could potentially show how advanced a tumour is, as well as a method to help identify which patients could benefit from certain targeted therapies for therapeutically attractive bromodomain containing proteins. The findings were recently published in Cell Reports

Personalised cancer treatment for prostate cancer

Another challenging promise of “personalised medicine” in cancer is to establish differences between tumours. These differences can be used to differently target defects of the cells that have allowed the cancer to grow and escape conventional chemotherapy. Ultimately, this would mean scheduling patients for different treatments depending on the different defects that have allowed the tumour to grow.

To understand such so-called biomarkers for treatment is, essentially, trivial but it does hold the key to a future where we can better use drugs that are already available, through re-purposing them for treating other diseases, such as those that are apparently different but genetically similar.

Androgen Receptor and prostate cancer

The Androgen Receptor (AR) is a protein that fuels prostate cancer growth, by ‘switching on’ genes that wouldn’t normally be associated with the disease. Androgens, or male sex hormones such as testosterone, send messages through the AR, into the prostate’s cells and tissues. If there is a fault in this messaging, cell division can be triggered which can lead to abnormal growth of the cells and, therefore, prostate cancer.

Standard treatments for prostate cancer involve targeting and blocking the AR, however some men can become immune to this therapy. This is when castration-resistant prostate cancer (CRPC) can develop, for which many drugs have been approved but, despite prolonged survival, none of them can ultimately ‘cure’ the patient.

Illustration from Cell Reports depicting chromatin relaxation
The image depicts tightly packed nucleosomes surrounded by a protective blue prostate cancer awareness ribbon. The shied knot symbol on the nucleosomes underscores the protected state the chromatin is in. The nature of their data (heatmaps) is cited by the more abstract background elements in the picture. Illustration by Oliver Hoeller.

Chromatin relaxation

In this study, Urbanucci and colleagues show how upregulated AR and bromodomain proteins regulated by AR, contribute to genome-wide chromatin relaxation, which then leads to increased DNA accessibility. This in turn leads to increased gene transcription in advanced prostate cancer. The study therefore shows, in very basic terms, that the relaxed chromatin is a typical feature of advanced prostate cancer.

Urbanucci and colleagues show that bromodomain-containing proteins (BRDs), such as BRD4, and androgen-regulated BRD2 and ATAD2, are the mediators of such increased DNA accessibility, and can be prognostic tissue markers. For instance ATAD2 was strikingly present in the tumours of those patients that relapsed after first treatment via androgen deprivation therapy.

New prognostic and predictive tools for prostate cancer

These findings constitute the potential for creating new prognostic and predictive tools, whereby chromatin accessibility can be used as an indicator of prostate cancer progression and severity, and help indicate the most suitable form of treatment for the patient.

By studying the chromatin and DNA accessibility, Urbanucci and colleagues have also determined a 10-gene signature, BROMO-10, that can be used as a genetic biomarker to show which patients fall into different categories in terms of the severity of their cancer.

Using BROMO-10, they also predicted which tumours responded to treatments with bromodomain inhibitors, thereby helping to provide further tools for personalising prostate cancer treatment.

The findings were recently published in Cell Reports. Read the full article on Cell Reports: Androgen Receptor Deregulation Drives Bromodomain-Mediated Chromatin Alterations in Prostate Cancer.

 

Published June 19, 2017 11:48 AM - Last modified June 20, 2017 10:48 AM