AR alterations and therapy resistance in prostate cancer

Bethan Warman Posted in General News, Publications 16 May 2019

Dr Prabhakar Rajan

Recent findings from a study published in JAMA Oncology have identified genetic markers within blood samples which may indicate whether patients with prostate cancer will respond to hormonal therapies. The study, performed in collaboration with Dr Prabhakar Rajan from our Centre for Molecular Oncology and researchers from the Karolinska Institutet (Sweden) and the University of Antwerp (Belgium) may represent an important step forward for the development of more personalised treatments for advanced prostate cancer.

A group of hormones known as androgens contribute to prostate cancer cell growth by binding to a protein called the androgen receptor (AR) found in prostate tissues. Therefore, many treatments target the interaction between androgens and AR, either by reducing androgen levels or by blocking the AR. Although these treatments can be effective initially, resistance is inevitable.

Although continued hormonal therapy can have a positive outcome in some patients, not all patients respond well to these treatments. Knowing which patients will not respond to certain treatments would be a valuable tool, making it possible to avoid unnecessary side effects for the patient, offer alternative treatments that may be more effective and limit pharmaceutical expenses.

Looking at the bigger picture

The development of resistance is associated with a variety of genetic changes in the AR gene, and also other genes such as the TP53 gene. Previous studies have looked at the genetic changes associated with resistance individually, which has led to conflicting findings between different studies. To overcome this, the team of researchers have developed a method for investigating all known changes associated with resistance in the AR and TP53 genes, allowing them to look at the bigger picture.

laboratory 3827735 1920In order to determine the prognostic value of AR alterations, the team applied this method to test blood samples of patients with prostate cancer and a normal TP53 gene. The researchers found that the number of changes in the AR gene were indicative of treatment prognosis. A larger number of AR alterations, termed in this study as the ‘AR burden,’ was associated with a poorer response to treatment.

Personalised treatments for improved outcomes

Prostate cancer is the most common cancer in males in the UK, with approximately 47,700 new cases diagnosed each year. It is important to identify which patients possess gene alterations that render their cancer resistant to particular therapies so that the best possible treatment option can be offered to them.

The team now endeavour to validate their method in a prospective trial to determine the effectiveness of using AR alterations to stratify patients to different therapies. The team hope that their findings could lead to the development of a minimally invasive test that can be used in the clinic so that patients can receive more personalised treatments.

The research was funded by the Belgian Foundation against Cancer, the Flemish Cancer Society, Cancer Research UK, the Radiumhemmet Research Funds, the Erling-Persson Family Foundation, the Swedish Research Council and the Cancer Foundation.

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