Navigation Links
Study shows additional role for abiraterone in blocking tumor growth in CRPC
Date:3/15/2013

Arnhem, 14 March 2013 - As part of an EU-supported IMI-PREDECT consortium (http://www.predect.eu), a Dutch study showed that anti-androgenic properties of the drug abiraterone may provide an additional mechanism of action in blocking tumour growth of castration resistant prostate cancer (CRPC).

The study, which won the first prize for best abstract in oncology at the 28th European Association of Urology (EAU) Congress to be held in Milan from March 15 to 19, demonstrated that although the use of abiraterone can potentially lead to an accumulation of precursor hormones, its anti-androgenic properties may stop precursor hormone-induced androgen receptor (AR) activation.

"Our results show that high concentrations of androgen precursors can drive CRPC growth through direct activation of (overexpressed) AR and not necessarily via the result of (intratumoural) CYP17-metabolism. This suggests that CRPC may not rely solely on de novo androgen synthesis," said lead author Dr. Jan Matthijs Moll of the Erasmus Medical Center, Dept. of Urology in Rotterdam, Netherlands.

Men with castration resistant prostate cancer are a difficult group to treat. Although metastatic prostate cancer may respond well to androgen ablation therapy initially, castration resistance usually develops within three years. Even though circulating testosterone levels are low in these patients, the androgen receptor reactivates, which indicates the AR remains an important target in CRPC.

The Rotterdam-based group has previously demonstrated that conversion of adrenal androgens into testosterone, rather than intratumoural de novo steroidogenesis, is the major source of testosterone in CRPC tumours. [1]

Clinical trials have demonstrated that abiraterone acetate plus prednisone/prednisolone can increase survival in CRPC patients even after chemotherapy [2]. "Blocking androgen synthesis (pregnenolone and progesterone are converted to androgens via CYP17A1 enzymatic activity) in CRPC patients has demonstrated a prolonged survival, but may eventually fail because androgen precursors can activate the AR directly," explained Moll.

In their study, the researchers generated castration resistant clones by long-term culture of VCaP and DuCaP cell lines in steroid-stripped medium (DCC), with or without addition of anti-androgens used in the clinic. Experiments were conducted with a subset of AR-overexpressing CRPC clones to test cell growth and AR-activation in the presence of adrenal androgen precursors, pregnenolone and progesterone or dihydrotestosterone in combinations with increasing levels of abiraterone.

The results showed that high (100 nM) levels of progesterone, but not of pregnenolone, induced cell growth in VCaP and DuCaP CRPC clones, which could not be blocked by low levels of abiraterone (0,1 M) that are known to fully inhibit CYP17A1 activity (and thus potential subsequent testosterone production).

In a second experiment, the researchers showed that high levels of precursor androgens can directly activate the AR using a model with a fluorescent AR and that ligand-induced AR-translocation from the cytoplasm to the nucleus was slowed down by abiraterone.

"However, high levels of abiraterone (>5 mM) inhibited steroid-induced, but not basal growth of these (CRPC) cells. This finding, together with the observation that DHT-induced growth was inhibited by high levels of abiraterone, indicates that abiraterone can act as an anti-androgen," the researchers wrote.

"We show that abiraterone, a CYP17A1-blocking drug that has recently been approved in the treatment of CRPC, possesses an additional antiandrogenic property and can block androgen precursor-induced AR-activation at higher concentrations than what is needed for CYP17A1 specific inhibition. This may be a good argument to increase abiraterone exposure in the treatment of CRPC," added Moll.

Moll also said that "it is clear that the AR remains the most important target in the treatment of CRPC."

"Blockade of androgen synthesis seems not sufficient to prevent AR activation. New drugs that block AR activation irrespective of the activating ligand may provide new ammunition to last another 'round' for clinicians to treat CRPC," he said. "We believe it is vital to identify which metabolites have the potential to activate the mutated or overexpressed AR present in CRPC, which under normal conditions may not activate the AR. In that perspective, we are currently working together with our partner, Janssen, and other partners within the IMI-PREDECT consortium on developing new model systems for CRPC to further understand its biology and test new potential pathway perturbations that may benefit CRPC patients in the future."


'/>"/>

Contact: Ivanka Moerkerken
i.moerkerken@uroweb.org
31-026-389-0680
European Association of Urology
Source:Eurekalert

Related medicine news :

1. Study: 15% of Children Ages 10 - 14 Consider Using Steroids; polyDNA Recommends Muxscle for Safe Muscle Building
2. Blacks With Kidney Disease Should Watch for Blood Pressure Shifts: Study
3. Study of dragonfly prey detection at MBL wins PNAS Cozzarelli Prize
4. Study shows how vitamin E can help prevent cancer
5. Autism Speaks trailblazer study -- Blocking cell distress signals can ease autism symptoms
6. Clot Buster Safe for Stroke Patients on Blood Thinners: Study
7. Study: Dynamic new software improves care of aging brain
8. Breast Cancer Radiation Has Long-Term Heart Effects: Study
9. Gene Therapy Helped Mice Withstand Arthritis: Study
10. Bel Marra Health Reports on a New Study: Female Obesity Could Be Due to Less Participation in Household Tasks
11. Study: Steroid Abuse in Teens is Increasing; polyDNA Recommends Muxscle for Safe Muscle Building
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:10/13/2017)... ... 13, 2017 , ... ProVest Insurance Group, a family managed ... Raleigh regions, is organizing an extended charity drive to benefit the family of ... , After struggling since birth with several health challenges, T.J. was later diagnosed ...
(Date:10/13/2017)... ... ... The American Board of Family Medicine's (ABFM) Board of Directors has selected Warren ... James C. Puffer upon his retirement. Dr. Newton will serve in the position of ... end of 2018. Upon assuming the role of President and CEO on January 1, ...
(Date:10/13/2017)... ... October 13, 2017 , ... Lori R. Somekh, founder of ... ElderCounsel, a national organization of elder law and special needs planning attorneys. “Membership in ... It also provides a forum to network with elder law attorneys nationwide,” said Somekh. ...
(Date:10/13/2017)... ... 13, 2017 , ... Ellevate Network, the leading network for professional women, brought ... gender equality at their inaugural Summit in New York City in June. The event ... audience of over 3 million. To watch the Mobilize Women video, click here ...
(Date:10/13/2017)... ... 13, 2017 , ... Coveros, a leader in agile coaching ... contract by the Center for Medicare and Medicaid Services (CMS). The Enterprise Agile ... of Agile methodologies in a consistent and high value manner across CMS programs. ...
Breaking Medicine News(10 mins):
(Date:9/19/2017)... ZirMed Inc ., a recognized leader in cloud-based revenue cycle ... ranked #1 by its users for the seventh consecutive year ... ZirMed was recognized as the top-ranked end-to-end revenue cycle management ... 200 beds and holds one of the longest #1 ranking ... ...
(Date:9/18/2017)... 18, 2017 EpiVax, Inc. ("EpiVax") ... and immune engineering, today announced a new ... (H7N9) vaccine. ... influenza and presents a challenge for traditional ... to be effective. Using state-of-the-art bioinformatics and molecular ...
(Date:9/12/2017)... NEW YORK , Sept. 12, 2017   EcoVadis ... global supply chains, has published the first annual edition of its Global ... more than 20,400 companies evaluated by EcoVadis, based on Scorecard Ratings that ... ... Risk & Performance Index ...
Breaking Medicine Technology: