Hormone therapy (ADT) eventually stops functioning. When this happens, a man who is castrated from hormone therapy continues to have their prostate cancer progresses.
This failure of the therapy is the result of the activation of the androgen receptor (AR) and AR splice variants, the under lying driver of resistance to the anti-androgen treatment, a type of ADT treatment where the androgens are prevented from accessing the cancer cells.
The mechanisms and the roles of the AR and AR variants in the development of hormone resistance to androgen deprivation therapy (ADT), including both for the drugs bicalutamide (Casodex) and enzalutamide (Xtandi), treatment are not understood.
To determine whether AR variants play a role in the development of bicalutamide resistance, researchers used bicalutamide resistant prostate cancer cells. They found that these resistant cells had increased levels of AR variants, particularly AR-V7.
When AR-V7 expresses itself in bicalutamide sensitive prostate cells, they found the development of resistance to the drug.
The researchers also found that when they limited AR-V7 cells that were bicalutamide and enzalutamide resistant, they reversed the resistance.
They reduced the AR-V7 cells by using Niclosamide, a potent inhibitor of AR variants and currently FDA approved for the treatment of worm diseases in humans.
When given in combination, Niclosamide and bicalutamide not only suppressed the AR and AR variants expression but it also significantly induced apoptosis in bicalutamide and enzalutamide resistant cells. They also discovered that the combination of Niclosamide and bicalutamide inhibited the growth of enzalutamide resistant tumors.
In summary, the research results demonstrate that AR variants, particularly AR-V7, drive bicalutamide resistance and that targeting AR-V7 with Niclosamide can re-sensitize bicalutamide resistant cells to bicalutamide treatment.
Furthermore, a combination of Niclosamide with bicalutamide inhibits enzalutamide resistant tumor growth, suggesting that the mix of Niclosamide and bicalutamide could be a strategy to treat men with advanced prostate cancer, including those who fail to respond to enzalutamide therapy.
• Mol Cancer Ther; 16(8); 1–10. ©2017 AACR. Chengfei Liu, Cameron M. Armstrong, Wei Lou, Alan P. Lombard, Vito Cucchiara, Xinwei Gu, Joy C. Yang, Nagalakshmi Nadiminty, Chong-xian Pan, Christopher P. Evans and Allen C. Gao
• DOI: 10.1158/1535-7163.MCT-16-0912 Published May 2017
• Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/)
Joel T. Nowak, MA, MSW wrote this Post. Joel is the CEO/Executive Director of Cancer ABCs. He is a Cancer Thriver diagnosed with 5 primary cancers - Thyroid, Metastatic Prostate, Renal, Melanoma and a rare cancer, Appendiceal Cancer.
