AR-V7

[pjoshea13]

New full-text review of the AR-V7 problem below [1]. Not for everyone - TMI?

Basically, ever since Charles Huggins castrated his first dog over 75 years ago, the emphasis has been on denying PCa androgen. Which boils down to targeting the androgen receptor [AR] directly or indirectly.

A weakness of any existing or future therapy that targets back-door production of androgen, or involves an antiandrogen, is that PCa has an elegant response - an AR mutation [AR-V7] that lacks the ability to bind to androgen for activation, but is nonetheless able to move from the cytoplasm to the cell nucleus, as though it were activated, & stimulate growth.

AR-V7 is a significant cause of drug resistance, but solutions are being worked on. See the section "Therapeutic targeting of AR-V7" [1].

Clinical Trials:

[2] Cabazitaxel in mCRPC Patients With AR-V7 Positive CTCs (CARVE)

"This study is not yet open for participant recruitment."

"The investigators hypothesize that patients with AR-V7 positive CTCs do have a meaningful response to cabazitaxel."

[3] Biomarker-Driven Therapy With Nivolumab and Ipilimumab in Treating Patients With Metastatic Hormone-Resistant Prostate Cancer Expressing AR-V7 (STARVE-PC)

"This study is currently recruiting participants."

"This phase II trial studies how well nivolumab and ipilimumab work in treating patients with hormone-resistant prostate cancer that has spread to other places in the body and express androgen receptor-variant-7 (AR-V7). Tumor cells expressing AR-V7 has been shown to be resistant to hormone therapy and some chemotherapy in patients with prostate cancer. Biomarker-driven therapy, such as nivolumab and ipilimumab, may work by blocking key biomarkers or proteins that help tumor cells to escape the immune system surveillance and this may help the immune system to kill tumor cells that express AR-V7."

[4] A Study of Galeterone Compared to Enzalutamide In Men Expressing Androgen Receptor Splice Variant-7 mRNA (AR-V7) Metastatic CRPC (ARMOR3-SV)

"This study is currently recruiting participants."

"The purpose of this study is to compare galeterone to enzalutamide in men expressing androgen receptor spice variant-7 mRNA (AR-V7) in metastatic (M1) castrate resistant prostate cancer (CRPC).

Studies:

[5] "The response to cabazitaxel seems to be independent of the AR-V7 status of CTCs from mCRPC patients. Consequently, cabazitaxel might be a valid treatment option for patients with AR-V7-positive CTCs."

[6] "Galeterone and VNPT55 induce proteasomal degradation of AR/AR-V7, induce significant apoptosis via cytochrome c release and suppress growth of castration resistant prostate cancer xenografts in vivo."

"This study demonstrate that gal and VNPT55 utilize cell-based mechanisms to deplete both {full-length AR} and AR-Vs."

[7] The heat shock protein [HSP] family are induced in PCa. HSP is a survival response to stress, & cancer cells are particularly stressed while under treatment. The HSP protein acts as a chaperone to other proteins. HSP90 is an AR bodyguard & facilitates translocation to the nucleus.

"We demonstrate that AR-V7 and full-length AR (AR-FL) were depleted upon inhibition of HSP90." by Onalespib.

-Patrick

[1] onlinelibrary.wiley.com/doi...

[2] clinicaltrials.gov/ct2/show...

[3] clinicaltrials.gov/ct2/show...

[4] clinicaltrials.gov/ct2/show...

[5] ncbi.nlm.nih.gov/pubmed/261...

[6] ncbi.nlm.nih.gov/pubmed/261...

[7] ncbi.nlm.nih.gov/pubmed/271...

[dave2]

Thanks Patrick. Your ref 1 above is the most comprehensive I've read on AR splice variants. Lots of impressive research is underway in this area!

Dave

[Doofusthefirst]

Great post Patrick. I will be getting blood drawn for the AR-V7 test in a few weeks. I find it interesting that insurance will not cover the $1,000 cost but it will cover the much higher cost for Xtandi and Zytiga. You would thing that insurance companies would want to know if you will respond to these very expensive drugs before paying for months and months of treatment that may have no effect.

I will need to have my blood drawn outside of state of Florida, where I live, because John Hopkins has no agreement with Florida of New York. It makes this test expensive for me but I need to know if I have the splice variant before beginning Zytiga. If I test positive I do not want to begin Zytiga and commit to taking prednesone for the rest of my life.

[Terje]

Thanks Patrick, very interesting.

From what I can understand Niclosamide (used against tapeworm) also inhibit AR-V7 transcription. Seems almost too good to be true!

ncbi.nlm.nih.gov/pubmed/247...

ncbi.nlm.nih.gov/pubmed/259...

[pjoshea13 in reply to Terje]

Terje,

I'm amazed that researchers at Davis discovered the Niclosamide/AR-V7 connection so quickly! Niclosamide is inexpensive & does have side effects, but why wouldn't anyone who has failed Zytige/Xtandi because of AR-V7 want to try it? When the FDA finally approves a drug against AR-V7, it will be listed at $20,000 / month, & probably have greater side effects.

I suppose that if one can't get Niclosamide off-label, one might search out a tapeworm source! LOL.

-Patrick

"Development of resistance to enzalutamide is eventually inevitable with the development of several potential pathways of resistance (4, 28). Recent studies have linked AR alternative splicing, particularly AR-V7, to the development of enzalutamide resistance (18, 20, 21, 29). Targeting of AR signaling, especially AR variants, would improve current anti-androgen therapies for advanced prostate cancer. In this study, we identified niclosamide as a potent AR-V7 inhibitor in prostate cancer cells. We found that niclosamide significantly inhibits AR-V7 protein expression and AR-V7 transcription activity and reduces AR-V7 recruitment to the PSA promoter. Niclosamide inhibits prostate cancer cell growth in vitro and tumor growth in vivo. Furthermore, niclosamide significantly enhanced enzalutamide therapy in prostate cancer cells, suggesting that niclosamide can be used to treat, either alone or in combination with current antiandrogen therapies, patients with advanced prostate cancer, especially those resistant to enzalutamide"

clincancerres.aacrjournals....

[Terje in reply to pjoshea13]

Yes, I think it is a no-brainer. When my Zytiga stops working I will do a round of Niclosamide as I start enzalutamide .....just as a precaution!