The Androgen Receptor (more than you wanted to know…)

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The treatment of prostate cancer by depriving the cancer cells of testosterone is now over 70 years old. Charles Huggins along with Clarence Hodges, a medical student at the time, discovered that by either administering estrogen (which will inhibit the brain from signaling the testicles to make testosterone) or surgically removing the testicles, patients with prostate cancer would have remissions, sometimes lasting for years. He received the Nobel prize in 1966 and there is a nice article reviewing the discovery and Huggins’ humility here.

Nothing much changed in prostate cancer treatment after that until the early 80’s when leuprolide, a peptide that could inhibit the signaling (like estrogen) from the brain to the pituitary entered the picture. This is the hypothalamic-pituitary-gonadal axis, and another Nobel prize was awarded to Andrew Schally for elucidation of the role of GnRH as the key hormone driving the system. (leuprolide is an analog of GnRH) Surprisingly, given the rapid development of anti-estrogens for breast cancer, truly effective anti-androgens took another 25 years or so to emerge. The past decade has yielded several new drugs that are now in standard use for prostate cancer as shown in the following table.

https://www.hematologyandoncology.net/files/2021/04/ho0421IsaacsonVelho-1.pdf

But blocking androgen synthesis by the cancer cells (abiraterone), or blocking the androgen receptor (all the other drugs listed in the table) kills most of the cancer cells, but not all. How do they survive? The answer lies, in part, in the complexities of the androgen receptor (AR) itself. This is where it gets really interesting (but probably more than you wanted to know).

In an absolutely superb recent review article, Velho and colleagues review how the AR works and drugs that are in development to block its activity when resistance to the above drugs develop. You need to download the PDF to see the figures, but this one illustrates the basics. Androgens get into the prostate cancer cell, then bind to AR, which then partners (dimerizes) with another AR molecule, and the dimer enters the nucleus of the cell and sits on specific genes, causing their expression. PSA is the gene you would know best, but there are many other genes that are activated, some of which lead the cells to divide or develop characteristics that lead to them metastasizing to lymph nodes or bones.

Testosterone (androgen) drives gene expression via the Androgen Receptor (AR)
https://www.hematologyandoncology.net/archives/april-2021/new-approaches-to-targeting-the-androgen-receptor-pathway-in-prostate-cancer/

The good news is that understanding how this system works has led to a wealth of drugs that can inhibit various steps in the AR pathway of cell/gene activation. These are shown here:

New drug categories being developed to block T (androgen) stimulation of prostate cancer.

Although the details are very complex, two of the more interesting approaches are bipolar androgen therapy (BAT) and the category shown as PROTACs. BAT consists of giving patients large doses of testosterone monthly while they remain on drugs like leuprolide to suppress the normal levels. In the recently published TRANSFORMER trial Denmeade and colleagues demonstrated that BAT was a better first choice in patients who had failed abiraterone when compared to the anti-androgen, enzalutamide. Further, BAT can re-sensitize some patients to abiraterone after BAT stops working.

PROTACs are drugs that can target various cell proteins for destruction by normal cell machinery. As shown in this figure, the proteasome is like a disposal that chews up proteins that have been “tagged” by attaching a protein called ubiquitin to them. Imagine that the green folded protein is the AR. If you can tag it, you will get rid of AR altogether, and that is what an experimental drug called ARV-110 does, attaches ubiquitin to the AR.

Folded protein could be the AR, and ARV-110 can lead to degradation of AR.

Ongoing clinical trials with ARV-110 have shown impressive PSA responses in a few patients who have been heavily pretreated and are resistant to all the other approved AR targeting drugs.

So, the good news is that there is still room for improving on treating prostate cancer patients with drugs that attack the testosterone axis, even 80 years after the first proof of principle was shown. However, it is also true that cancer cells are very “smart”, and can learn to survive via other cellular pathways having little to do with AR signaling. Other approaches, such as stimulating the immune system to recognize these cells is under equally intense study. If this doesn’t make you a believer in “science”, and a cheerleader for further investment, I give up! 😁

12 Comments

Filed under General Prostate Cancer Issues, Prostate cancer therapy, Targeted treatment

12 responses to “The Androgen Receptor (more than you wanted to know…)

  1. Dick McClain

    My knowledge of biochemistry is limited enough that I don’t pretend to understand the details about which you’ve written. That said, it’s reassuring to see that way in which you stay on top of the latest research. I’m hoping that in the future, immunotherapies will prove to be safe and effective.

    • Thanks Dick. Trust me, I struggle to keep up as well, and the article itself was really dense. I tried my best to simplify and left out a huge amount of detail, like the structure of AR. I’m glad there are folks out there like the authors who do so much to keep things moving! As they say, if it was simple, it would have been worked out long ago…

  2. Sheldon Hays

    All good, but how can we be confident all this new info is actually reaching our treating physicians vs. their “standard of care” regimens.  Interesting article, and agree great things can and will happen….

     

    • Most of it is too early, but just to keep an eye on. The “standard of care” stuff becomes hard core reality when one gets into insurance coverage. It is “codified” in the NCCN guidelines, here: http://www.nccn.org. Otherwise, the really cutting edge approaches are all in clinical trials which is why I advocate everyone being familiar with http://www.clincaltrials.gov and doing searches there. For me, and the vast majority of treating physicians, trying to keep up with the trials is impossible, but I love it when patients can help me out. I always learn something by looking at a trial someone brings to my attention and asks whether I think it is worth them traveling for.

  3. Tom

    Don’t give up, play some golf!

  4. Tom Remenick

    Great post! Your explanation, figures, and the referenced article, put a lot of the terms and mechanisms of action I had heard/read about into a system context. Among other things I have better understanding of what AR-V7 is and how it plays a role. It does get very, very complex! Bringing it back to genetics and specific expressions was instructive too.

    I had previously read about ARV-110 and thought that was the ultimate answer. Just destroy the AR and all will be well. What could be easier! Pretty naïve, I’m sure. What do you think could be the ultimate weapon / mechanism to destroy PC, even if theoretical at this point?

    From one of your previous posts: has there been any trial results showing a beneficial relationship of reduced TMPRSS2 and COVID-19 “immunity” (I’m using that word loosely)?

    Appreciate the post… very instructive.

    • Thanks for the comments, Tom. I’m glad it was helpful, as I wanted to do some justice to the AR itself as well as the authors who did such a great job of unraveling the intricacies. I suspect we are near the end of tapping into the androgen axis well for answers. I think the “ultimate weapon” is probably the immune system. It seems to be able to keep up with various cancers’ ability to mutate under whatever pressures (hormonal, chemo, radiation, antiangiogenic, etc.) are brought into play. At least that works for ~1/3 of melanoma patients and some lung, kidney, or bladder cancers. Of course, ultimately the problem is aging – against which I have no solution, but the billionaire class in Silicon Valley is pursuing. 😁 Seems the fountain of youth will forever remain elusive…

  5. Regarding TMPRSS2 and the possible advantages of anti androgens, there are plenty of articles suggesting some effectiveness: https://scholar.google.com/scholar?hl=en&as_sdt=0%2C6&q=covid+19+antiandrogens&btnG=

  6. Molly Ireland

    Thanks for staying curious! Don and I only understand a fraction of the science, but it’s enough to be fascinating. Reading the patient comments on your blogs is also very worthwhile, because they bring up a lot of great questions.

  7. dendoc

    Mike, Your timing for this post was great for me. I am moving further down the path of resistance and it helps me to understand where I am and what my oncologist is thinking. I am a better informed patient by knowing this. Most important you give all of us with advanced metastatic disease cause for hope as new treatments become a reality.
    Bob

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