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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.
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.
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:
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.
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! 😁
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