Hi guys. It’s been a while since I’ve posted. I’ve been through a couple job transitions and haven’t had as much time to devote to this as I wanted. Anyway, I’ve been thinking a lot about the issue and wanted to bring up some points for discussion (sorry in advance for the long post). I still strongly believe that the root cause of PFS has to do with epigenetic modulation. For such a persistent effect, there is not much from a molecular biology standpoint that could cause such and extended effect aside from epigenetic changes (e.g., methylation, acetylation) and genetic mutations. I highly highly doubt that the issue stems from actual changes to our DNA because there is nothing in the structure of finasteride that suggests it would have DNA mutagenic properties. There are also a dozen more reasons which I can get into, but basically, for those worried about the condition being passed on to children (I saw someone post about it) I wouldn’t worry about it.
One thing Awor mentioned to me got me thinking a lot. As I mentioned in my last post, I was a prostate cancer researcher in my previous life and awor asked me about a condition called hormone refractory prostate cancer. Normally, for advanced stage prostate cancer, cells still require androgen to grow. Thus in this advanced stage, patients are treated with “hormone therapy” which basically blocks androgen production and simultaneously blocks residual androgen from binding to androgen receptors (ARs) in the cancerous cells, thereby shutting down the growth signal. Eventually, in most patients their cancer comes back as hormone refractory prostate cancer. In this case, cells no longer require androgen to grow and hormone therapy (HT) fails to block growth. Interestingly, the anti-androgens in the HT appear to stimulate growth and adding androgen in some cases can even inhibit growth (in vitro). Basically the androgen response is reversed. This has been covered many times in the forum so apologies for ppl who already know this.
The cause of this insensitivity to androgen therapy is correlated with many factors including overexpression of AR and epigenetic changes. The point that Awor brought up is that the situation is analogous to PFS because when individuals with PFS administer testosterone, they feel nothing or even feel worse. What I’ve read again and again on the forum is that increasing androgen levels really doesn’t help. Again, this points to the issue being one of androgen responsiveness.
So thus far I haven’t said anything new. But, what I was thinking about was there is a good amount of research being done in the prostate cancer field on restoring sensitivity to hormone therapy. It would be feasible that a treatment which re-sensitizes prostate cancer cells to the inhibitory effects of androgen blocking therapy, would also cause cells to grow in response to androgen. And by correlation, we could hypothesize that it would also cause PFS sufferers to become sensitized to androgen again.
I did some searching on this topic to see whether anyone had looked into this, and I came across this article:
Restoring chemotherapy and hormone therapy sensitivity by parthenolide in a xenograft hormone refractory prostate cancer model
Basically parthenolide co-administration allowed androgen-resistant cells to once again be inhibited by hormone therapy. Now the interesting thing is that parthenolide is an HDAC inhibitor/epigenetic modulator ncbi.nlm.nih.gov/pmc/articles/PMC2672871/ which fits nicely into the hypothesis. It is also the active ingredient in an herb called Feverfew. Before any you go trying feverfew, remember that this experiment was basically done in petri dishes with pure parthenolide and there is even a chance it could have the opposite effect in vivo. Most compounds, even if available in dietary supplements get broken down during digestion in the liver so that there is only minimal active ingredient in the bloodstream. Not to mention that we don’t even know how much parthenolide, if any, is available in most feverfew dietary supplements since it is not regulated. It is more likely that you would not be able to get levels high enough in the bloodstream to feel an effect. However, if there were a well characterized FDA approved version available, I would really be interested in seeing if administering parthenolide would re-sensitize individuals w PFS to androgen. Since PFS often causes low levels of androgen, you would probably need co-administer with a testosterone gel.
Another interesting compound is panobinostat, which is currently being tested in humans at NYU:
“Using what is known about androgen receptors and their effects on prostate cancer growth, our researchers are designing clinical trials of new drugs with the potential to inhibit androgen receptor activity and restore the sensitivity of prostate cancer cells to hormonal therapies. One example is panobinostat (LBH589), an inhibitor of an enzyme called deacetylase. Panobinostat causes genetic changes in the androgen receptor, and laboratory studies have shown that it makes prostate cancer cells sensitive to the hormonal therapy bicalutamide. Our investigators are leading research evaluating panobinostat plus bicalutamide in men with castration-resistant prostate cancer.”
cancer.med.nyu.edu/researchers/r … r-research
Surprise surprise, it is also an HDAC inhibitor.
Okay, so now we’ve established there is some evidence for parthenolide (albeit pre-clinical and in a pretty mediocre journal) that one can restore sensitivity to androgen. And at least some confirmation of this rationale by evidence of an ongoing trial with panobinostat. Where else can we look for potential leads for restoring sensitivity to androgens?
I’m glad you asked. One interesting aspect of androgen receptor, is that it is part of a larger family of receptors called “nuclear receptors”. (en.wikipedia.org/wiki/Nuclear_receptor) These receptors reside in the cytoplasm of cells and bind to circulating hormones. Each type is specific for a certain type of hormone and once it binds, it undergoes a structural change and translocates to the nucleus, binds to specific DNA sequences, and begins transcribing (activating) genes which are involved in a variety of functions. In the case of AR, this includes genes responsible for sexual development and secondary sex characteristics. The interesting part is that the other hormone receptors share a good deal of structure with AR, utilize similar signaling intermediates, and are also regulated by similar epigenetic mechanisms. Even more interesting is that in some cases, these related hormone pathways can also become faulty and unresponsive to their respective hormones.
The closest example of this is estrogen receptor which is involved in breast cancer. Similar to prostate cancer, advanced breast cancer is also treated by blocking hormone activity. And again, eventually breast cancer cells become unresponsive to this therapy. Some searching led me to this article:
Valproic acid restores ER alpha and antiestrogen sensitivity to ER alpha-negative breast cancer cells.
Again, here is another example of an HDAC inhibitor which restores sensitivity to a hormone, albeit estrogen. Some of you may be familiar with Valproic acid as “Depakote” or a treatment for epilepsy and bipolar disorder. Looking at the side effects however, it looks like it is associated with reduced libido so it’s probably not a cure for PFS. Although, if anyone is using the compound I would be interested to hear what the effects are in people with PFS. I would also be interested to see if it increased sensitivity to testosterone at lower (or even higher) doses.
One last example I wanted to put out there is a condition seen with the glucocorticoid pathway (another hormone receptor pathway) in patients with COPD. COPD is a respiratory illness treated with corticosteroids which activate the GC pathway and reduce inflammation. At a certain point the body stops responding and loses sensitivity to glucocorticoids. A paper published last year showed that sulforaphane, a compound present in broccoli at low doses, was able to directly activate HDAC2 restoring sensitivity.
Denitrosylation of HDAC2 by targeting Nrf2 restores glucocorticosteroid sensitivity in macrophages from COPD patients
Although this study was a small one, sulforaphane is currently in Phase 2 development and it will be interesting to see how things pan out:
clinicaltrials.gov/ct2/show/NCT0 … ane&rank=3
Again with this product, the problem is that there is no pharmaceutical grade formulation, but it would nonetheless be interesting to see whether it is able to restore androgen sensitivity in a similar manner.
In conclusion, whether or not the above treatments work for PFS, I believe there is very strong rationale that PFS can be treated with epigenetic modulation. We have already seen three examples and I haven’t even begun to look at the other more than 20 hormone pathways. Furthermore, work on HDAC inhibitors is in its infancy and there are products coming out every year targeting new HDACs not to mention those targeting DNA methylation. This is good because you may need a combinatorial approach to targeting HDACs, activating some and repressing others, to effectively treat PFS. There are a daunting number of avenues to explore yes, but there are very promising leads with strong rationale.
Lastly, I just wanted to add a personal aside on this forum. I feel like all the members of this forum have been through a lot. Many feel jaded and hopeless, and have every reason to be. I know that it’s not much but as a formally trained molecular biologist, I am hugely optimistic. I see a mind-boggingly huge number of avenues to explore and possibilities for cure. I hope you got that sense even from just my brief research on hormone receptors which I presented here, that we are by no means at a dead-end in fighting this condition. In fact, with the establishment of the PFS Foundation and the new genomic tools being created everyday, we are just at the beginning. My colleagues in the biotech industry are in agreement that we are just at the early-stage of the genomic revolution. With personalized gene sequencing and gene expression analysis tools becoming cheaper and cheaper, over the next 10 years you will be seeing an advance in the understanding of disease that mirrors the impact the internet had on our lives. With these tools, and once we understand the molecular mechanism behind the disease, it’s really not a matter of how but when.
Thanks for reading this far and if anyone has had any experience with the above compounds, or have anything to add, I would love to hear it.