We need more testosterone, not less!

[Hotoneii]

According to this, it would appear Samuel Denmeade was right all along. It seems rather simple but it makes sense

corporate.dukehealth.org/ne...

[Tall_Allen]

You misunderstand the study. It was only a lab study:

nature.com/articles/s41467-...

So far, tests in humans have been equivocal.

[Doctorsceptic in reply to Tall_Allen]

Hi Allen. You will remember that I have also drawn attention to this and other studies which explore whether T is quite the villain we think it is.

I am sorry to say this but it is your assumption to say that Hoto has misunderstood. How do you know he has misunderstood? Your use of the word “only” rather dismisses the value of lab studies. There are not many modern medicines or new therapeutic paradigms which did not start out as “only” a lab study.

I think it is important that we as patients keep abreast of new ideas because frankly a lot of our doctors do not. So we should welcome discussion of lab studies which raise fresh ideas and challenges the current wisdom, especially whether the relentless pursuit of T and AR blockade is the right one - given its toxicity. Pharma might not be happy with ideas that challenge their income stream!

As far as I am aware, to date there has been no specific clinical study designed to examine this new model for the action of T. BAT is a straw in the wind but does not test this model specifically. The in vitro work also challenges the idea that saturation of T receptors precludes beneficial cellular action of T on the AR and PCa at higher concentrations.

While we should be critical let’s not become dismissive.

[Watcher24 in reply to Doctorsceptic]

There has been many studies with BAT, approx 450 patients altogether. The best results are for those who has a high AR activity ( copy gain), about 1/3. If you add a PARPi it’s even better due to the inflicted DSB. I have been on alternating ARSi and BAT for 18 months. Current knowledge has sparked off the STEP-UP trial, 150 participants. But even for those whose ARa is medium BAT can resenzitise by lowering of AR.

Study this article: pmc.ncbi.nlm.nih.gov/articl...

[Doctorsceptic in reply to Watcher24]

Thank you I will take a look.

[Doctorsceptic in reply to Watcher24]

The in vitro work in that paper demonstrates much more extensive metabolic /DNA damage effects than those reported in the Nature work - with various mechanisms leading to apoptosis/ cell death as well as a switch to an androgen responsive phenotype.

The two articles (refs 10, 11) in the reference list I was most interested in were those using supraphysiogical levels of T. As you know not controlled studies so to be interpreted wth caution. STEPUP results will be interesting.

What I would really love to see is a d/blind controlled study of sufficient power comparing supraphysiological T levels alone with SOC as control in early non-metastatic and hormone responsive disease before too much genetic mutation has happened (or been induced by therapy) in the tumour population.

Probably not in my lifetime though! Anyway thank you for pointing the papers out.

[Tall_Allen in reply to Doctorsceptic]

I disagree completely. Lab studies are not meant for patients, they are meant for other research scientists. Their purpose is only to encourage or discourage clinical research. 98% of pre-clinical research never even makes it to clinical trials, and only a small percent of those wind up being practice-changing.

For every 10,000 compounds screened->250 (2.5%) are entered into a preclinical study -> 5 (2%) are tested in clinical trials -> 1 gets FDA approval

Actually,In BAT trials, an exploratory analysis helps to explain why BAT has limited effectiveness (only 20-30% of mCRPC men derive any benefit from BAT), and what might be done to make it more effective. They focussed on the protein called c-MYC, which is known to be upregulated in advanced prostate cancer. They found:

• High androgen receptor (AR) activity is required for BAT to work. Only about ⅓ of CRPC men have high AR activity.

• But AR inhibition first is needed for T to raise its activity

• High AR activity downregulates c-MYC.

• High doses of testosterone (T) increases AR activity.

Xtandi (but not Zytiga or other advanced antiandrogens) prevents acquired resistance to T because it upregulates the AR while it inhibits it. AR activity (requiring tumor biopsy) may be a valuable biomarker.

jci.org/articles/view/16239...

This is similar to the findings of the lab study, except lacking the clinical component, the lab study failed to find and identify the critical AR activity biomarker.

Let's not encourage agnorance.

[Watcher24 in reply to Tall_Allen]

You state that high doses of T increases AR activity? Are you sure about that?

[Tall_Allen in reply to Watcher24]

That's what the researchers found in BAT-responders.

[Watcher24 in reply to Tall_Allen]

The responders had already high levels of AR because of exposure to an inhibitor. Receiving high amounts of T should then logically lower AR activity - is that correct?

[Tall_Allen in reply to Watcher24]

What they found is that high AR activity is necessary for BAT to work. Supraphysiologic doses of T encourages high AR activity in some men. The ADT then kills the active cancer cells.

[Watcher24 in reply to Tall_Allen]

Allen, I believe you are completely wrong. High T lowers AR activity, ARSi increases. This is the whole idea behind STEP-Up.

Quote from the research:

«Acquired resistance is a significant limitation to the use of BAT. We show that acquired resistance to SPA can be driven by downregulation of AR in vitro. BAT induced downregulation of AR mRNA and protein in most patients in our study, consistent with prior reports indicating that ligand-bound AR exhibits negative autoregulation at the level of AR gene transcription (31). We found that acquired resistance could be prevented in the SPA-sensitive cell line LNCaP through constitutive AR expression, which is not subject to negative autoregulation. Therefore, methods to prevent AR negative autoregulation have the potential to preventacquired resistance to BAT. To our knowledge, no such methods currently exist, however, AR-axis inhibitors are widely known to induce adaptive upregulation of AR in patients with CRPC (10, 11).

Thus, we tested sequential treatment of prostate cancer models with SPA followed by the AR inhibitor enzalutamide. Our results indicate that acquired resistance to SPA can be overcome by treatment with enzalutamide, which induced upregulation of AR and increased susceptibility to SPA.»

You are the person with the most authority on this site, it’s highly important that you have correct statements.

[Tall_Allen in reply to Watcher24]

"These data suggest that repeat cycling of SPA[supraphysiologic androgens] and AR inhibition may prevent the development of acquired resistance and lead to more durable growth inhibition of prostate adenocarcinoma."

Androgens (principally T) activate and decrease the expression of ARs.

Enzalutamide inhibits and increases the expression of ARs.

[Doctorsceptic in reply to Tall_Allen]

Hi Allen. I can see that I might have to disagree, but not completely and of course politely. In doing so I am also conscious that you are speaking primarily about work in oncology and the needs of this forum. While acknowledging we do not want to encourage ignorance (as you rightly say) I am going to suggest a wider view and understanding of where ideas and advances come from is no bad thing.

You are absolutely right to say "98% of pre-clinical research never even makes it to clinical trials, and only a small percent of those wind up being practice-changing". That reflects the process of screening drugs in the industrial setting which is not only very time consuming but also often just plain wrong. A great example is cyclosporin originally screened as an antifungal, but turned out to be a great immunosuppressant!

But to assert, as I think you do in your statement "Lab studies are not meant for patients, they are meant for other research scientists" is curiously both right and wrong.

With just a few exceptions, there are barely any clinical "inventions" in the 21C field of medical science that do not have its origins in laboratory experimentation, some driven by curiosity (I plead guilty) , some goal driven, some from very basic science and some just from serendipity. My student obstetrics oncall bedroom at St Mary's was in an old tower above the lab where Fleming noticed the effects of penicillinium mould in a bacterial culture. Serendipity at work in a laboratory whose purpose was curing infection, laid the basis for modern antibiotics and the hunt for more organic products made by nature - and not just antibiotics eg vinca alkaloids in cancer.

Chemists (lab) have played a huge role in antimicrobial development from the very earliest days eg heavy metal compounds, then sulpha drugs. The synthesis of mustard gas (bad news) designed by a chemist (lab) later led to the early cytotoxics - cyclophosphamide etc. Subarrow, working in the Lederle labs discovered the role of ATP in muscle and the synthesis of folic acid. He then developed methotrexate as an inhibitor of folate synthesis - with multiple uses in medicine today.

Modern radiotherapy goes all the way back to the physicists of the late 19th and 20thC - Curie, Rutherford et al. Xray crystallography (lab) by Rosalind Franklin (credit stolen by Watson & Crick) gave us the structure DNA and the first step in the huge field of molecular biology and all the lab work which ensued (you gave examples in your reply, ie cMYC and all the known mol biol pathways) and which we see the fruits of today. Even now, the design of agents to inhibit specific proteins in biological pathways requires knowledge of detailed protein structure (lab), what the protein does (lab), the chemistry of agents (including immuno-agents) which might fit into protein folds (lab) plus the array of lab kit a modern lab needs.

Sorry I could go on and on because the examples are infinite. But in the end each therapy we use has its origins in multiple different types of basic laboratory research and could not have appeared without - physics, radiophysics, organic chemistry, radiochemistry, inorganic chemistry, metallurgy, biochemistry, biology, molecular biology etc etc. I nearly forgot mathematics (its lab requiring pencil, paper and a brain)

Our next revolution will be the use of AI to improve the efficiency of drug design. But AI originates from the transistor (Bell labs which had a reputation for encouraging unapplied science ie undirected playing in the lab), electronics (physics) making pure crystals of silicon (physical chemistry) and information science (maths). And it all ends up, as you rightly say, in a well designed clinical trial (maths essential) to see whether it works or not. By the way we used to have a trial called the 'N=1 trial'. It still has its place if well designed.

All the best, and fun debating with you. I hope we are not talking at cross purposes because I absolutely agree with you that the final test is always in the human with well controlled/designed clinical trials. . Are you happy to leave it there? I am exhausted to be honest!

[Hotoneii in reply to Tall_Allen]

Thanks, obviously not the only one who does; although equivocal doesn't prove otherwise neither

[JohnInTheMiddle]

"seems rather simple" 😳

[Doctorsceptic in reply to JohnInTheMiddle]

No not simple in fact. The Nature Comms study shows that T has a biphasic action on PCa in vitro. At higher concentrations, well above AR saturation, T causes dimerisation of AR receptors by triggering release of so called chaperone proteins from the AR. Thus in turn results in triggering of a beneficial change in PCa phenotype to a differentiated state and stops proliferation. This has not been specifically tested in humans although BAT is a straw in the wind.

[MikeMartin]

there are enough men using BAT today with results!

[Doctorsceptic in reply to MikeMartin]

Yes quite a bit of anecdotal/small scale evidence but which does not qualify as high quality evidence. We need some decent controlled studies of sufficient power to test the role of highT - whether BAT or continuous - at different points in the evolution of PCa .

[Tall_Allen in reply to MikeMartin]

Yes, results are poor -¼ to ⅓ may have some benefit.

[Mrtroxely]

Very interesting.Looks like a nother peice of the puzzle, may not fit in there perfectly, but I think we all know it's a peice of the puzzle.

I've not heard of anyone totally cured, just by removal of 100% testosterone...

All that climbing mountains, bike rides, shaving heads, walking and sponsoring cancer research.

All that money for research

And cancers on the increase???

I think I'd be happy go do trials on that and put some money into that area....

[maley2711]

Do you think we should discard human-tested treatments in favor of lab-only studies?????

I see no way that this lab study means high T is equal of better than zero T. Maybe in the future human trials will prove such an hypothesis.

[EdBar]

BAT does not mean that one remains on a high level of T, it’s the extreme, sudden highs and lows that make cancer cells more susceptible. Generally you don’t remain on it for long extended periods. BAT is not for everyone it is dependent on tumor burden, location of tumors, age, risk factors etc.

Ed

[RMontana]

Here is the take away from this article;

"It turned out to be rather simple. When androgen levels are low, the androgen receptor is encouraged to “go solo” in the cell. In doing so, it activates the pathways that cause cancer cells to grow and spread. However, as androgens rise, the androgen receptors are forced to “hang out as a couple,” creating a form of the receptor that halts tumor growth."

I found a study for men with rising PSA after RP without MET disease, that I believe speaks to this dichotomy. There are some counterindications in this podcast regarding TET therapy and its impacts, especially in the 1st year of ADT treatment. Its important to see the results of the one study posted but the implications from this presentation are clear; higher TET is not protective during the 1st year of ADT…afterwards it appears that intermittent treatment with its introduction of TET, does not appear to affect OS in men without MET disease and can improve QOL.

healthunlocked.com/active-s...

[Justfor_]

I am an example of living with high T. Before taking any medication my T was 800-900. Starting Avodart it bursted to 1200-1500. Adding Bicalutamide 2000-3000+. Currently, after 6 years it has settled "down" to 1500-1700. One 10th of standard Bicalutamide dosage (half a tablet every 5 days) has kept my PSA to 0.005-0.028 two years now.