Supraphysiological androgen [SPA]

[pjoshea13]

New study below [1].

When I think of supraphysiological androgens I think of BAT [Bipolar Androgen Therapy] & Dr. Sam Denmeade. & sure enough, he is a co-author.

No mention of BAT, but: the study used "biospecimens from PC patients receiving SPA {supraphysiological androgen} as part of ongoing Phase II clinical trials." BAT?

The BAT therapy uses a monthly injection of testosterone [T] cypionate [Tcyp] designed to induce T blood levels of ~2,000 ng/dL. Many men don't reach that level - some don't get above 1,000 ng/dL. No attempt is made to adjust Tcyp to meet the target.

Before I switched from a rapid androgen cycle (3 months castrate, 3 months high T) to BAT, I aimed for T to be ~1,000 ng/dL. That is close to the limit of the observed range. 2,000 ng/dL is basically twice the normal high maximum.

While I see no reason to drive my T that high (what is the point once androgen receptors [AR] are fully saturated with T), I do inject more Tcyp than before.

"However, supraphysiological androgen (SPA) concentrations can produce paradoxical responses leading to PC growth inhibition. We sought to discern the mechanisms by which SPA inhibits PC and to determine if molecular context associates with anti-tumor activity."

"SPA produced an AR-mediated, dose-dependent induction of DNA double-strand breaks (DSBs), G0/G1 cell cycle arrest and cellular senescence. SPA repressed genes involved in DNA repair and delayed the restoration of damaged DNA which was augmented by PARP1 inhibition. SPA-induced DSBs were accentuated in BRCA2-deficient PCs, and combining SPA with PARP or DNA-PKcs inhibition further repressed growth."

An aim of the use of supraphysiological androgen was to induce DNA damage. PARP is a cell division repair mechanism, so a PARP inhibitor might ensure that affected cells are scrapped.

"Patients with mutations in genes mediating homology-directed DNA repair were more likely to exhibit clinical responses to SPA. These results provide a mechanistic rationale for directing SPA therapy to PCs with AR amplification or DNA repair deficiency, and for combining SPA therapy with PARP inhibition."

-Patrick

[1] ncbi.nlm.nih.gov/pubmed/313...

J Clin Invest. 2019 Jul 16;130. pii: 127613. doi: 10.1172/JCI127613.

Supraphysiological androgens suppress prostate cancer growth through androgen receptor-mediated DNA damage.

Chatterjee P, Schweizer MT, Lucas JM, Coleman I, Nyquist MD, Frank SB, Tharakan R, Mostaghel E, Luo J, Pritchard CC, Lam HM, Corey E, Antonarakis ES, Denmeade SR, Nelson PS.

Abstract

Prostate cancer (PC) is initially dependent on androgen receptor (AR) signaling for survival and growth. Therapeutics designed to suppress AR activity serve as the primary intervention for advanced disease. However, supraphysiological androgen (SPA) concentrations can produce paradoxical responses leading to PC growth inhibition. We sought to discern the mechanisms by which SPA inhibits PC and to determine if molecular context associates with anti-tumor activity. SPA produced an AR-mediated, dose-dependent induction of DNA double-strand breaks (DSBs), G0/G1 cell cycle arrest and cellular senescence. SPA repressed genes involved in DNA repair and delayed the restoration of damaged DNA which was augmented by PARP1 inhibition. SPA-induced DSBs were accentuated in BRCA2-deficient PCs, and combining SPA with PARP or DNA-PKcs inhibition further repressed growth. Next-generation sequencing was performed on biospecimens from PC patients receiving SPA as part of ongoing Phase II clinical trials. Patients with mutations in genes mediating homology-directed DNA repair were more likely to exhibit clinical responses to SPA. These results provide a mechanistic rationale for directing SPA therapy to PCs with AR amplification or DNA repair deficiency, and for combining SPA therapy with PARP inhibition.

KEYWORDS:

Endocrinology; Oncology; Prostate cancer

PMID: 31310591 DOI: 10.1172/JCI127613

[cesanon]

That would be consistent with Dr. Sartor's proposition of skipping the bipolar and just hitting the cancer with elevated testosterone.

He seemed very self confident with himself when expressing this proposition. Like it was a grand new insight.

[henukit]

Being a BRCA mutant, I find this fascinating. Thanks for posting!

[cigafred]

SPT=Supraphysiological testosterone?

[sammamish]

Patrick, was wondering about your preference for BAT(monthly shots with a pause if PSA begins to rise, ( I presume?)) versus 3 month on 3 month off. Do you think the tail off to castrate at the end of each month is a net benefit? If so why? Seems to me if you're going for epigenentic remodeling of the AR receptor gene that the longer you run hi T the better?

Curious to your thinking on this..

[pjoshea13 in reply to sammamish]

I loved being on the 3/3 protocol. The 3 months of high-normal T was a treat. It worked for me for years. It was still working when I switched to BAT late last year.

I have only just begun to realize that the monthly BAT cycle is too short for me. With my weekly T shots while on 3 months of T, T levels were still above 1,000 ng/dL before the next weekly shot. With BAT, the monthly T shot is much higher - the goal is 2,000 ng/dL. While I may very well be castrate by the end of the month, I doubt that I am castrate long enough to get any real ADT benefit.

Early this year, I became afflicted with sciatic pain. A scan showed nothing in April, but a repeat on Monday shows something in the sacrum. I will be discussing it with my doctor tomorrow. Meanwhile, after a long month (31 days), I suddenly have a lessening of pain after 6 months. I am not going to inject today (Aug 1st), since I decided a couple of weeks ago to switch to a 2-month BAT cycle.

It would be interesting to discover how much T I have on days 8, 15 & 22. T cypionate is not cleared quickly in my body. T patches would give greater control. One could step down from supraphysiological to near zero in 24 hours, I think. Instead, with T cypionate, it's more like a sine curve.

It's unfortunate that I have had 6 months of pain for no good reason. I should have monitored T during the 1st BAT month.

But, anyway, while the T exposure might not be optimal with BAT, I suspect that it is at least 2 weeks (in my case).

-Patrick

[sammamish in reply to pjoshea13]

Patrick, what was your weekly shot dosage on the 3/3 plan? I assume also you were on either Dega or Lupron continuously.

[pjoshea13 in reply to sammamish]

The little bottles I have contain 200 mg/mL & I injected 0.4 mL weekly.

I was not on continuous Lupron (or anything) - I used a daily capsule of Prostasol, which used to be spiked with something, perhaps DES.

-Patrick