AAS & Prostate Cancer

[Michael Scally MD]

Here is an interesting concept: Is it possible that AAS cycling with the AIH that occurs after stopping AAS might protect one from Prostate Cancer? Recall, AIH occurs 100% of the time after stopping AAS. The variables are the duration & severity. Is it conceivable that the AAS cycling of non-prescription AAS users find its way into the clinic? Comments ... Thoughts ...

 

[Michael Scally MD]

Thelen P, Heinrich E, Bremmer F, Trojan L, Strauss A. Testosterone boosts for treatment of castration resistant prostate cancer: An experimental implementation of intermittent androgen deprivation. The Prostate. Testosterone boosts for treatment of castration resistant prostate cancer: An experimental implementation of intermittent androgen deprivation - Thelen - 2013 - The Prostate - Wiley Online Library

BACKGROUND The primary therapeutic target for non-organ-confined prostate cancer is the androgen receptor (AR). Main strategies to ablate AR function are androgen depletion and direct receptor blockade by AR antagonists. However, incurable castration resistant prostate cancer (CRPC) develops resistance mechanisms to cope with trace amounts of androgen including AR overexpression and mutation in the AR ligand binding domain.

METHODS The CRPC cell model VCaP derivative of a prostate cancer bone metastasis was used in vitro and in nude mice in vivo to examine the effects of immediate testosterone boost on CRPC cells. In addition, a testosterone tolerant cell model was established by incremental acclimatization of VCaP cells to 1?nM testosterone. The effects of androgen withdrawal and testosterone boosts on gene expression were assessed by quantitative real-time polymerase chain reaction, ELISA, and Western blots. Tumor cell proliferation was evaluated with a BrdU test.

RESULTS Testosterone boosts on CRPC VCaP cells eliminate tumor cells to a higher extent than androgen withdrawal in androgen tolerant cells. The pronounced decrease of tumor cell proliferation was accompanied by a marked downregulation of AR expression regarding full-length AR and splice variant AR V7.

CONCLUSIONS Acquiring castration resistance of prostate cancer cells by AR overexpression and amplification obviously sensitizes such cells to testosterone concentrations as low as physiological values. This introduces novel therapeutic means to treat CRPC with non-toxic measures and may find clinical implementation in intermittent androgen deprivation regimens.

 

[MR10X]

I was on ADT for 7 months for confined prostrate cancer,had the seed implants in November 2012 and then 25 radiation treatments in Jan 2013,My last ADT shot was dec 2012 the 1 month release version 7.5 mg. I went to my primary doc in June and had bloodwork done,my TT was 32 and my FT was 0.2,LH was 2.0. MY PSA was 0.1 so there was no detectable cancer.My primary refered me to a Endo which i will see next week and see about getting my test back up or start TRT.My Onocologist said it was ok to get my Test in normal range.I would be happy with test range in the normal range,even if i have to do TRT. My test was in the mid 400 to mid 500 range before i started the ADT. It will interesting to see what he has to say about the situation.

 

[solo47]

Sounds good, 10X, after a pretty scary period.

Solo

 

[Sworder]

Wait a minute Dr Scally!!!

Is that study suggesting downregulation of ARs after administering testosterone? Which for AAS users may suggest a, dare I say, tolerance?

 

[Michael Scally MD]

Wait a minute Dr Scally!!!

Is that study suggesting downregulation of ARs after administering testosterone? Which for AAS users may suggest a, dare I say, tolerance?

No.

 

[Michael Scally MD]

Bipolar Androgen Therapy (BAT) [Periods of high androgen levels followed by very low androgen levels. "Cycling"]

The mechanism underlying the therapeutic use of testosterone is termed Bipolar Androgen Therapy (BAT). IMO, they could have found a better name than "Bipolar." Androgen replacement therapy normally is deemed paradoxical in prostate cancer since it is (in early stages) dependent on hormones. However, under therapeutic castration it becomes castration-resistant, and this in turn obviously creates a soft spot in cancer cells to AAS, which can be targeted by BAT or a testosterone boost.

Traditional forms of hormone therapy for prostate cancer are based on the idea that you reduce testosterone levels as low as you can so as to stop the ability of testosterone and its metabolites (e.g., dihydrotestosterone) to stimulate growth of prostatic tissues — including prostate cancer cells.

These traditional forms of hormone therapy — also known as androgen deprivation therapy or ADT, using drugs like LHRH agonists, LHRH antagonists, and antiandrogens – are highly effective in the palliation of symptoms of metastatic prostate cancer (e.g., bone pain) but eventually ALL men will relapse.

What we have been learning about during the development of some of the currently investigational types of “second-line” hormone therapies (e.g., abiraterone acetate and MDV 3100) is the paradoxical idea that the growth of some “androgen-sensitive” prostate cancer cells can also be inhibited by “supraphysiologic” levels of androgens. In other words, the presence of testosterone and other androgens in levels far higher than normal may also help to inhibit growth of some prostate cancer cells.

Why does this happen?

The effect may be a consequence of the way that high levels of androgens affect the DNA of cells that express high levels of specific androgen receptors. One such recently described effect might be the way in which androgens can induce breaks into the double strands of DNA.

The authors have now initiated a small clinical trial in men with castration-resistant prostate cancer (CRPC). http://clinicaltrials.gov/ct2/show/NCT01750398 The trial is designed to test the effect of monthly treatments with an intramuscular depot injection of testosterone. This injection raises levels of testosterone far beyond what can be achieved with standard, gel-based testosterone applications (found in testosterone patches). The induction of a supraphysiologic level of testosterone is immediately followed by the use of etopside to augment any effect on breaks in the patient’s DNA and then by standard ADT to induce a rapid drop of testosterone levels down in to the castrate range with each cycle of therapy.

The authors have termed this “bipolar androgen therapy.” According to their theory, bipolar androgen therapy eliminates the time needed for prostate cancer cells to adapt their androgen receptor expression to the environmental conditions in the body. “The goal is to determine if a clinical response can be achieved through this non-adaptive rapid cycling approach in men with CRPC.”

I have sent off for the full-text.

Isaacs JT, D'Antonio JM, Chen S, et al. Adaptive auto-regulation of androgen receptor provides a paradigm shifting rationale for bipolar androgen therapy (BAT) for castrate resistant human prostate cancer. Prostate 2012;72(14):1491-505. Adaptive auto-regulation of androgen receptor provides a paradigm shifting rationale for bipolar androgen therapy (BAT) for castrate resistant human prostate cancer - Isaacs - 2012 - The Prostate - Wiley Online Library

Cell culture/xenograft and gene arrays of clinical material document that development of castration resistant prostate cancer (CRPC) cells involves acquisition of adaptive auto-regulation resulting in >25-fold increase in Androgen Receptor (AR) protein expression in a low androgen environment. Such adaptive AR increase paradoxically is a liability in castrated hosts, however, when supraphysiologic androgen is acutely replaced.

Cell synchronization/anti-androgen response is due to AR binding to replication complexes (RC) at origin of replication sites (ORS) in early G1 associated with licensing/restricting DNA for single round of duplication during S-phase. When CRPC cells are acutely exposed to supraphysiologic androgen, adaptively increased nuclear AR is over-stabilized, preventing sufficient degradation in mitosis, inhibiting DNA re-licensing, and thus death in the subsequent cell cycle.

These mechanistic results and the fact that AR/RC binding occurs in metastatic CRPCs directly from patients provides a paradigm shifting rationale for bipolar androgen therapy (BAT) in patient progressing on chronic androgen ablation. BAT involves giving sequential cycles alternating between periods of acute supraphysiologic androgen followed by acute ablation to take advantage of vulnerability produced by adaptive auto-regulation and binding of AR to RC in CRPC cells. BAT therapy is effective in xenografts and based upon positive results has entered clinical testing.


Denmeade SR, Isaacs JT. Bipolar androgen therapy: the rationale for rapid cycling of supraphysiologic androgen/ablation in men with castration resistant prostate cancer. Prostate 2010;70(14):1600-7. Bipolar androgen therapy: The rationale for rapid cycling of supraphysiologic androgen/ablation in men with castration resistant prostate cancer - Denmeade - 2010 - The Prostate - Wiley Online Library

Androgen ablation is highly effective palliative therapy for metastatic prostate cancer but eventually all men relapse. New findings demonstrating that androgen receptor (AR) expression continues in androgen ablated patients has resulted in the classification "Castration Resistant Prostate Cancer" (CRPC) and has led to the development of new second-line "anti-ligand" hormonal agents.

In this background is the paradoxical observation that the growth of some AR-expressing "androgen sensitive" human prostate cancer cells can be inhibited by supraphysiologic levels of androgens. This response may be due to effects of high-dose androgen on inhibiting re-licensing of DNA in cells expressing high levels of AR. It may also be due to recently described effects of androgen in inducing double strand DNA breaks.

Based on available preclinical data described in this review demonstrating the effects of supraphysiologic levels of testosterone on inhibition of growth of CRPC xenografts, we initiated a clinical trial in men with CRPC testing the effect of monthly treatments with an intramuscular (IM) depot injection of testosterone. This IM formulation achieves supraphysiologic levels of testosterone that cannot be achieved with standard testosterone gel-based applications. The supraphysiologic testosterone level is followed by a rapid drop to castrate levels of testosterone with each cycle of therapy.

This "bipolar androgen therapy" will not allow time for prostate cancer cells to adapt their AR expression in response to environmental conditions. The goal is to determine if a clinical response can be achieved through this non-adaptive rapid cycling approach in men with CRPC.

 

[Michael Scally MD]

I posted this back in September 2011. https://thinksteroids.com/community/posts/782130

[This IS NOT a typo! The research calls for testosterone use in PrCa. Moreover, at levels of 2500-3500 ng/dL, which is north of 200 mg/week.]

Androgens As Therapy For Androgen Receptor Positive Castration Resistant Prostate Cancer

Based on the results from the researchers’ model, patients developing relapsed hormone-refractory prostate tumors after androgen ablation therapy should be biopsied for expression level of Androgen Receptor (AR) protein in tumors. Intermittent Androgen Deprivation (IAD) and/or administration of exogenous androgen at a concentration 2500-3500 ng/dl will benefit patients with AR-rich relapsed tumors by suppressing tumor growth, improving quality of life, and reducing risks for cardiovascular diseases and diabetes. Combined treatment of androgen ablation therapy with anti-androgen causes a rapid and irreversible selection of more aggressive advanced prostate cancer cells. Exogenous androgen treatment can cause regression of these tumors and a subgroup of these tumors will disappear.

Androgen deprivation therapy alone may promote a slow adaptation to androgen ablation-resistance, thus shortening the period of androgen deprivation therapy may retard the diseases progression and reduce side effects. Aromatase inhibitors should be considered in combination with androgen treatment to prevent the conversion of testosterone to estradiol (E2) by aromatase to avoid potential cardiac toxicity. Since several clinical trials already confirmed that testosterone is a safe, feasible, and reasonably well-tolerated therapy for men with early hormone-refractory prostate cancer, we believe that manipulating androgen/AR signaling can be a potential therapy for AR-positive advanced prostate cancer.


Chuu CP, Kokontis JM, Hiipakka RA, et al. Androgens as therapy for androgen receptor-positive castration-resistant prostate cancer. J Biomed Sci 2011;18:63. Journal of Biomedical Science | Full text | Androgens as Therapy for Androgen Receptor-Positive Castration-Resistant Prostate Cancer

Prostate cancer is the most frequently diagnosed non-cutaneous tumor of men in Western countries. While surgery is often successful for organ-confined prostate cancer, androgen ablation therapy is the primary treatment for metastatic prostate cancer. However, this therapy is associated with several undesired side-effects, including increased risk of cardiovascular diseases. Shortening the period of androgen ablation therapy may benefit prostate cancer patients. Intermittent Androgen Deprivation therapy improves quality of life, reduces toxicity and medical costs, and delays disease progression in some patients.

Cell culture and xenograft studies using androgen receptor (AR)-positive castration-resistant human prostate cancers cells (LNCaP, ARCaP, and PC-3 cells over-expressing AR) suggest that androgens may suppress the growth of AR-rich prostate cancer cells. Androgens cause growth inhibition and G1 cell cycle arrest in these cells by regulating c-Myc, Skp2, and p27Kip via AR. Higher dosages of testosterone cause greater growth inhibition of relapsed tumors. Manipulating androgen/AR signaling may therefore be a potential therapy for AR-positive advanced prostate cancer.

 

[Michael Scally MD]

Castration-resistant prostate cancer does not necessarily require the presence of testosterone and growth in the absence of hormonal stimulation is frequently observed.

Thus, standard androgen deprivation therapy is ineffective at this stage of the disease.

Now, Schweizer et al. have pursued a different approach, based on evidence that cancer cells adapted to low-androgen conditions may not be able to tolerate high amounts of testosterone.

A clinical trial of “bipolar androgen therapy,” leading to alternation between very high and low concentrations of testosterone in the patients’ blood, showed that the regimen was well tolerated and has therapeutic potential.

In addition to its direct anticancer effects, intermittent testosterone dosing may restore the tumors’ sensitivity to antiandrogen agents, further expanding patients’ treatment options.

Schweizer MT, Antonarakis ES, Wang H, et al. Effect of bipolar androgen therapy for asymptomatic men with castration-resistant prostate cancer: Results from a pilot clinical study. Science Translational Medicine 2015;7(269):269ra2. http://stm.sciencemag.org/content/7/269/269ra2.abstract

Targeting androgen receptor (AR) axis signaling by disrupting androgen-AR interactions remains the primary treatment for metastatic prostate cancer.

Unfortunately, all men develop resistance to primary castrating therapy and secondary androgen deprivation therapies (ADTs).

Resistance develops in part because castration-resistant prostate cancer (CRPC) cells adaptively up-regulate AR levels through overexpression, amplification, and expression of ligand-independent variants in response to chronic exposure to a low-testosterone environment.

However, preclinical models suggest that AR overexpression represents a therapeutic liability that can be exploited via exposure to supraphysiologic testosterone to promote CRPC cell death.

Preclinical data supported a pilot study in which 16 asymptomatic CRPC patients with low to moderate metastatic burden were treated with testosterone cypionate (400 mg intramuscular; day 1 of 28) and etoposide (100 mg oral daily; days 1 to 14 of 28).

After three cycles, those with a declining prostate-specific antigen (PSA) continued on intermittent testosterone therapy monotherapy.

Castrating therapy was continued to suppress endogenous testosterone production, allowing for rapid cycling from supraphysiologic to near-castrate serum testosterone levels, a strategy termed bipolar androgen therapy (BAT).

BAT was well tolerated and resulted in high rates of PSA (7 of 14 evaluable patients) and radiographic responses (5 of 10 evaluable patients).

Although all men showed eventual PSA progression, four men remained on BAT for ≥1 year.

All patients (10 of 10) demonstrated PSA reductions upon receiving androgen-ablative therapies after BAT, suggesting that BAT may also restore sensitivity to ADTs.

BAT shows promise as treatment for CRPC and should be further evaluated in larger trials.

 

[Michael Scally MD]

Zhang Q, Gray PJ. From bench to bedside: bipolar androgen therapy in a pilot clinical study. Asian J Androl. http://www.asiaandro.com/news/upload/20150205-201520.pdf

Prostate cancer remains a leading cause of cancer death in Europe and the United States and is an emerging problem in Asia despite significant improvements in available treatments over the last few decades.

Androgen deprivation therapy (ADT) has been the core treatment of advance-staged disease since the discovery of prostate cancer’s androgen dependence in 1941 by Huggins and colleagues.

Options for initial medical treatment include GnRH analgoues such as leuprolide (LHRH agonist) and degarelix (LHRH antagonist) and androgen receptor (AR) binding agents such as bicalutamide.

Although most patients will initially respond to either surgical or medical castration there is almost always progression to castration-resistant prostate cancer (CRPC) necessitating treatment with more novel agents.

However, even drugs such as abiraterone and enzalutamide, two next-generation agents used commonly in metastatic CRPC, have failed to demonstrate persistent efficacy in most patients

Emerging research has proposed several mechanisms of resistance to ADT including constitutively active AR splice variants, overexpression of AR, and mutations of the ligand-binding-domain (LBD) of AR.

Pre-clinical studies published by Isaacs et al. and Haffner et al. on adaptive auto-regulation of AR and induction of DNA damage with testosterone therapy in CRPC cells provide a rationale for a novel approach to overcoming castration resistance: bipolar androgen therapy (BAT). http://stm.sciencemag.org/content/7/269/269ra2.abstract

By actively exposing cells with adaptive changes in AR function to supraphysiologic levels of androgen, nuclear AR loses the flexibility to be removed from origin of DNA replication sites (ORS) thereby interrupting mitosis and causing tumor cell death.

This is then followed by a return to a castrate level of testosterone leaving surviving cells with baseline low AR or adaptive down-regulated AR again vulnerable to cell death.

This initial clinical study shows encouraging results for BAT as a novel treatment for patients with metastatic CRPC.

 

[rambosmurf]

so testosterone may help prevent some prostate cancer?

 

[slashlove]

REally? I didnt know about this, it is interesting due that i,m getting close to that age....


"Pain is temporary, Pride is forever»

 

[Koul]

Awesome reading , so many thanks to you, brother!

 

[MR10X]

been there done the ADT...that really sucks you will feel miserable,seed implants and ext radiation....3 years and PSA still low. doing the supraphysiologic test level now....250mg test e every 4 days....

 

[Michael Scally MD]

Bipolar Androgen Therapy (BAT) In Men With Hormone Sensitive (HS) Prostate Cancer (PC)
Bipolar androgen therapy (BAT) in men with hormone sensitive (HS) prostate cancer (PC). | 2016 Genitourinary Cancers Symposium Abstracts

Bipolar androgen therapy (BAT) — The intermittent use of high-dose testosterone therapy—is safe and possibly effective in patients with advanced hormone-sensitive prostate cancer (PC), according to findings of a small study that will be presented at the 2016 Genitourinary Cancers Symposium.

Background: We documented a paradoxical anti-tumor effect when castration-resistant prostate cancer patients were treated with intermittent, high-dose testosterone (i.e. BAT) [PMID: 25568070]. Since the adaptive increase in androgen receptor expression that follows chronic androgen deprivation therapy (ADT) may underlie this effect, we tested whether men with HS PC would also respond to BAT if given following a 6-month ADT lead-in.

Methods: Men with asymptomatic HS PC and low metastatic burden (N = 20) (no visceral disease, ≤ 10 bone metastases, no lymph nodes > 5 cm short axis diameter) or non-metastatic biochemically recurrent disease (N = 13) were enrolled.

Following 6-months of ADT, those with a PSA < 4 ng/ml went on to receive 2 cycles of BAT.

A cycle of BAT was defined as intramuscular testosterone (T) cypionate or enanthate 400 mg on Days (D) 1, 29 and 57 followed by ADT alone D 85-169. ADT was continued throughout the study to allow for rapid cycling from near castrate to supraphysiologic range T following T injections.

The primary endpoint was the percent of patients with a PSA < 4 ng/ml after 2 cycles of BAT, with the study designed to reject a null rate of 40% at a one-sided alpha = 0.1. Secondary endpoints included quality of life (QOL) as measured by the SF-36, FACT-P, IIEF and IPSS surveys.

Results: Twenty-nine of 33 patients received BAT following the ADT lead-in (1 withdrew consent, 3 had PSA > 4 ng/ml). The primary endpoint was met, with 17/29 men (59%, lower bound 90% confidence interval = 45%) having a PSA < 4 ng/ml after 2 cycles of BAT.

Ten patients receiving BAT had RECIST evaluable disease, and 8 (80%) objective responses were observed (4 complete; 4 partial). Three patients progressed per RECIST criteria and 3 had unconfirmed progression on bone scan.

Men treated with 6-months of ADT had improved QOL after the first cycle of BAT.

The median improvement in SF-36, FACT-P, and IIEF total scores were 3.2 (range, -20 to 48; P = 0.21), 3.5 (range, -30 to 50; P = 0.04), and 10 (range, -4 to 59; P < 0.001) points, respectively. There was no change in total IPSS score (median change 0 [range, -9 to 8; P = 0.87]).

Conclusions: BAT demonstrated preliminary efficacy in men with HS PC following 6-months of ADT. BAT may improve QOL in men that have received ADT.

Clinical trial information: NCT01750398. https://clinicaltrials.gov/show/NCT01750398

 

[Michael Scally MD]

Hedayati M, Haffner MC, Coulter J, et al. Androgen deprivation followed by acute androgen stimulation selectively sensitizes AR-positive prostate cancer cells to ionizing radiation. Clinical Cancer Research. Androgen deprivation followed by acute androgen stimulation selectively sensitizes AR-positive prostate cancer cells to ionizing radiation

Purpose: The current standard of care for patients with locally advanced prostate cancer is a combination of androgen deprivation and radiation therapy. Radiation is typically given with androgen suppression when testosterone levels are at their nadir. Recent reports have shown that androgen stimulation of androgen deprived prostate cancer cells leads to formation of double strand breaks (DSBs). Here, we exploit this finding and investigate the extent and timing of androgen induced DSBs and their effect on tumor growth following androgen stimulation in combination with ionizing radiation (IR).

Experimental Design: Androgen induced DNA damage was assessed by comet assays and γH2A.X foci formation. Effects of androgen stimulation and radiation were determined in vitro and in vivo with xenograft models.

Results: We document that androgen treatment of androgen deprived prostate cancer cell lines resulted in a dose and time dependent induction of widespread DSBs. Generation of these breaks was dependent on androgen receptor (AR) and topoisomerase II beta (TOP2B) but not on cell cycle progression. In vitro models demonstrated a synergistic interaction between ionizing radiation and androgen stimulation when IR is given at a time point corresponding with high levels of androgen-induced DSB formation. Furthermore, in vivo studies showed a significant improvement in tumor growth delay when radiation was given shortly after androgen repletion in castrated mice.

Conclusions: These results suggest a potential cooperative effect and improved tumor growth delay with androgen-induced DSBs and radiation with implications for improving the therapeutic index of prostate cancer radiation therapy.

 

[Michael Scally MD]

Schweizer MT, Wang H, Luber B, et al. Bipolar androgen therapy for men with androgen ablation naive prostate cancer: Results from the phase II BATMAN study. Prostate. Bipolar androgen therapy for men with androgen ablation naïve prostate cancer: Results from the phase II BATMAN study - Schweizer - 2016 - The Prostate - Wiley Online Library

BACKGROUND: We have previously documented a paradoxical anti-tumor effect when castration-resistant prostate cancer patients were treated with intermittent, high-dose testosterone (i.e., Bipolar Androgen Therapy; BAT).

Because, an adaptive increase in androgen receptor expression following chronic androgen deprivation therapy (ADT) may underlie this effect, we tested whether men with hormone-sensitive (HS) prostate cancer (PC) would also respond to BAT if given following a 6-month ADT lead-in.

METHODS: Asymptomatic HS PC patients with low metastatic burden or non-metastatic biochemically recurrent disease were enrolled. Following 6-month of ADT, those with a PSA <4 ng/ml went on to receive alternating 3-month cycles of BAT and ADT.

BAT was administered as intramuscular testosterone (T) cypionate or enanthate 400 mg on Days (D) 1, 29, and 57. ADT was continued throughout the study to allow rapid cycling from near castrate to supraphysiologic range T following T injections. The primary endpoint was the percent of patients with a PSA <4 ng/ml after 18 months. Secondary endpoints included radiographic response and quality of life (QoL).

RESULTS: Twenty-nine of 33 patients received BAT following the ADT lead-in. The primary endpoint was met, with 17/29 men (59%, 90% confidence interval: 42-74%) having a PSA <4 ng/ml at 18 months.

Ten patients receiving BAT had RECIST evaluable disease, and eight (80%) objective responses were observed (four complete; four partial). Three patients progressed per RECIST criteria and three had unconfirmed progression on bone scan. Men treated with 6-month of ADT had improved QoL following the first cycle of BAT as measured by the SF-36, FACT-P, and IIEF surveys.

CONCLUSIONS: BAT demonstrated preliminary efficacy in men with HS PC following 6-month of ADT. BAT may improve QoL in men treated with ADT.

 

[new to the game]

I appreciate these articles... but sadly it takes a lot of brain power to understand them. Is there a summary or something that gets to the point more rapidly? It might be my ADD, but I can't focus long enough to get through them

 

[Michael Scally MD]

Growth Inhibition by Testosterone in an Androgen Receptor Splice Variant-Driven Prostate Cancer Model

BACKGROUND: Castration resistance creates a significant problem in the treatment of prostate cancer. Constitutively active splice variants of androgen receptor (AR) have emerged as drivers for resistance to androgen deprivation therapy, including the next-generation androgen-AR axis inhibitors abiraterone and enzalutamide. In this study, we describe the characteristics of a novel castration-resistant prostate cancer (CRPC) model, designated JDCaP-hr (hormone refractory).

METHODS: JDCaP-hr was established from an androgen-dependent JDCaP xenograft model after surgical castration. The expression of AR and its splice variants in JDCaP-hr was evaluated by immunoblotting and quantitative reverse transcription-polymerase chain reaction. The effects of AR antagonists and testosterone on JDCaP-hr were evaluated in vivo and in vitro. The roles of full-length AR (AR-FL) and AR-V7 in JDCaP-hr cell growth were evaluated using RNA interference.

RESULTS: JDCaP-hr acquired a C-terminally truncated AR protein during progression from the parental JDCaP. The expression of AR-FL and AR-V7 mRNA was upregulated by 10-fold in JDCaP-hr compared with that in JDCaP, indicating that the JDCaP and JDCaP-hr models simulate castration resistance with some clinical features, such as overexpression of AR and its splice variants.

The AR antagonist bicalutamide did not affect JDCaP-hr xenograft growth, and importantly, testosterone induced tumor regression. In vitro analysis demonstrated that androgen-independent prostate-specific antigen secretion and cell proliferation of JDCaP-hr were predominantly mediated by AR-V7.

JDCaP-hr cell growth displayed a bell-shaped dependence on testosterone, and it was suppressed by physiological concentrations of testosterone. Testosterone induced rapid downregulation of both AR-FL and AR-V7 expression at physiological concentrations and suppressed expression of the AR target gene KLK3.

CONCLUSIONS: Our findings support the clinical value of testosterone therapy, including bipolar androgen therapy, in the treatment of AR-overexpressed CRPC driven by AR splice variants that are not clinically actionable at present.

Nakata D, Nakayama K, Masaki T, Tanaka A, Kusaka M, Watanabe T. Growth Inhibition by Testosterone in an Androgen Receptor Splice Variant-Driven Prostate Cancer Model. Prostate. Growth Inhibition by Testosterone in an Androgen Receptor Splice Variant-Driven Prostate Cancer Model - Nakata - 2016 - The Prostate - Wiley Online Library

 

[master.on]

I'd rather die from prostate cancer
than to undergo Androgen Deprivation Therapy.
and it doesn't fully work as the studies say that ALL men will relapse.

So in short
if you get prostate cancer
you'd better tell your doctor to GTFO with his proposed ADT treatment
get on TRT asap
and spend your whole reverse mortgage turning tricks til you die?