Sam

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Jul 29, 2012, 3:49:47 AM7/29/12

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Prostate. 2012 Mar 6. doi: 10.1002/pros.22504. [Epub ahead of print]

Adaptive auto-regulation of androgen receptor provides a paradigm shifting rationale for bipolar androgen therapy (BAT) for castrate resistant human prostate cancer.

Isaacs JT, D'Antonio JM, Chen S, Antony L, Dalrymple SP, Ndikuyeze GH, Luo J, Denmeade SR.

Source

The Chemical Therapeutic Program, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Urology, Brady Urological Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland. isa...@jhmi.edu.

Entered clinical testing. Maybe worth following up.

Abstract

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. Prostate © 2012 Wiley Periodicals, Inc.

PMID:: 22396319; [PubMed - as supplied by publisher]
PMCID:: PMC3374010; [Available on 2013/9/6]

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Patrick OShea

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Jul 29, 2012, 4:22:16 PM7/29/12

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I can't find anything on ClinicalTrials.gov regarding a new study.

Here is a snip from a 2009 Phase I Trial paper:

"Although all of these patients met the definition of castration-resistant metastatic disease, they likely still represented a biologically heterogeneous group. They had various exposures to prior hormonal therapies and chemotherapy and likely also had variable AR expression. Regarding the latter, when the present study was designed, there were few means by which patients might be selected on the basis of AR overexpression, which, as previously mentioned, predicts for response preclinically. Now, however, such methods exist. Patients with AR-rich tumors, for example, can be identified using fluorinated dihydrotestosterone (FDHT) PET tracers [17,18]. Additionally, circulating PCa cells can be isolated and identified on the basis of AR gene amplification [19]. These techniques as well as further efforts to reduce patient heterogeneity can be used to enrich the patient population for likely responders in future trials. Patient selection is of particular importance in this approach because although testosterone may be beneficial to some patients, it may activate cancer growth in others, representing a deleterious rather than a beneficial effect."

Full Text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2738932/?tool=pubmed

-Patrick

Dx04 @ 56 (DRE nodule 2002) |bPSA 3.3 (0.8 when nodule found)| GS=4+3, RP - no LN, no SV, but PSA nadir-0.3. DT=3 months Salvage RT 2005. Again, nadir=0.3. No HB. Arimidex. AndroDerm.

From: Sam <georgias...@gmail.com>
To: prostatic-diseases-treatments <prostatic-dise...@googlegroups.com>
Sent: Sunday, July 29, 2012 3:49 AM
Subject: [PDT:1178] Bipolar Therapy

--
Prostate cancer is an exceptionally heterogenous disease. What is good for one man may not be so kind on the next. Be sure to research and test any new supplement or treatment before adopting it - and in any case run it past a medically qualified person for a second opinion.

EdF

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Jul 31, 2012, 12:59:27 AM7/31/12

to prostatic-dise...@googlegroups.com, Patrick OShea

On Sunday, July 29, 2012 3:22:16 PM UTC-5, Patrick OShea wrote:

I can't find anything on ClinicalTrials.gov regarding a new study.

Patrick,

I don't know why their trial is not listed that web site, but in the article it says "accrual to this trial is ongoing". Also it says for the first four patients they tried BAT on, two of them experience a greater than 50% drop in PSA after 3 months. This may sound encouraging, but my model predicts that this protocol will fail in the long run because they are doing nothing to prevent the conversion of T to E2, and E2 is the real killer in PCa.

Ed Friedman

dtc

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Jul 31, 2012, 8:26:18 AM7/31/12

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Ed,

What are your methods to hold down E2?

Doug

EdF

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Jul 31, 2012, 3:53:07 PM7/31/12

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Doug,

As far as I know, nothing works except for Arimidex and Aromatase, and those are only available with a prescription (but they are generics now, so less expensive). However, even though not lowering E2 is eventually fatal, lowering E2 is not sufficient to stop the progression of PCa. I have heard rumors that using very high T plus finasteride (like Dr. Leibowitz) and then adding aromatase inhibitors is a very effective protocol for many PCa patients. However, if this doesn't work, then you have to use something like this BAT protocol, or the protocol that I had published in Prostate in which you alternate finasteride with high T (teenage levels) while continually using aromatase inhibitors.

Ed Friedman

Patrick OShea

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Jul 31, 2012, 5:40:58 PM7/31/12

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Doug,

I looked at my records:

- up to last year, I was using Arimidex at $4.72 per 1 mg pill - a two-day supply.

- I switched to the generic Anastrozole, which is closer to $0.75.

That's what I pay under my plan, if the doctor agrees to a 3-month mail shipment.

I just had my prescriptions renewed & CVS Caremark sent me one box of AndroDerm instead of three. They charged me $85 instead of $40 (i.e. I usually pay $120 for 3 months.) Outrageous, but luckily I noticed the price difference & got it fixed. It's an insane situation. There was a similar problem with the Anastrozole: $1.50.

Who knows what these things cost when one has no insurance?

Oh no! I just Googled & discovered that a one-month supply of AndroDerm at CVS would cost me $346.33!

Retail for Arimidex (90 pills) is $11.90 per 1 mg.

The amount of Arimidex one needs will vary by person. I monitor E2 when I have T checked every 6 months. Theoretically my dose is 1.5 mg / week. My integrative medicine doctor has no problem prescribing it to male patients. In fact, he suggested it to me after learning I was using chrysin.

But many doctors consider it is a female-only drug.

Losing every ounce of visceral fat will help keep E2 down. But aromatase is overexpressed in PCa cells, so low circulating values might mislead.

-Patrick

Dx04 @ 56 (DRE nodule 2002) |bPSA 3.3 (0.8 when nodule found)| GS=4+3, RP - no LN, no SV, but PSA nadir-0.3. DT=3 months Salvage RT 2005. Again, nadir=0.3. No HB. Arimidex. AndroDerm.

From: EdF <e...@math.uchicago.edu>
To: prostatic-dise...@googlegroups.com
Sent: Tuesday, July 31, 2012 3:53 PM
Subject: Re: [PDT:1183] Bipolar Therapy

Sam

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Jul 31, 2012, 6:59:44 PM7/31/12

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My urologist and then my GP Rx'd Testo gel and Arimidex without batting an eyelid a few years back. Now they are counting every penny.

Ed would you be good enough to postm the PMID of the article you mention in Prostate. I must have read it, but just to make sure .. Tnx

Sam.

Sam

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Aug 1, 2012, 8:22:51 AM8/1/12

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Possibly, BAT will give a different PSA response for each separate
clonal population. So, whilst BAT kills some populations, others might
thrive in a hi-T/E environment. This may indicate failure of BAT.
However, all is not lost since the surviving populations may be
high-PSA producers with a longer PSAV and lower metastatic threat.
This in turn could mean it is worthwhile to continue BAT despite a
slowly rising PSA (provided other markers are not flagging a dire
warning). Sam

On 29/07/2012, Sam <georgias...@gmail.com> wrote:
> Prostate. <http://www.ncbi.nlm.nih.gov/pubmed/22396319#> 2012 Mar 6. doi:

> 10.1002/pros.22504. [Epub ahead of print]
> Adaptive auto-regulation of androgen receptor provides a paradigm shifting
> rationale for bipolar androgen therapy (BAT) for castrate resistant human
> prostate cancer.
> Isaacs

> LinkOut - more resources <http://www.ncbi.nlm.nih.gov/pubmed/22396319#>
>
> -

>
>
>
> Supplemental Content
> [image: Icon for John Wiley & Sons,

> Inc.]<http://dx.doi.org/10.1002/pros.22504>
> Save items
> <http://www.ncbi.nlm.nih.gov/pubmed/22396319#>
> View more options <http://www.ncbi.nlm.nih.gov/pubmed/22396319#>
> Related citations in PubMed
> <http://www.ncbi.nlm.nih.gov/pubmed/22396319#>
>
> - Bipolar androgen therapy: the rationale for rapid cycling of

> supraphysiologic androgen/ablation in men with castration resistant

> prostate cancer. <http://www.ncbi.nlm.nih.gov/pubmed/20607766>
> [Prostate.
> 2010]
> - Review DNA licensing as a novel androgen receptor mediated therapeutic
> target for prostate cancer.
> <http://www.ncbi.nlm.nih.gov/pubmed/19240183> [Endocr
> Relat Cancer. 2009]
> - Nrdp1-mediated regulation of ErbB3 expression by the androgen receptor

> in androgen-dependent but not castrate-resistant prostate cancer

> cells.<http://www.ncbi.nlm.nih.gov/pubmed/20587519> [Cancer
> Res. 2010]
> - Distinct transcriptional programs mediated by the ligand-dependent

> full-length androgen receptor and its splice variants in
> castration-resistant prostate

> cancer.<http://www.ncbi.nlm.nih.gov/pubmed/22710436> [Cancer
> Res. 2012]
> - Review Androgens as therapy for androgen receptor-positive
> castration-resistant prostate
> cancer.<http://www.ncbi.nlm.nih.gov/pubmed/21859492> [J
> Biomed Sci. 2011]
>
> See
> reviews...<http://www.ncbi.nlm.nih.gov/pubmed?linkname=pubmed_pubmed_reviews&from_uid=22396319>
> See
> all...<http://www.ncbi.nlm.nih.gov/pubmed?linkname=pubmed_pubmed&from_uid=22396319>
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> PubMed
> - Denmeade SR[Author]
> (88)<http://www.ncbi.nlm.nih.gov/portal/utils/pageresolver.fcgi?recordid=1343546981049253>
> PubMed
> - Engineering Enzymatically Activated "Molecular Grenades" for
> Cancer.<http://www.ncbi.nlm.nih.gov/portal/utils/pageresolver.fcgi?recordid=1343543660185815>
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"Prostate cancer. A 21st century perspective: Natural history, ecology and
sociology of a malignant epidemic" ISBN 9780954993511

This is a free download plus supplements as follows: 1. A reader's guide to
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bookmarks); 2b. Searchable, printable download; 3. An update on current
thinking; 4. WHO mortality database (Excel spreadsheet adapted with
permission from WHO) for a wider discussion of BCa : PCa comparisons &
global implications mentioned in the book:

1. Guide.html
2a. ProstateCancer.pdf (online - bookmarks)
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Aug 1, 2012, 1:12:45 PM8/1/12

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On Tuesday, July 31, 2012 5:59:44 PM UTC-5, Sam wrote:

My urologist and then my GP Rx'd Testo gel and Arimidex without batting an eyelid a few years back. Now they are counting every penny.

Ed would you be good enough to postm the PMID of the article you mention in Prostate. I must have read it, but just to make sure .. Tnx

Sam.

Sam,

The PMID is 22396319.

Ed

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