Backdoor Dihydrotestosterone [DHT] & CRPC.

[pjoshea13]

New study below.

"One mechanism that provides CaP resistance to ADT is primary backdoor androgen metabolism, which uses up to four 3α-oxidoreductases to convert 5α-androstane-3α,17β-diol (DIOL) to dihydrotestosterone (DHT)."

In other words, a possible pathway to CRPC involves the generation of DHT other than from testosterone [T]. i.e. other than from 5alpha-reductase [5AR] conversion of T to DHT.

Dutasteride (Avodart) is a 5AR inhibitor [5ARI]. In the U.S., the FDA has approved Dutasteride for the treatment of benign prostatic hyperplasia (BPH). Avodart is not generally used against PCa, because castration therapy is assumed to remove enough T, that DHT cannot possibly be a problem. & so, doctors might measure T while men are on ADT, but ignore DHT.

Yet, as Dr. Myers has said - T is not the problem, DHT drives PCa. Myers would prescribe Avodart for men with castrate T but non-castrate DHT. Sometimes, one cap per week was enough to control DHT.

IMO, it is prudent to use Avodart while on ADT. I use it as prophylactic, rather than corrective.

Myers tested DHT, but does serum DHT reflect DHT levels in CRPC cells? Why would it?

Avodart might perhaps prolong the effectiveness of ADT for some (although you can't block all of the CRPC escape pathways.)

Is a 5ARI sufficient?

"... combined treatment using catalytically inactive 3α-oxidoreductase mutants and the 5α-reductase inhibitor, dutasteride, decreased DHT levels in CaP cells better than dutasteride alone. Combined blockade of frontdoor and backdoor pathways of DHT synthesis provides a therapeutic strategy to inhibit CRPC development and growth."

Dr. Myers seems to have been able to get serum DHT to castrate levels with Avodart alone, in backdoor DHT producers, so I'm not inclined to be overly concerned about the new findings.

-Patrick

ncbi.nlm.nih.gov/pubmed/295...

Oncotarget. 2018 Jan 10;9(13):11227-11242. doi: 10.18632/oncotarget.24107. eCollection 2018 Feb 16.

Inhibition of dihydrotestosterone synthesis in prostate cancer by combined frontdoor and backdoor pathway blockade.

Fiandalo MV1, Stocking JJ1, Pop EA1, Wilton JH1,2, Mantione KM2, Li Y1, Attwood KM3, Azabdaftari G4, Wu Y1, Watt DS5, Wilson EM6, Mohler JL1.

Author information

1

Department of Urology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.

2

Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.

3

Department of Biostatistics and Bioinformatics Roswell Park Cancer Institute, Buffalo, NY 14263, USA.

4

Department of Pathology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.

5

Center for Pharmaceutical Research and Innovation and Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536, USA.

6

Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599, USA.

Abstract

Androgen deprivation therapy (ADT) is palliative and prostate cancer (CaP) recurs as lethal castration-recurrent/resistant CaP (CRPC). One mechanism that provides CaP resistance to ADT is primary backdoor androgen metabolism, which uses up to four 3α-oxidoreductases to convert 5α-androstane-3α,17β-diol (DIOL) to dihydrotestosterone (DHT). The goal was to determine whether inhibition of 3α-oxidoreductase activity decreased conversion of DIOL to DHT. Protein sequence analysis showed that the four 3α-oxidoreductases have identical catalytic amino acid residues. Mass spectrometry data showed combined treatment using catalytically inactive 3α-oxidoreductase mutants and the 5α-reductase inhibitor, dutasteride, decreased DHT levels in CaP cells better than dutasteride alone. Combined blockade of frontdoor and backdoor pathways of DHT synthesis provides a therapeutic strategy to inhibit CRPC development and growth.

KEYWORDS:

3α-oxidoreductases; androgen deprivation therapy; androstanediol; dihydrotestosterone; dutasteride

PMID: 29541409 PMCID: PMC5834294 DOI: 10.18632/oncotarget.24107

[Canoehead]

Interesting, but how does this relate to the published warning that Avodart use increases risk of developing high grade PCa? Are we saying that an increased risk of developing a condition we already have is of no consequence?

[pjoshea13 in reply to Canoehead]

Now that we have very long term follow-up reports, we see that there have been no excess deaths in the two prevention trials (Finasteride & Dutasteride).

It turns out that the increase in higher-grade disease was probably due to detection bias, owing to smaller prostate sizes at follow-up biopsy.

-Patrick

[gusgold]

Pat,

Myers said T is not the problem and DHT is....then why with hormone sensitive PCa does the PSA increase when blocking DHT with avodart but not taking lupron

[podsart in reply to gusgold]

If I remember Dr Myers correctly, it’s not that DHT solely is the problem, T also is, however, Pca affinity for DHT is 5 Times higher,

[pjoshea13 in reply to gusgold]

Gus,

Standard Avodart dose significantly lowers DHT, but doesn't eliminate it.

-Patrick

[petercraig2]

Patrick,

As always thanks for your technical knowledge insight.

I asked my Oncologist last week for a script for DHT in my blood work as a Baseline for future reference and he agreed. My estrogen patches continue to work as expected and PSA is now down to .11 from a high of 12.5 six months ago.

If/when PSA changes in the wrong direction I will be able to get another DHT test and better identify what is happening with metastasis and determine the most effective therapy.

From another post i read that significant increases in serum bone specific alkaline phosphatase in PCa patients with PSA higher than 20 ng/ml can be due to metastatic activity involving bones.

Are you aware of a test for alkaline phosphatase? It's another marker I'd like to get a reference Baseline value for future reference.

I like to be proactive rather than be wrong footed in a potential rising PSA crisis.

Thanks

Peter

[RJ-MN in reply to petercraig2]

I get an "Alkaline Phosphatase" test monthly @ NIH as part of the "Hepatic Panel." Is this the count we are talking about here, or does "serum bone specific" imply a different source/manner of testing?

[pjoshea13 in reply to RJ-MN]

Looks like you are getting the general test (which is OK).

Wikipedia:

"If it is unclear why alkaline phosphatase is elevated, isoenzyme studies using electrophoresis can confirm the source of the ALP." [1]

That's when the bone-specific test might be useful. [2]

-Patrick

[1] en.wikipedia.org/wiki/Alkal...

[2] healthline.com/health/alp-i...

[pjoshea13 in reply to petercraig2]

Hi Peter,

Life Extension [LEF] blood tests (which go on sale in a month or so) includes alkaline phosphatase as part of the inexpensive "Chemistry Panel & Complete Blood Count (CBC)":

lifeextension.com/Vitamins-...

But they have a much more expensive "Bone-Specific Alkaline Phosphatase" test:

lifeextension.com/Vitamins-...

I'm assuming because my alkaline phosphatase on the general test was low - 23 IU/L (39-117), that the bone isoenzyme (ALP-2) would be pointless right now.

-Patrick

[EdBar in reply to petercraig2]

Hey Peter I've been getting Alka Phos levels and ALT levels tested every month for the past 2-3 years. It was one of the primary markers Myers used to detect whether PCa had become active again. Any doc should be familiar with it.

Ed

[petercraig2 in reply to EdBar]

Thanks Ed

That's great now I know I'm not the only one working on proactive basis to get Baseline blood work markers in order to respond if/when the bugger rears up again.

My Oncologist is very receptive to my innovative but clinically sound requests.

In the cancer hospital I am at I am first person to request Estrogen patches so my success has been an eye opener for the whole oncology team. I hope it translates into a new therapy option for other guys who may benefit from my experience.

Peter

[EdBar in reply to petercraig2]

I been using estrogen patches since 2015 when I started seeing Myers. First for ADT SE’s, then to heal scars on bones left behind by mets and as another form of HT. Sartor agrees with using them as well. All part of a multidimensional approach.

Ed

[Dan59]

I have often wondered how I made it so far out on the tail of the survival curve for for the high grade stage 4 I was dxed with. Avodart is one thing I did from the beginning, besides a lot of prayer.

[EdBar]

Been using Dutasteride daily for the past 3+ years ever since reading Snuffys book. My GP prescribed it for me upon request after I explained the reasoning behind it (stage 4 cancer, he probably figured what the heck). I became a patient of Myers in 2015 and he always recommended staying on it as does his replacement Dr. Sartor. I plan on continuing to take it - if it works don't fix it.

One more cast...

Ed

[Dan59 in reply to EdBar]

Ed, I was able to successfully rechallenge with E patches 4 times, on the 5th I think I had a withdrawl response. I also saw Myers once and then was a Patient of Sartor when he was in Boston. I wish you the best, good to know these 2 Docs still approve of E patches. I did them right along with zolodex.

Dan