[EAU-2020] Enzyme inhibition for overcoming CRPC.

[pjoshea13]

See full article below [1]. & Abstract [1a].

"Inhibition of steroid sulfatase (STS) may be a viable strategy for treating patients with castrate-resistant prostate cancer (CRPC) and improving their response to enzalutamide (Xtandi), according to preclinical research presented by Allen Gao, MD, PhD, during the 2020 European Association of Urology Virtual Congress."

"'Dehydroepiandrosterone sulfate (DHEAS) is the most abundant steroid in male circulation and can be transported into prostate cancer cells where it can be converted into DHEA by STS,” explained Gao. “Then, DHEA is further processed into the more biologically active compounds, testosterone and dihydrotestosterone.'"

"'Significant circulating concentrations of DHEAS still exist in patients with prostate cancer being treated with abiraterone,” Gao continued. “The circulating DHEAS, which is present at a level 4000 times higher than the castrate level of circulating testosterone, can serve as a depot for intracrine androgen synthesis.'"

***

Abiraterone [Abi] blocks production of DHEA [dehydroepiandrosterone] fom pregnenolone in the adrenal gland. (See [2] for the steroidogenesis chart.)

DHEA-S [DHEA-sulfate] is converted from DHEA to form an inert reservoir of (potential) DHEA. It is strongly bound to albumin, which makes for a longish half-life. Thus, although Abi rapidly shuts down DHEA production. DHEA-S represents a back-door access possibility to DHEA - & one that may linger for months.

DHEA-S levels increase rapidly during puberty & peak around age 20. Thereafter, there is a steady decline until, at age 75 they are back at age 13 levels. About 23% of peak. [3]

DHEA supplementation is often used to increase DHEA-S levels. It is argued that if there is benefit at age 20, why accept the >50% reduction that has occurred by age ~48. So, depending on age & recent supplementation history, there can be significant variation in DHEA-S levels at Abi commencement.

Nalakrats is on his sabatical, so I'll speak for both of us - we already have a way to stop DHEA-S ending up as DHT: Avodart.

The blood test for DHEA & DHEA-S is not expensive [4].

-Patrick

[1] urologytimes.com/view/enzym...

Enzyme inhibition shows promise for overcoming castration resistance in prostate cancer

July 20, 2020

Cheryl Guttman Krader, BS, Pharm

Inhibition of steroid sulfatase (STS) may be a viable strategy for treating patients with castrate-resistant prostate cancer (CRPC) and improving their response to enzalutamide (Xtandi), according to preclinical research presented by Allen Gao, MD, PhD, during the 2020 European Association of Urology Virtual Congress.

He reported on a series of studies that showed STS increases intracrine androgen production in CRPC cells, promotes CRPC progression, and confers resistance to enzalutamide and abiraterone acetate (Zytiga), whereas inhibition of the enzyme suppresses cancer cell growth and improves enzalutamide treatment.

Gao who is a professor of urology at the UC Davis School of Medicine in Sacramento, California, described the rationale for using STS inhibition as a treatment to for patients with advanced prostate cancer.

“Dehydroepiandrosterone sulfate (DHEAS) is the most abundant steroid in male circulation and can be transported into prostate cancer cells where it can be converted into DHEA by STS,” explained Gao. “Then, DHEA is further processed into the more biologically active compounds, testosterone and dihydrotestosterone.”

"Significant circulating concentrations of DHEAS still exist in patients with prostate cancer being treated with abiraterone,” Gao continued. “The circulating DHEAS, which is present at a level 4000 times higher than the castrate level of circulating testosterone, can serve as a depot for intracrine androgen synthesis.”

As a first step to exploring STS inhibition as a therapeutic strategy, Gao and colleagues undertook studies to confirm that STS was expressed in CRPC cells. In 2 separate experiments, they found STS was overexpressed in metastatic prostate cancer cells compared to benign prostate and primary tumor cells.

Next they showed that STS expression was involved in prostate cancer growth. Using C4-2B cells, Gao and colleagues demonstrated that downregulation of STS expression using STS-specific siRNA reduced cell growth and androgen signaling.

Studying the relationship between STS and intracrine androgen synthesis, the investigators found that when supplemented with DHEAS, cells overexpressing STS produced increased intracellular testosterone compared with controls. Cells overexpressing STS also demonstrated increased resistance to enzalutamide.

Moving forward, the researchers explored STS as a therapeutic target by synthesizing a family of 11 potential STS inhibitors. Initial testing of the novel compounds showed a correlation between their STS inhibitory activity and effect on reducing growth of VCaP cells. The 2 most potent STS inhibitors were selected for use in an in vivo vehicle-controlled study performed in a castration-relapsed VCaP xenograft tumor mouse model. Both STS inhibitors significantly suppressed tumor growth.

In a second experiment performed in the same mouse model, animals were treated with vehicle, enzalutamide, 1 of the STS inhibitors, or enzalutamide plus the STS inhibitor. Treatment effects were determined based on assays of tumor size and proliferation, and the results showed that for both outcomes, the best results were achieved with the combination regimen.

Gao noted that extensive toxicity testing of the STS inhibitor candidates has not yet been done; however, no signals emerged based on limited preliminary observations in the mice.

The live virtual session was moderated by Peter Albers, MD, professor and chairman, department of urology, Heinrich-Heine University, Dusseldorf, Germany. Albers described the work as a breakthrough study in prostate cancer research.

“The results are very interesting and may alter treatment for metastatic prostate cancer,” he said. “We hope you can continue this work as it is important for understanding endocrine resistance to prostate cancer and may be useful as new drugs emerge.”

The research was awarded first prize in the Oncology Best Abstract Session at the meeting.

Gao is co-inventor of a patent application of selected small molecule inhibitors of STS.

Reference

Gao A. Inhibition steroid sulfatase suppresses androgen signaling and improves response to enzalutamide. 2020 European Association of Urology Virtual Congress. July 17-26, 2020. Abstract PT090.

***

[1a] Abstract:

resource-centre.uroweb.org/...

[2] en.wikipedia.org/wiki/Stero...

[3] en.wikipedia.org/wiki/Dehyd...

[4] lifeextension.com/lab-testi...

[Hidden]

I am not CRPC but I don't do ADT. High T (400mg cyp a week).

I use finasteride 5mg a day and dutasteride (avodart) .5mg a day. And zytiga (1000mg a day).

I monitor my DHT. Do you think it is worth trying reducing the finasteride to every other day and keeping dutasteride every day? I'd keep monitoring DHT to see how it reacts.

[Shanti1 in reply to Hidden]

Are you using Tcyp on an ongoing basis of as part of BAT? Wondering what your thought process is behind taking both T and Zytiga. Thanks.

[Hidden in reply to Shanti1]

It's not part of BAT. I started doing the high T and a half a year later told my SOC oncologist. I think she suspected something from my muscle gain and labwork. I asked her about the Zytiga along with the cyp injections. She said that I'm doing far better than she predicted so keep doing what I'm doing.

I asked my "high T" doctor and he said the same thing, don't change anything.

[tango65 in reply to Hidden]

Why do you take zytiga if you are injecting testosterone? Please help me to understand how zytiga works to control Stage iv PC when taking T.

[Hidden in reply to tango65]

I have no idea.

I started the zytiga almost two years ago when I did ADT (estrogen based) for 5-6 months. I wasn't sure if I should stop when I started injecting cyp. So I didn't and maybe 6 months or so after starting the cyp (nobody advised me to do that) I asked my doctors what they thought. Both of my primary oncologists told me to continue the zytiga. As far as I know their only reason was that so far I've beaten the odds so they don't want me to change anything.

[tango65 in reply to Hidden]

I wonder if you could do a brief summary of your clinical condition. Age, gleason, treatments, number of mets and location, actual T and PSA etc. Thanks

[Hidden in reply to tango65]

I'm 57.

Gleason 9 (4+5)

Local lymph node positive

Bladder wall. Seminal vesicle. No Mets known. Pos margin of course.

Had RP 12/2018. Mayo gave me 3 months unless I did adt followed by radiation.

Today I'm ned 8/2020). No adt. No radiation.

Blog has history and current treatments prostatecancer.health.blog

High T. No ADT.

[TheTopBanana in reply to Hidden]

hello, also curious about your treatment. do I understand correctly that you are doing no ADT only T?

[pjoshea13 in reply to Hidden]

Well, having read the other posts & your responses, I am also against changing anything that is working, but I don't see what Zytiga is doing for you, given that your T shots are weekly, rather than monthly (or every 2 months in my case.)

Finasteride & Dutasteride together is a Nalakrats protocol & I'm fuzzy as to the add-on benefit of the former. But his protocol has been amazingly effective - considering the nature of his PCa.

400mg T-cyp weekly is a lot of T in the sense that your T was probably still over 1,000 ng/dL when you injected the second dose. You may be maintaining a level well above 2,000 ng/dL. Worth checking.

Perhaps you are inducing the double-strand breaks that Denmeade claims?

Best, -Patrick

[Hidden in reply to pjoshea13]

I'm at a loss with zytiga also. I'm going to ask my oncologist again. Might be worth it to try a two month hiatus and see if my PSA or CEA changes (CEA isn't the most accurate but it is very cheap and readily available).

My total t is about 2400. SHBG used to be about 300 (ridiculously high). Now it has come down (probably driven down by the T). It's around 120 now. Still high but not by a lot. So my free T is 25 and my bioavailable is 620. I hope that the high T is inducing double-strand breaks. It certainly has me feeling good.

I think I'll stay on the duta and cycle the fina one month on/one month off.

Cheers, Russ

[Hidden]

Would having an antagonist as ADT cut the problem, because it puts DHT to zero?

[Hidden in reply to Hidden]

I think that ADT works because T is taken low. Which means E is low. And DHT is low.

But do we need to take T low if we can take E and DHT low? I hope not because this is my approach.