Neuroendocrine Prostate Cancer. - Advanced Prostate...

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Neuroendocrine Prostate Cancer.

pjoshea13 profile image
25 Replies

New study below [1].

15 years ago, with the immediate failure of my prostatectomy, Lupron was offerred as an option. Having read a large number of papers where ADT mostly failed within 18-24 months, & being only 56 at the time, I was puzzled why anyone would rush into a short-lasting palliative therapy that selected for cells that were increasingly difficult to manage.

I was thinking of this as I read the intro to the new paper:

"Increasingly effective therapies targeting the androgen receptor have paradoxically promoted the incidence of neuroendocrine prostate cancer (NEPC), the most lethal subtype of castration-resistant prostate cancer (PCa), for which there is no effective therapy."

My issue is with premature use. The drugs are valuable & doubtless in my future. But how do we deal with treatment-induced cell changes?

The short Abstract will read like Greek to many. Luckily, we have j-o-h-n to translate!

But a key feature of the remarkable reprogramming that occurs to create neuroendocrine PCa cells, is the increase of "intracellular S-adenosyl methionine (SAM) levels to feed epigenetic changes that favor the development of NEPC characteristics.".

I have a number of posts on the SAM system. Briefly, it relys on the diet containing methyl donors such as folate (or folic acid-fortified grain products - or supplements). SAM is the universal methyl donor in the body. PCa cells want to be hypermethylated. Some of the most significant changes that occur in PCa cells are not due to mutation, but rather because of epigenetic silencing via methylation.

In an article on the study [2]:

"Epigenetic patterns associated with NEPC were ... discovered, including an expression of an enzyme called phosphoglycerate dehydrogenase (PHGDH), according to the study. The findings revealed a currently FDA-approved treatment called decitabine {which inhibits epigenetic changes} that may hold promise as an NEPC treatment ..."

[3] "Decitabine is a hypomethylating agent. It hypomethylates DNA by inhibiting DNA methyltransferase." "Decitabine is used to treat myelodysplastic syndromes (MDS)"

Off-label use of Decitabine may prevent the emergence of treatment-induced neuroendocrine PCa, which is far more common than it once was.

-Patrick

[1] ncbi.nlm.nih.gov/pubmed/308...

Cancer Cell. 2019 Feb 11. pii: S1535-6108(19)30052-2. doi: 10.1016/j.ccell.2019.01.018. [Epub ahead of print]

Increased Serine and One-Carbon Pathway Metabolism by PKCλ/ι Deficiency Promotes Neuroendocrine Prostate Cancer.

Reina-Campos M1, Linares JF2, Duran A2, Cordes T3, L'Hermitte A2, Badur MG3, Bhangoo MS4, Thorson PK5, Richards A6, Rooslid T7, Garcia-Olmo DC8, Nam-Cha SY9, Salinas-Sanchez AS10, Eng K11, Beltran H12, Scott DA13, Metallo CM3, Moscat J2, Diaz-Meco MT14.

Author information

1

Cancer Metabolism and Signaling Networks Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA; Sanford Burnham Prebys Graduate School of Biomedical Sciences, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA.

2

Cancer Metabolism and Signaling Networks Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA.

3

Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA.

4

Division of Hematology-Oncology Scripps Clinic, 10666 N. Torrey Pines Road, La Jolla, CA 92037, USA.

5

Depatment of Pathology, Scripps Clinic Medical Group, 10666 Torrey Pines Road, La Jolla, CA 92037, USA.

6

Proteomics Facility, Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA.

7

Conrad Prebys Center for Drug Discovery, Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA.

8

Centre de Recerca Experimental Biomèdica Aplicada (CREBA), IRBLLEIDA, 25138 Lleida, Spain.

9

Pathology Department, Director of the Research Unit Biobank, University of Castilla-La Mancha, School of Medicine, 02006 Albacete, Spain.

10

Urology Department, Research Unit, University Hospital Complex of Albacete, School of Medicine, 02006 Albacete, Spain.

11

Department of Computational Biomedicine, Weill Cornell Medicine, New York, NY 10065, USA.

12

Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.

13

Cancer Metabolism Core, Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA.

14

Cancer Metabolism and Signaling Networks Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address: mdmeco@sbpdiscovery.org.

Abstract

Increasingly effective therapies targeting the androgen receptor have paradoxically promoted the incidence of neuroendocrine prostate cancer (NEPC), the most lethal subtype of castration-resistant prostate cancer (PCa), for which there is no effective therapy. Here we report that protein kinase C (PKC)λ/ι is downregulated in de novo and during therapy-induced NEPC, which results in the upregulation of serine biosynthesis through an mTORC1/ATF4-driven pathway. This metabolic reprogramming supports cell proliferation and increases intracellular S-adenosyl methionine (SAM) levels to feed epigenetic changes that favor the development of NEPC characteristics. Altogether, we have uncovered a metabolic vulnerability triggered by PKCλ/ι deficiency in NEPC, which offers potentially actionable targets to prevent therapy resistance in PCa.

Copyright © 2019 Elsevier Inc. All rights reserved.

KEYWORDS:

ATF4; PKClambda; aPKC; cancer metabolism; epigenetics; lineage plasticity; mTOR; neuroendocrine; prostate cancer; serine metabolism

PMID: 30827887 DOI: 10.1016/j.ccell.2019.01.018

[2] specialtypharmacytimes.com/...

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

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pjoshea13
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25 Replies

Hello Patrick, although this does read to me like Greek there something about it that sounds Interesting and I’d like to bring it to Dr. OH at Mount Sinai this Tuesday as my husband’s PSA is rising and he’s going in for some scans (bone and CT scans) with results on Wednesday. Perhaps a different treatment route is needed

softwaremom00 profile image
softwaremom00

Thanks for posting about Neuroendocrine Prostate Cancer. I know it is a rare one..but one my sweetie is dealing with. I appreciate the information.

pjoshea13 profile image
pjoshea13

Apologies Nala, I should have included a mention & the link [1].

Once again, ahead of the curve.

While I'm at it, I'll include the link to a study that reported:

"The overall incidence of t-SCNC {treatment-emergent small-cell neuroendocrine prostate cancer} detection was 17%." [2]. Not the <1% from back in the days of yore.

-Patrick

[1] healthunlocked.com/advanced...

[2] ncbi.nlm.nih.gov/pubmed/299...

Longterm101 profile image
Longterm101

Can u repost it

AZjame profile image
AZjame

I just read your excellent post. Thanks to you and pjoshea for bringing this potentially life saving drug to our attention. Like you I'm filing the information away in case it's needed in the future.

Advo__cate profile image
Advo__cate

what type of doc would be experienced at dodge & administering the Decitabine as it is an infusion over a period of time. Maybe I’m missing something?

gusgold profile image
gusgold

Looks like when you fail ADT the next step should be Xtandi or Zytiga + Decitabine

Longterm101 profile image
Longterm101

Thx !! Just did

Advo__cate profile image
Advo__cate

Lol...dosage, not “dodge”

podsart profile image
podsart

Thanks for always providing great references and info. I have been interested in hyper methylation ever since I found out my PTEN was epigentically silenced by hyper methylation.

Back then I discussed it a few times with dr Myers and asked about some promising drugs that might reverse this thereby restoring the braking action of PTEN. He told me there were drugs being tested but they were not there yet and these drugs were very toxic.

He said that he saw evidence (never provided the references) that a long term program of resveratrol and isoflavones might make it happen. So he started me on this path. When I asked how long he thought it might take to work, if successful, he said years.

I know dr Myers spent a lot of time typically researching before coming up with his strategy, but never found anything that directly discussed this approach.

pjoshea13 profile image
pjoshea13 in reply to podsart

I use high-dose genistein. It is a demethylation agent ... in the lab. [1]-[5]

I use the LEF product at the full dose of 5 caps: [6]

-Patrick

[1] ncbi.nlm.nih.gov/pmc/articl...

[2] ncbi.nlm.nih.gov/pubmed/206...

[3] ncbi.nlm.nih.gov/pubmed/221...

[4] ncbi.nlm.nih.gov/pmc/articl...

[5] ncbi.nlm.nih.gov/pubmed/258...

[6] lifeextension.com/Vitamins-...

podsart profile image
podsart in reply to pjoshea13

Thanks for your wonderful and greatly informative response.

I wonder why these studies didn’t look at P53 and PTEN, which aside from the braca 1/2 are key to Pca.

Again the seem to give um units for the agents used in the study rather than the gram related units we deal with when obtaining our supplements. Is it that we need to know the “molar” number for our product or whatever? What mg did u find equivalent to their units for your supplements? Is there a separate assessment as to what constitutes the max safe level for us?

pjoshea13 profile image
pjoshea13 in reply to podsart

When I was diagnosed 15 years ago, the LEF PCa protocol called for 5 caps four times daily. I couldn't handle that. After a few years, LEF reduced the frequency to once daily. Whether due to efficacy or safety, I don't know. But that's the dose I use. Very unscientific.

-Patrick

podsart profile image
podsart in reply to pjoshea13

thanks again

CalBear74 profile image
CalBear74

You say you use "high-dose genistein" as a demethylating agent. Are there other supplements known to be hostile to neuroendocrine cell biology? Does a hormone-sensitive PCa patient need to worry or is this a problem only to be faced by the castrate-resistant patients more prone to these epigenetic changes? Is this the only actionable info we can at this point derive from these insights?

Nal, please jump in to this if you have opinions on these questions.

pjoshea13 profile image
pjoshea13 in reply to CalBear74

Not aware of other supplements.

As we know, ADT, which targets the androgen receptor axis, allowed the cancer to find a variety of escape pathways in the old days. The neuroendocrine path was rarely followed. The modern add-on ADT drugs have removed the once-common escape pathways, but the treatments still tend to fail in time. The result is that the once-obscure has become common & difficult to treat. Build a better mousetrap & you'll get smarter mice.

The transition starts during ADT - before CRPC. Who knows how to determine when these cells emerge.

The attraction of BAT, is that Denmeade doesn't wait for resistance to set in. The monthly T shot resets the clock. In other therapies, the man has to stay the course until failure. Acceptable, perhaps, if failure is >20 years away, but <5 years?

-Patrick

CalBear74 profile image
CalBear74 in reply to pjoshea13

One reads of "androgen-dependent cells" and "androgen-independent cells" in the cancer journals. Is a "neuroendocrine" cell another name for androgen-independent? What if any is the connection?

pjoshea13 profile image
pjoshea13 in reply to CalBear74

In the old days, before the term CRPC took over, ADT failure was assumed to be because the cells no longer needed androgen. The surprise to researchers was that the androgen receptor [AR] was still in play in "androgen-independent cells". Cells were managing on low levels of androgen.

Since that time, a tremendous amount of effort has gone into 'improving' on castration. But with unexpected consequences.

Neuroendocrine cells are cells that have given up the so-called AR addiction & retreated into 'stemness'. Stem-like cells do not have or need AR in order to survive. (& so they don't produce PSA.)

With a scorched earth approach to androgens, the irony is that modern treatments are now inducing the appearance of true "androgen-independent cells".

Unfortunately, neuroendocrine cells are very aggressive & quite lethal.

-Patrick

FRTHBST profile image
FRTHBST

I am new to the forum. Diagnosed 10/18, PSA 11, Gleason 7 (4+3). Your discussion is very well informed. Does anyone have knowledge of, or experience with, apalutamide? I am scheduled to be evaluated for participation in a trial where apalutimide is given for 6 months prior to prostatectomy. Is there a risk for creation of androgen independent cells with this protocol?

pjoshea13 profile image
pjoshea13 in reply to FRTHBST

Is this the M.D. Anderson study? [1]

"To determine whether 6 months (24 weeks) of neoadjuvant apalutamide prior to prostatectomy {RP} for intermediate risk prostate cancer results in a reduction of aggregate pathologic risk features that drive post-operative radiotherapy recommendations from 35% to 15%."

6 months is a long time.

Apalutamide is a newish drug & I don't think there is any data on what to expect when given as monotherapy. As an antiandrogen, it will compete with your testosterone for binding to the androgen receptor [AR]. This will highly inconvenience the cancer.

At what point does any pre-RP benefit to you cease, & resistance appear? Something to discuss with the study doctors.

-Patrick

[1] clinicaltrials.gov/ct2/show...

FRTHBST profile image
FRTHBST in reply to pjoshea13

Thank you for your reply. It is the M.D. Anderson study. Probably all of the studies of administering Apalutamide in advance of prostatectomy are in concert. At the Cleveland clinic their version was Apalutamide and Lupron for one month. Unfortunately my case didn't fall into the category they were looking for , because, yes, 6 months might be a long time.

Your suggestion of taking my question up with the doctors is a good one that I will follow up. It seems that doctors conducting a study and the patients who've received the treatment can wind up with differing perspectives on the results, hence my question here. It may simply be that the drug is too new to have produced much long term data yet.

In your post at the top of the thread you begin with saying that 15 years ago ADT seemed a suspect strategy to you. What was your way forward then given failure of the prostatectomy?

pjoshea13 profile image
pjoshea13 in reply to FRTHBST

I had no real options, but I thought that balancing testosterone [T] & estradiol [E2] might help. It did slow the PSA doubling time [PSADT] down. I don't write about that, since I don't want responsibility for someone trying it.

That got me through ~5 years, but the PSADT shortened to where I needed some form of ADT, except that I didn't want to risk more than 3 months at a time. In between, I did 3 months of T. I became open about that after Denmeade published his BAT papers. I figured if anyone was interested, they could go see him.

5 months ago I switched to his protocol. A T shot on the first of the month. I take an oral castration drug from the 8th to month end. I miss the 3 month T phases, but I think the rapid cycling makes more sense. Wish I had invented it.

I have written about a number of things which I believe helped me. The control of inflammation. Controling coagulation to prevent metastasis. & other stuff. It's all in the archives somewhere - LOL.

-Patrick

monte1111 profile image
monte1111

J-o-h-n please translate ASAP. I am not Greek and my expiration date is in less than 6 months.

sammamish profile image
sammamish

Perhaps Vitamin A could be added to a regimen while on long term ADT to suppress hypermethylation and retard the march towards NEPC?

ncbi.nlm.nih.gov/pubmed/229...

ncbi.nlm.nih.gov/pubmed/218...

ncbi.nlm.nih.gov/pubmed/301...

pjoshea13 profile image
pjoshea13 in reply to sammamish

See my post of 3 years ago:

"Foods/Supplements-Vitamins: Vitamin A (Retinol, Retinoic Acid [RA], Beta Carotene)"

healthunlocked.com/advanced...

-Patrick

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