New (to PubMed, but published in January) paper below. [1]
"As androgen receptor (AR) signaling is critical for the proliferation and metabolic functions of prostatic tumor cells, the mainstay of treatment is hormonal therapy, aimed at reducing the systemic level of circulating androgens (i.e. GnRH agonists and antagonists), inhibiting intratumoral androgen synthesis (i.e. abiraterone acetate) or competitive inhibition of AR itself (i.e. enzalutamide). This treatment, although initially effective, eventually fails after the tumor cells develop various mechanisms of resistance. The diseases at this stage are known as castration-resistant prostate cancer (CRPC), an advanced form of the disease with a median survival of 9–36 months."
"Unfortunately, agents that further inhibit AR have not significantly improved patient survival and a growing theme has evolved to search for AR-independent strategies to target PCa."
"Importantly, every case of prostate adenocarcinoma also contains a minor component of NE {neuroendocrine} cells that are negative for AR and PSA. Because NE cells are AR negative and androgen-independent, they are spared by hormonal therapy and subsequently, enriched in the tumor. Furthermore, 17%–30% of recurrent castration-resistant tumors display a variant histology known as small cell neuroendocrine carcinoma (SCNC) with the tumor composed entirely of NE cells. SCNC is resistant to traditional hormonal therapy and carries the poorest prognosis of all cancers of the prostate. It is therefore hypothesized that to achieve maximal therapeutic efficacy, the NE cells must be targeted as well. This review provides a modern perspective on the role of NE cells in PCa ..."
Full text link below.
Grim reading, I suppose, but useful to know what the problem of the long-lasting obsession with the androgen receptor [AR] axis is. Dr. Myers has said that effective management of other cancer types (including cures) always requires three or more drugs. (Lupron +Zytiga or +Xtandi counts as one because the target is the same.)
In old papers, I don't recall NE cells being a significant portion of treatment-emergent resistant problems. Options were very limited in 2004 when I was 56, but I decided to do everything I could to defer my first Lupron shot. I used testosterone to achieve that. There was no BAT then & I had a good number of years with a 3-month cycle of testosterone & an otc drug that may have contained DES.
The idea is to permit proliferation but shock the cells back to their starting point before the ADT phase has selected for the crazy types of cells.
For 18 months, though, I have been on a form of BAT. I'm still tweaking it, but am currently doing 3mg DES & a two month cycle.
I don't know how long it will be before it all comes crashing down, but I feel I should mention the BAT option,
There have been interesting papers on NE inhibition:
[2] an oldie: "Melatonin reduces prostate cancer cell growth leading to neuroendocrine differentiation ..."
[3] "A Phase II Trial of the Aurora Kinase A Inhibitor Alisertib for Patients with Castration-resistant and Neuroendocrine Prostate Cancer"
"Although the study did not meet its primary endpoint, a subset of patients with advanced prostate cancer and molecular features supporting Aurora-A and N-myc activation achieved significant clinical benefit from single-agent alisertib."
[4] "Repurposing of the Antiepileptic Drug Levetiracetam to Restrain Neuroendocrine Prostate Cancer and Inhibit Mast Cell Support to Adenocarcinoma"
"A relevant fraction of castration-resistant prostate cancers (CRPC) evolve into fatal neuroendocrine (NEPC) tumors in resistance to androgen deprivation and/or inhibitors of androgen receptor pathway. Therefore, effective drugs against both CRPC and NEPC are needed. We have previously described a dual role of mast cells (MCs) in prostate cancer, being capable to promote adenocarcinoma but also to restrain NEPC. This finding suggests that a molecule targeting both MCs and NEPC cells could be effective against prostate cancer. Using an in silico drug repurposing approach, here we identify the antiepileptic drug levetiracetam as a potential candidate for this purpose."
"Our results demonstrate that levetiracetam can directly restrain NEPC development after androgen deprivation, and that it can also block adenocarcinoma progression through the inhibition of some MCs functions."
Very good perspective m, Patrick, looking beyond the AR signaling paradigm altogether and addressing evolution to both CR as well as NEPC. That is why I am currently developing my own strategy for intermittent ( don’t call it BAT) SRT.My overall approach to limiting progression from HSPC is to try and limit the progression of all cancers through the “Hallmarks off Cancer”. As per a previous post of mine.) This progression is driven by two common factors: genome instability and inflammation. So much of my regimen is directed towards epigenetic and ROS genome protection factors and anti inflammatories.
I am intrigued by the melatonin angle. As this is so available and non toxic. Perhaps intermittent higher dose may be wiser than continuous. Also curious about the role of Zinc and zinc ionophores along similar lines.
Thanks for all the great, out of the box, research and thinking. Paul
My MRI spine a week ago reported :"previous bone lesions seen in 2019 are not visible at all on this MRI scan of entire spine" PSA 0.9 ALP 51. CRP 0.3. Total T 455.
I do not know but suspect that a combo of things collectively may be responsible for good results so far..(1) Intermittent Bicalutamide monotherapy (2) Ionic Zinc with Clioquinol 3% cream, (3) Sulforaphane, Resvesterol , polyphenolic and Quercetin rich diet. A bunch of anti inflammatory dietary supplements. Lox and Cox2 inhibitor natural substances Plus Melatonin before bedtime.
I admit that it is only 2 years and its too early to tell how it will evolve. I strongly suspect that Heavy, Continuous ADT (lupron+ Zytiga or Extandi etc.) creates Neuro Endocrine transformation faster and more frequently.
In Old research papers, as noticed by Patrick ...we do not see mention of treatment emergent NE variants. Only papers published in last 10 years are talking about NE variant.
This may be due to the fact that in the past.. Doctors used to use either Lupron only or Bicalutamide monotherapy. Add ons were added after the initial treatments showed resistance.
My question is: Can any one tell if Lupron like meds are more likely to cause treatment emergent NE variant compared to Anti Androgen monotherapy where T remains high.
That last is such a great question! Congratulations on your current results seen on the scan. All that you are doing is certainly beyond SOC. I’m hopeful now that my TRT/SRT intermittent may restore response to bicalutamide. Perhaps. The journey continues and I love life.
Some here will know more about NE tumors than I do.
"Our study confirms PSMA expression in the neovasculature of a wide spectrum of malignant neoplasms. Specifically, we found PSMA expression in various epithelial tumors (carcinomas), neuroendocrine tumors, and mesenchymal tumors (soft tissue sarcomas) and in malignant melanoma and glioma."
Grim reading indeed But, we need to know the effects that the meds used to treat PCa have on our (OS) overall survival.
In my case, l had ADT and 15 Taxotere sessions in 2015 with a great response - PSA going from 840.2 down to 0.1 in the Summer of 2017
Had Abiraterone in 01/2020, and then Xtandi in 09/2020 with both failing with PSA rising to 9.6 in 12/2020. PCa resistance?
On a Taxotere rechallenge now, with 6th(last) chemo this Friday. PSA down to 4.2
I've read here on HU that the subsequent use of chemo, may resensitize the PCa to those meds that failed.
Does Taxotere affect the AR signaling? And how does it get the PCa to respond to reintroduction of Abiraterone or Xtandi? Also, do I ask MO to restart with Abiraterone after my last session?
If any of y'all have previously posted about the above on HU, please forgive me.
Normal cells have an array of defense responses to viral & bacterial assaults and cancer cells are merely making use of them. Whether the treatment is radiation, chemical or hormonal, the defensive response starts on day one. The survival pathways are well-known, but we (the docs, rather) don't make any effort to block them. If a treatment is successful in killing a lot of cells, it is, in effect, selecting for the cells that were not killed. As the authors state, the population will be "enriched".
"Does Taxotere affect the AR signaling?" Not sure how to answer that. It's more the other way around, perhaps. Taxotere works best on castrate-sensitive cells + ADT. Testosterone + Taxotere in the lab does not produce good results. So Taxotere will give better survival when AR is silenced. Functional AR inhibits Taxotere to some degree,
With a period of high testosterone there is a chance of selecting for less aggressive cells. However, in heavily treated men the odds diminish.
Also, old studies that used DES (Diethylstilbestrol) on CRPC men found tha a certain percentage responded, Alternating between T & DES would certainly be a shock to the cancer cell population, but there are no studies & I'm not suggesting that you should be guinea pig #1.
Thanks for the input on this and for all your valuable posts.
Battling PCa is like any other foe, they adapt to to stay alive.
So, with my early CHAARTED based treatments (ADT & Chemo) in 2015, taking out a lot of PCa, but the remaining survivors may be harder to deal with now. Like killing off early bad guys in a video game and now having to deal with the Big Boss. I need a BFG (Big F'n Gun) now BAT?
But, I got to my 6th year in dealing with the d*mn thing.
So, in my case, the CHAARTED research proved beneficial
Will post next week about the next Axumin scan and PSA result
There is an FDA approval for "somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors" only, but this Lu177 DOTATATE will also work against neuroendocrine prostate cancer:
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But, we need to know the effects that the meds used to treat PCa have on our (OS) overall survival.
on this and for all your valuable posts.
Neuroendocrine Differentiation 
Testing for glutamine levels to check for transformation to neuroendocrine cancer from adenocarcinoma?
Quercetin targets hnRNPA1 to overcome enzalutamide resistance in prostate cancer cells
Neuroendocrine PCA mutation
Study: Cannabidiol Inhibits the Proliferation and Invasiveness of Prostate Cancer Cells 
