"One thing the investigators found was that the tumors were very heterogeneous, with several distinct subpopulations of cells. Another major finding was that the mouse NEPC tumor cells harbored clinically relevant epigenomic changes (e.g., DNA methylation). This type of change alters the way that DNA is transcribed into RNA. The analysis also allowed them to characterize in more detail the mechanisms by which MYCN and RB1 acted on each other to drive the progression to more aggressive cancer cells.
“This research, including our data on single cells and the characterization of heterogeneity, can now be mined to identify potential new therapeutic targets,” Dr. Rickman said. “We want to find a way to treat these tumors and stop the progression, before they actually get to this lethal form of prostate cancer.” He explained that this approach could include both new drugs and existing drugs, including those that target some of the epigenomic changes seen in NEPC.
One next step for the research is to go back to the clinical samples to identify markers that are associated with this tumor progression. These markers could be used to predict which patients are most likely to develop NEPC."
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SimonHL
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It is becoming more and more known that Long term ,Continuous ADT with 2nd generation Anti Androgens such as Enzalutamide, Abiraterone etc. lead to Treatment Emergent Neuro Endocrine Prostate Cancer in 20 to 30% men.2 years ago, saying this on this forum would invite wrath of SOC protectors. But, evidence keeps piling up and it is becoming harder and harder to tell people that Neuro Endocrine change does not happen with long term ADT.
We need to keep a watch on this with checking 3 biomarkers in blood every 6 months..these are Chromogranin A, Neuron Specific Enolase (NSE) and Synaptophysin. If all three are above normal and rising , it is very likely that treatment is causing Neuro Endocrine change.
There is a very specialized scan. .called PSMA DOTATATE which can light up Neuro Endocrine Cell population. And of course, Biopsy can confirm it .
I recently read a research article which said that Neuro Endocrine conversion can be slowed by using Beta Blocker, Atenolol. So if some one has High BP, Atenolol should be discussed with Doctor.
Treatment of NE type is Specialized Platinum based Chemotherapy. Survival still remain less than 3 years in men with NE tumor. Another reason to consider Intermittent ADT for men who are suitable candidates based on Biomarkers, Histology and Imaging.
What evidence or thesis do you have that those biomarkers rise implies a Neuro Endocrine change? And why are most MOs not aware of these including the ones at UCLA?
These are biomarkers for detecting NE cells. You can read a standard textbook of Oncology or go on PubMed and read articles stating this. Good MOs who are up to date on this subject Do know about this subject.
"Nearly one-fifth of men with metastatic prostate cancer whose tumors were resistant to hormone therapy subsequently developed an aggressive prostate cancer subtype, a new study has shown. Men with this subtype, called treatment-emergent small-cell neuroendocrine prostate cancer (t-SCNC), appear to have shorter survival than men with other subtypes."
"“The fact that nearly 20% [of men in the study] had this subtype is a surprise,” said William Dahut, M.D., head of the Prostate Cancer Clinical Research Section of NCI’s Center for Cancer Research. “That’s a greater percentage than we thought.”"
Yes - of course - 2nd line androgen receptor [AR] axis treatments [ARAT] have changed the numbers.
One way to avoid NEPC is to avoid CRPC. Which might mean avoiding ARAT or some version of BAT.
It's scary to think that one-in-five ARAT patients may progress to NEPC.
I wonder why we never knew before that approx. 30% develop NE down the road when first generation Androgen antagonists like Flutamide, Bicalutamide used to be used for several decades ??It is only in last 10 years or so....after second generation anti androgen started being added to Lupron that all this new information about NeuroEndo, differentiation started appearing. It is likely that stronger the blockade of Androgen axis ...possibly more likely the NE emergence. We will find out in next few years more.
1st-gen failures include those where there is a 2nd-gen response. The effect is to increase the importance of the other failure types..
NEPC cells might well be present in 1st gen failure, without being the main cause of failure. That would have kept them under the radar.
When we tighten-up the ARAT attack, we are effectively selecting for NEPC, since NEPC is the ultimate survivor - NEPC has no need for androgen and is not AR-dependent.
First generation ARATs are considered milder suppressors of AR and may be they fail when AR amplification starts happening. But then the stronger ARATs (second generation ones) can still work because of their intense AR suppression. But how do we explain some one on first gen (bicalutamide) for several years and still has not developed NEPC.
Do you think milder AR suppression delays NEPC compared to stronger AR suppression ?
Do you think Intermittent AR suppression can also delay NEPC phenomenon ?
The question always bugs me is that why are we seeing so many NEPC only in last 8 or 10 years as per research articles ?
Patrick,,Your point of view on the above questions will be greatly appreciated.
My take on this is that with Lupron, say, the easiest paths to resistance include AR amplification, which you mention. It comes up a lot in the older literature because it was common. So for most men, there wasn't selection pressure that favored NEPC, splice variants, etc. Those types of cell might have been present in a tumor, but they were vastly outnumbered.
The reason I turned down Lupron 16 years ago is that I was youngish & nearly all men failed treatment within 18-24 months.
When Abi & Enza came out, they were hailed as breakthroughs (for men who had become resistant to everthing.) At the same time, there was disappointment that survival was only prolonged for a handful of months.
The life expectancy tables before diagnosis probably gave me close to another 30 years. After diagnosis, it looked as though I'd be hormone refractory [CRPC] within 3 years.
Has that really changed that much? Perhaps an extra year has been added, with the downside being treatment-emergent disease of greater lethality.
Would intermittent treatment help? Not unless you were to press reset by restoring testosterone.
I have mentioned that I really enjoyed the years where I was on 3 months of ADT followed by 3 months of testosterone (~1,000 ng/dL).
Ultimately, I moved closer to Denmeade's BAT, but it's basically the same (if you disregard the double-strand breaks idea.)
There is no approved curative ARAT protocol. And that makes ARAT palliative only. Given the short mean time to resistance, ARAT should not be rushed into, IMO.
Lupron and Zytiga took my T from 650 to less than 5 in first 3 months. Both Lupron and Zytiga were stopped after 9 months. Bicalutamide plus Dutasteride is keeping PSA below 2.0. ALP below 50. Interestingly , T came back to 450 in 4 months after stopping Lupron and Zytiga. and with T coming back, energy, mental wellbeing, physical strength, memory and sexual part...everything improved dramatically. T is staying at around 450 now.
I can push T up in range of 1000ish. Do you think it will make much difference between T around 500 or T around 1000 in the matter of delaying castration resistance
Lately, the sound bite "No castration means No Castration Resistance " has been vibrating in my ears.
Continuous means without any breaks...Long term means for many years...and heavy means Lupron Plus second generation Anti Androgens like Enzalutamide, Abiraterone etc.
There are hundreds of identified biomarkers associated with PCa and yet, only a few drugs which are approved as of yet to address their specific biomarker. And even then, the result isn't anything that provides a permanent reversal as the PCa adjusts! As noted here, identification of cellular characteristics based upon the presence of biomarkers. But once they start digging, the association of biomarkers and cellular function gets lost. Turning on or off one switch (DNA) has had cascading effects unforeseen and unpredictable. It will be years, decades even in all probability venturing down this path until real benefit is achieved.
I mean after all, let's look at the general paradigm of medical application in regard to treating PCa. It hasn't really changed since the 1940's in it's basic principles, ie, Surgery, Radiation, Drugs! To be sure, yes, the surgery has gotten more precise as has radiation delivery, and test imaging more sensitive as well, and the drugs have expanded by volume but they still attack the same things. Methodology has changed somewhat to include multi rather than mono therapies applied concurrently to provide better results. But the entrenched mentality hasn't changed, surgery, radiation, drugs (ADT).
It's all good, and interesting of course... But when reading these and looking at hope for the future, I'm always held down by the anchor of SOC! It's not like these new pathways are made available to all, or early as the reports would make it seem they might be useful, again, the SOC paradigm gets in the way.
Until we can get true individualized treatment given to patients, the heterogeneous nature of the disease is ignored, even though again and again, it is affirmed in studies like this. As I always like to point out, it's a conundrum!
Nice topic and discussion SimonHL, thank you.I may be wrong but this is how I understand PCa progression. Appreciate your input.
Initially most PCa are hormone sensitive and express PSA. Cancer can be controlled with ADT and if PSA is low and stable you are fine. HSPC may or may not be metastatic. PSMA PET/CT would confirm if cancer is metastatic or not. I guess you can also have CT or MRI (whole body?) to detect metastasis if there is any.
Then, PCa evolves into castrate resistant PCa which is a much more complex disease. Cancer may or may not express PSA and can be controlled with ADT and chemotherapy for some time. A sub type of CRPC is Neuroendocrine PCa (NEPC) which has fewer treatment options. In any case prognosis is poor. Knowing that you have CRPC or NEPC earlier may help to extend survival. So blood tests and scans are important at this stage. NSE, CgA and LDL tests will help to diagnose NEPC, but didn’t know that there is a Synaptophysin blood test. I guess there are some other blood tests to diagnose CRCP. Regarding scans, I think FDG PET/CT and Ga68 DOTA-TATE PET/CT are used to diagnose NEPC.
Lupron Only OR Bicalutamide Only.. have been widespread practice prior to 10 years ago. When $10,000 a months pills came, the marketing push was extreme and every body now is being prescribed whether they have milder version or moderate or severe version. This SOC has become Opium of the masses but is causing too many toxic side effects. Some men who have aggressive version do need stronger treatments but not everyone. More emphasis is needed on right kind of food and lot of exercise.My primary Doctor's father lived for 14 and 1/2 years with metastatic PCa and he was only on Lupron all these years. Died of heart issue. She believes treatment should be individualized and prescribed on case by case basis.
As a case study..My last lupron inj was on Dec04,2019...I am only on Bicalutamide for last 18 months...Lets see how much more time I can get with this medicine which has almost no side effects for me except slight Gynecomastia (not even noticeable). I am a walking clinical trial of One !
This old study below says that the survival advantage of Lupron on Bicalutamide is only 6 weeks more. But quality of life with Bicalutamide is several folds more.
This is a very interesting thread. I fit this category very well. I was treated with Lupron alone for almost 12 years. Three years ago I developed very aggressive tumors on the pleura of my left lung along with a malignant effusion. I also had some nodes along the aorta. The biopsy showed NEC so I was treated with Carboplatin and Etoposide successfully in that the tumors have been stable and the effusion is gone. We, my MO and myself, were under the impression that the change from adenocarcinoma to NEC involved all the PC cells. While on Enzalutamide my PSA began a slow but very linear rise and some of the lymph nodes began to increase in size in my chest and abdomen. It seems clear that what I have is a hybrid tumor, some NEC, which has responded to treatment and some adenocarcinoma which is resuming it's growth despite Lupron and Enzalutamide. I am not on Abiraterone waiting to see if it is dropping my PSA.
I don't think this is as simple of all cell lines being the same but the articles stated are very interesting and support the idea that we still have much to learn.
Thanks for sharing this experience. How did you know that biopsy is needed to find out NEPC part..were their some specific signs ?Differentiating that the progression is due to ADT failure or due to NEPC conversion is very crucial to select right treatment.
I insisted to my MO to check for Chromogranin A and LDH early on to see if there is any NEPC component from the very beginning. . Thankfully, both tests came in low normal range giving some peace of mind. IMO, everyone should get Baseline NEPC markers in first year of ADT and check every 6 months.
I agree that today I would recommend that but at the time there were few cases of long term ADT and the transition to NEPC. It was over 12 years ago that a lesion was found in my left upper lobe and my mediastinum. I was scheduled for a semi-lobectomy. Upon opening the surgeon found my left lung pleura covered with tiny micromets which all looked like adenocarcinoma so they stopped the surgery and my ADT was begun. My PSA remained very low (0.1) for a long time.
3 1/2 years ago I traveled to Mexico and upon arrival in Denver became extremely short of breath. This is when they found the large pleural tumors and the malignant effusion requiring an indwelling chest drainage tube. It was very simple to biopsy those tumors and send material for genetic testing as well. The biopsy revealed the NEPC cells and I was begun on chemo.
I have been dealing with this disease for almost 27 years and so much has changed in testing, treatment and prognosis. 3 1/2 years ago I was told to "get my affairs together" but here I am having just celebrated my 80th birthday and though limited, I am still able to enjoy life. No high altitude hikes but I can drive over 12,000 foot passes to enjoy the mountains and still fish but now in a boat with a guide instead of wading in a fast moving river.
Hi, an informative post, albeit not the news that we with PCa on long term ADT wanna hear :-(.
In my case, had Lupron/Casodex after the diagnosis of #stageivpca in 01/2015. Per the CHAARTED research, began Taxotere chemos, ended up with 15 total in 2015.
That drove the PSA down to 0.7 in 2015 and then a nadir of 0.1 in the Summer of 2017. The last Lupron for a Hormone "Holiday" was 03/17/17 and then had to restart Lupron on 12/14/18 as the PSA hit 10.2 with T at 547.
Started Abiraterone in 01/2020 and then PSA got to 4.1 and rose to 5.2 in 08/2020 with T < 3
Then Xtandi in 09/2020 and the PSA went from 9.2 down to 8.9 and then up to 9.6!
Kaiser MO got me a Taxotere rechallenge for 6 sessions starting 12/31/2020
So, the newer ADT meds drove the PSA up. Six Taxotere sessions got the PSA down to 2.2 (2.3 this month), the lowest since 04/2018.
Haven't had a test looking for NEPC biomarkers and that may be the next step if the PSA rises significantly.
I'm hopeful that the rechallenge with chemo resensitized the PCa to the meds that failed
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