I am starting to see that there is new way of seeing how resistance forms, especially for those with low or undetectable PSA- the role of the senescent cells [or as my internist says, cancer cells that are asleep]. It was never clear to me how they wake up and become active again and I thought, in that state ,they were kind of neutral. I visualized different mutations, ie, ARV7 etc as the driving function. But as I read about them I see they play a dual role.
As a result, should we focus more on what they call Senomorphic and Senolytic drugs to help suppress these "sleeping" cells from causing problems?
Unfortunately, the same word, senescent, is used for cancer cells that are driven to dormancy by cancer cells and for healthy cells that are aged and not replicating. I know, it's confusing.
Senescent cancer cells are driven to dormancy by some as yet poorly understood self-protective mechanism. While dormant, they are impervious to treatment. They are not totally dormant though - the put out proteasomes that travel to nearby cells and turn them cancerous - very insidious. They also interfere with immune killing of the cancer cells. There is no clinically tested way of interfering with their function - there are no clinically tested senolytic drugs for cancer cells. The proposed drugs are highly toxic.
Senescence and cancer stem cells have been a reading focus of mine post my ePLND - I did not presume I was cured, even with nadir of <0.010. I share a bit in my bio on the supp's I use - more based on hope than 'proven science'.
IMHO, the thing about human trials is that innovative thinking, early science, precede trials. For many of us, we do not have the time to wait. Back in 2015, I learned of Genomic testing from a UK doctor. The test, OncotypeDX, from a US company, was in use in UK but not approved in US. I appealed to my insurance carrier BCBS and still have in hand their denial letter stating this testing would never be approved. Opps, it was, just two years later.
In 2018 I travelled to Europe for PSMA imaging. It was well established there whilst in tightly controlled trials in US. I could not get into US trials.
From my perspective, whether market stage broccoli or supp, such a rabbit hole question hey? Conversion and yield, bioavailability, how does one cook broccoli, fresh, frozen, etc; supp's seem to be easy button answer, but are they? IMHO all a guess really. This said, I make sure supp includes myrosimax and glucoraphanin. Sufficient answer?
BAT (high dose testosterone) is used in patients who have become therapy resistant in order to reactivate PCa and render it susceptible to therapy again.
As far as I know BAT was not specifically intended as a test of the senescent cell hypothesis, but may have a bearing on it. However, I will need to read up the BAT papers again to see what they said at the time, as I honestly cannot recall exactly why and how BAT came about.
Idle thoughts of an idle fellow........Just from a personal standpoint I do think there are some odd things about the relationship between testosterone and PCa. For example one big study (CANCER EPIDEMIOLOGY Open Access "Circulating free testosterone and risk of aggressive prostate cancer: Prospective and Mendelian randomisation analyses in international consortia" Eleanor L. Watts, et al) looking at testerone (free-T and bound-T) as predictor of PCa (using genetic markers and blood samples) found that above a certain threshold of free-T there was an increased risk of PCa. However what is odd is that there was no dose relationship between that risk and free-T. They have published another paper showing raised IGF-1 as a risk factor which did show a dose relationship. Raised levels of sex hormone binding globulin seem to offer protection.
My comment is, we know that circulating oestradiol in men is synthesised from testosterone and is effective as ADT. But as far as I know studies have not yet looked at levels of estradiol as a risk factor fro PCa. Is estradiol a missing link in the PCa story??
This person (from a theoretical perspective) thinks E2 plays a role. I don't know if he is regarded as a crank, what he writes seems pretty surprising.
I've concluded docs generally don't know what to do with findings; so why test? Not within narrower SOC spectrum, general practice guidelines, education, etc.
failed to include IMHO many (most) US docs seem very constrained by throughput, coding and billing that they do not have time for these types of investigative and individualized matters. This is most obvious to me when I consult as a private patient with docs in Europe.
A he presence of Senescent cancer cells is problematic for us. The therapies we use for treatment cause some cancer cells that are not killed to transition into “treatment emergent cancer cells”. While they do not divide they can excrete various compounds, co-factors that can enable other cancer cells to invade, spread and develop resistance. This is called SASP (Senescent associated secretory phenotype).
We know this happens but it is difficult to measure. Perhaps CTC (circulating tumor cell) techniques might soon identify markers for SASP cells.
However, for now I personally apply low toxicity intervention that has been shown to be effective for non cancer senescent cells and SASPs. I do this intermittently every 4 or 6 months or so. Three substances have been shown to have senolytic potency. Two have no potential toxicity, Quercetin and Fisetin. The third is a medication with some potential for toxicity: Dasatinib. I find the risk to be low.
My regimen uses all three of these it only for three days every four or six months to attempt to clear emergent senescent cells. This is 1000 mg each of liposomal Quercetin and Fisetin. Plus 100 mg of Dasatinib also for three consecutive days only I have no perceptible side effects. Or lab abnormalities from this. Not SOC. MB
Let me throw this out there. What about Fisetin combined with Chrysin every other weekend? I have notes I have taken over the years and this post made me go back to the 30+ pages. Just random notes. There are some cites but never looked them up.
Fisetin - Try fisetin. 1500 mg 3X a day for 2 days every 2 weeks. After a couple of months get a PSA test. Nearly no side effects but my PSA did drop. Yours might too but realize what works for one person does not always work for another. Fisetin is the strongest "senolytic" to be found.
Neem Leaves - Friends who are interested in how the chemical NIMBOLIDE found in Neem leaves kill androgen independent Prostate cancer cells can read on PubMed articles: Oral nimbolide reduces prostate tumor size by up to 70%, decreases metastasis 50% (medicalxpress.com)
(1) Nimbolide inhibits androgen independent prostate cancer cell survival and proliferation by modulating multiple prosurvival signaling pathways ....By Singh P R et al (2016)
(2) Anti proliferative and apoptosis inducing effects of Nimbolide by altering molecules involved in apoptosis and IGF signaling via PI3K/ Akt in prostate cancer (PC3 cell line)
just started looking at your reference to Neem/NIMBOLIDE. Seems to be a complex plant, with possible benefits. My question is how this plant may interfere with SOC Pca meds one may be taking? In my case, could it interfere with Relugolix?
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