Over time many of us will grow resistant to Zytiga and Xtandi.
I thought I'd share some of my experiences on how I've managed to re-sensitise Zytiga. Since we only have a given amounts of bullets in our belt to fight PC we do of course want each one to last as long as possible.
Zytiga worked beautifully for me for more than 3 years. When my PSA started to go up significantly, I started a shock Testosterone treatment which pushed my T-level to a peak of around 1,500 ng/dl (from 20-30ng/dl). This took my PSA back down to undetectable for 7 months before it started to move again..
I continued with ketoconazole (inexpensive) for about 8 months before the PSA again started to move. I tried the shock-T treatment one more time, but this time my PSA shot up dramatically so I decided to stop after 2 months.
Having read that the shock-T could re-sensitize Zytiga I decided to started this again and I am happy to report that I have now been on Zytiga for more than 6 months and it still works! (touch wood!!)
Naturally, I am thrilled that I've managed to eek out more time from this bullet. So the big question is what to do next when this stops working? I came across an articles I printed out a while ago (memory is shot after years of ADT) and re-discovered Niclosamide.
It seems that Niclosamide also has the potential to re-sensitize both enzalutamide (Xtandi) and abiraterone acetate (Zytiga). A few find that Zytiga and Xtandi doesn't work for them which is often due to the presence of the splice variant AR-V7.
Researchers have found that Niclosamide which is a treatment for tape worm, has the potential to re-sensitize both Xtandi and Zytiga.
If Zytiga and Xtandi never worked for you in the first place, maybe you should discuss this publication with your oncologist? These are 2 wonderful drugs that have been added to our arsenal and it is a pity that they don't work for everyone. In this respect I do find Niclosamide very intriguing.
Please understand that I have no medical training and you should discuss with your oncologist before starting any new regiment. My oncologist has always supported my 'research', but we are all different and what works for me might not work for you.
If anyone has similar experiences I would love to hear about them.
Kind regards
Terje
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Terje
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Niclosamide is poorly absorved in the GI. High doses are needed to reach a level in blood high enough to affect the cancer. These doses are usually not tolerated.
There is a new product called PDMX1001/Niclosamide which is better absorved in the GI. It is a propietary product and can be obtained only in clinical trials. UC Davis has clinical trials for PDMX/niclosamide and enzalutamide or abiraterone. They also have clinical trials for indomethacin and enzalutamide. It seems indomethacin can reverse resistance to enza.
Great info... thanks for sharing. Helpful news to hear, as I have a rising PSA after several years of Lupron and will likely be moving on to these bullets soon enough.
Thank you for taking the time to post this good information. Maybe we will never completely eradicate this disease (the elusive "cure"), but it is encouraging that perhaps we can keep beating it back with these drugs and combinations thereof.
I hope the Zytiga continues to work for you a long time.
I've abandoned the quest for a "cure" and instead am managing the cancer as a chronic disease. I want to die with prostate cancer but not of it.
The trials underway at the Moffitt Cancer Center testing this approach have shown positive results, and are ongoing. Men with metastatic castration resistant prostate cancer were given Zytiga and a gonadotropin-releasing hormone (GnRH) analog (e.g. Lupron) concurrently but only until their PSA dropped by 50%. Treatment was halted until the PSA rose to the pre-treatment value - 1 cycle. Of 18 men in the treatment group, only 4 had radiographic progression after 34 months. All 15 men in the standard of care arm, taking the drugs until they failed, had progression after a mean time of 15 months.
This is a huge result, although it requires confirmation in a larger trial. More importantly, the trial was designed using models based on evolutionary genetics. Genes which are not necessary are generally burden to an organism and eventually are lost or not expressed. This has been known since Charles Darwin discovered a species of fish that live in dark underwater caves and had evolved to loose eyes.
PCa cells pay a high metabolic price to maintain treatment-resistant genes and the cellular machinery they control. When treatment is halted, these cells find themselves at a disadvantage to the treatment-sensitive cells that don't expend the resources to provide resistance.
The cycles in the Moffitt trials ranged from 4 months to 1.5 years. The total dose of expensive abiraterone (Zytiga) was cut in half, while the duration of sensitivity of the cancer to treatment was more than doubled. They don't yet know the mean time to progression, but if every man in the trial developed resistance tomorrow, the mean would be over 38 months.
I've read it many places. Expressing any gene requires protein synthesis at a minimum, and in many cases a fair amount of molecular machinery is required to do something like produce testosterone-like substances inside a mCRPC cell.
It's old news, as I mentioned Darwin observed the effect long before we understood anything about DNA and gene expression.
As long as they can prove a success with their treatment, the theory why it works is not so important.
Anyway, in the following article they write: "In the absence of therapy, the sensitive cells out-compete the resistant cells due to their fitness advantage."
However, the sources they provide why the sensitive cells have a fitness advantage did not convince me yet. They point to research by the same group with cells of different cancer types.
In the article they defined three groups of prostate cancer cells: "three competing cancer “species”: androgen dependent, androgen producing, and androgen independent." So the independent ones do not produce androgen/testosterone.
Different studies found that independent PCa cells have androgen receptors without ligand-binding domain and therefore do not require activation by steroid molecules, i. e. testosterone.
I disagree. Having a theory allows them to tailor an effective therapy without subjecting thousands of men to hit-and-miss guesswork about what might be happening.
Having a theory, one that can be tested and proved or disproved, is science. Just randomly poisoning a bunch of men and seeing what happens is evidence-based medicine, not science.
It's not a question of "food" but of energy spent to express those genes and create the molecular machinery that the genes encode. It's not a question of being more or less fit but rather that cells that don't expend energy on resistance to a treatment that is not being given can out-compete cells that maintain their treatment resistance.
The researchers in the Moffitt Center paper you cite put this into computer models. What they showed is that treatment-sensitive cells, which are the ones that are all killed with continuous ADT, will out-compete treatment-resistant cells - IF you halt the treatment and let them regrow. That flies in the face of continuous treatment until failure used by modern cancer medicine - which doesn't have an equivalent theory to back up that approach.
Their model was a reflection of their theory. Their clinical trial appears to support their theory, as men on their cycling approach lasted well over twice as long before becoming resistant to abiraterone. If a new drug did that it would be a multi billion-dollar blockbuster. These folks, armed with a plausible theory, are doing the same thing while cutting the cost of the drugs in half. That's what having a theory to guide you will do.
Great comment, FC: "Just randomly poisoning a bunch of men and seeing what happens is evidence-based medicine, not science." This is not a trivial point - medicine often has the power to camouflage and advocate EBM as science.
Thank you. Here's another way to understand the difference between "food" and metabolic energy expenditure.
Cancer cells grow until they are limited by access to food. Tumors trick the body into growing additional arteries to increase their supply of food. But the population of cancer cells are all competing for the same limited amount of food.
So take two cells, let's posit that each gets access to the same amount of food. The mutated prostate cancer cell that has activated the genes to make its own testosterone has to expend some of the energy it gets from that food to transcribe the gene, assemble the proteins, and synthesize the testosterone. The "simple" prostate cancer cell that depends on external testosterone doesn't have to do any of that. So even though both get the same amount of food, the cell that makes its own testosterone (which makes is resistant to basic ADT) will grow more slowly than the simple cell, because it is expending extra energy on synthesis at the expense of growth.
This is true only if there are both kinds of cells competing for access to food. If you kill all the "simple" cells with ADT, the testosterone-synthesizing cells no longer have to compete with them, and they can now grow and become dangerous.
I do not think you can compare Ketoconazole and Niclosamide. Ketoconazole was frequently used before Zytiga became available. Both inhibit the CYP17 enzyme and block testosterone production in the testis and the adrenal glands. Therefore I think the 8 months on Ketoconazole could have been achieved with Zytiga as well. Zytiga did work after the second T-shock and probably would have worked after the first too. Niclosamide is just used in trials with mice plus the unsuccessful one mentioned by tango65.
You can revert CRPC with radiation too, at least according to this article:
Great post for my situation. Thanks for posting. Read my profile. I like Zytiga, no significant side effects so I want to maximize my time on it. Been on it for 14 months now. My plan is to have high dose radiation to a neck tumour beginning of June 2019 and then try prednisone to dexamethasone switch and then cycle BAT and Zytiga when my PSA rises significantly. Some questions.
1. How many Mets and where do u have?
2. When did you start BAT.. what was your PSA rise from and to before you started BAT?
3. What BAT protocol did u use? I was thinking of 400 mg testosterone every 28 days for 3 cycles to get up to 1200ng/do level or so testosterone and then back to castrate levels over the 28 days while remaining on Zoladex 3 monthly injections.
4. Where do you live. I am in Vancouver Canada.
If this does not work or when this fails Lu177 is in my radar but this is an out of pocket expense and involves travel to Germany or elsewhere.
Otherwise there is always chemo but not on my most wanted list!
Of course our worry is that resensitizing has the distillation effect of creating disprportional adapted variants...ie the darwinian winners...although cancer cells have no conjugal capacity that we know of, antigenic to darwins model. There are cancer cells kept alive in research labs decades old...immortal by all accounts...the ultimate zenith of life...measured by persistence.
Cancer clones can be homogeneous or not..the later being possible drug resistent..ergo castrate resistant..what you're experiencing seems to suggest contrarily to this clonal Darwinian model, rather, winnowing the numbers of mostly treatable variants.
Keep it up...we can all learn from your exception experience.
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