Interesting summary

[Ann]

Hi All,  Just FYI. I have seen this before and wonder if there is anything here of benefit. I apologize if I posted this already!  Ann From Healthboards Prostate cancer group - written by Tall Allen. Together with a dear friend of mine, who is also on IADT, having failed RP, failed RT, pGleason 9, N0 and M0, I've been investigating whether it might be of benefit to try now certain available cancer therapies that are normally only tried later with mCRPC. Our hypothesis is that attacking the cancer on a number of fronts; i.e., a cocktail, while it is still hormone responsive may actually provide a chance at curing it. He noted that cocktails are used for HIV and many cancers, so why should we wait until our cancers become castrate-resistant before bringing out the big guns? (Most clinical trials only allow men with metastatic castrate-resistant PC.) At the same time, he didn’t want something he took now to preclude taking it or something else later. Using docetaxel, abiraterone, or Provenge now, which probably all have a good shot at being more effective if used earlier in the game, may preclude the use of the next generation of chemo, hormone therapies and vaccine/immune stimulants when they become available for clinical trials. He was looking for something more powerful than nutritional supplements and dietary interventions, which he is doing anyway. We ignored for now the question of whether insurance would pay for it. So we came up with the following requirements: 1. Has a good chance of working with your hormone therapy 2. Available by Rx now, outside of clinical trials 3. Won't interfere with getting on clinical trials or other meds later Based on those requirements, I came up with several classes of medications that might improve the effectiveness, long-lastingness, and, stands a chance at putting the cancer into remission: angiogenesis inhibitors, somatostatin analogues, Selective Estrogen Receptor Modulators (SERMs), Tyrosine Kinase Inhibitors (TKIs), mTOR Inhibitors, Histone Deacetylase (HDAC) Inhibitors, Metformin, Statins, and COX-2 Inhibitors. I mention only a couple of nutritional supplements that pertain to those categories. There are some other substances (e.g., HSP blockers. IGF inhibitors, prolactin inhibitors, matrix metalloproteinase inhibitors, Custirsen) that might be useful in a cocktail and are in clinical trials, but I don’t know of any that are already approved. We showed our investigations, together with all the peer-reviewed references, to his oncologist, Dr. Scholz, who is amenable to trying the cocktail approach. However, we decided to hold that off for now while we try some advanced imaging approaches first in order to determine if his disease is in an oligometastatic stage that may be slowed by SBRT to a few lymph nodes. If you or others are interested, I will post an extensive explanation of the "good witches brew" that we came up with. - Allen

08-31-2012, 10:33 PM

#4

Tall Allen  Senior Veteran (male)   Join Date: Aug 2010 Location: Los Angeles, CA Posts: 549 Hugs: 25 Hugged 5 Times in 5 Posts Thanks: 11 Thanked 146 Times in 136 Posts

Re: Recovery from Hormonal Therapy. My latest results It's rather lengthy -- about 10 pages including all the references. Maybe I'll exclude the government references for now, but if in discussions with your oncologist, he would like to see them, let me know. Many of these are quite powerful. They all have drug interactions, contraindications and side effects that should be carefully analyzed. I'm not a doctor and don't recommend any of these -- I'm hoping that it may be a good kickoff to a conversation with your oncologist as it was to my friend's. Angiogenesis inhibitors Thalidomide is the oldest, and a newer version, called lenalidomide (Revlimid) may possibly be more effective or have fewer sides. I know Jim has been taking thalidomide. These drugs will make you very sleepy though, which can be a good thing if hot flashes keep you awake. They may also have immune suppressive effects. The hot new one in this category, Tasquinomod, is in clinical trials and will probably get fast-tracked for FDA approval. A previous one, Avastin, did not prolong survival for PC and was disapproved by the FDA for breast cancer. Somatostatin Analogues Lanreotide and Octreotide are synthetic versions of somatostatin, the hormone responsible for antagonizing somatotropin (growth hormone). As prostate cancer progresses, the somatostatin receptor is less expressed, allowing the cancer to grow more quickly. It would seem to make a lot of sense to use this sooner rather than later. It is always given with a corticosteroid. A new version called Pasireotide has been approved in Europe. It’s only a single case study, so I throw it in just as a curiosity, but it seemed to completely cure the advanced hormone-responsive PC of one man: "Complete response to the combination therapy with androgen blockade and somatostatin analogue in a patient with advanced prostate cancer" http://www.ncbi.nlm.nih.gov/pubmed/17316966 As an interesting side note, a recent study of over a million people showed an association between height and PC that could not be explained away by other risk factors. Maybe tall guys like me have a surplus of growth hormone: "Adult height and the risk of cause-specific death and vascular morbidity in 1 million people" http://www.ncbi.nlm.nih.gov/pubmed/22825588 SERMs (Selective Estrogen Receptor Modulators) The role of estrogen and estrogen receptors in prostate cancer is very complex. Estrogen is an old therapy and is sometimes still used as a second-line therapy because it acts in the brain to inhibit the production of androgens, called negative feedback. However, estrogen receptor beta (ERβ) is highly expressed in prostate cells, and when activated, it seems to have anti-proliferative properties. ERα may have an opposite effect, so the trick is to activate ERβ without activating ERα, hence the selective ER modulators (SERMs). The estrogen story is even more complex: a person may have damaged estrogen receptors that are unresponsive to ERβ stimulation, or the receptors may disappear -- estrogen receptors diminish as the cancer progresses (the opposite of the androgen receptor). Therefore, it makes sense to use this earlier rather than later in the progression.  Gamma and delta-tocotrienols are thought to enhance ERβ activity. It is available as a pure annatto extract from health food stores and on the internet. It’s important not to try to obtain it from other mixed Vitamin E extracts – even small amounts of alpha-tocopherol seem to suppress absorption of tocotrienols. Clomiphene is a relatively cheap and effective SERM that may be worth trying. It selectively blocks ERα. Also, soy isoflavones stimulate ERβ, so taking the two together may be a good one-two punch. I should add about clomiphene that it would not make sense to take it while on Lupron, and could be dangerous with it. Clomiphene blocks the ERα receptor, which in turn controls the negative feedback between steroids and GnRH in the brain. Therefore taking Clomiphene with a GnRH agonist (like Lupron) may cause a runaway super-flare of testosterone production. It should work fine, however, with a GnRH antagonist like Firmagon, or with Casodex plus a 5-ARI. Here’s something that’s as confusing as it is interesting about all this. There is a drug in clinical trials now called Capesaris that could potentially be used instead of Lupron. It does the opposite of what clomiphene does in the brain -- it is ERα receptor agonist. In the brain, the ERα receptor mediates the negative feedback between steroids and GnRH. That’s why estrogen was given as an old treatment for PC – it shuts down the pituitary signal that stimulates androgen production. Capesaris similarly enhances the negative feedback to GnRH, thus shutting down androgen production. The hope is that it will be less harsh than Lupron or Firmagon. It remains to be seen if its anti-proliferative effect of shutting down androgen stimulation from the brain exceeds its pro-proliferative effect on the ERα receptors in the tumor. If I were a betting man, I'd wager that it slows down the tumor at first, but will stimulate growth of the tumor eventually. Tyrosine Kinase Inhibitors (TKI) There are about a dozen different tyrosine kinase inhibitors in clinical trials now for PC, and dozens more for other cancers. They represent the hottest area of cancer research right now. They work by inhibiting certain growth factors within the cancer cell. They are usually used in conjunction with other cancer therapies like hormones and chemo, and they can be combined. The hottest one for PC is called Cabozantinib (formerly XL 184) and seems to clear bone mets almost miraculously in 12 weeks. Exelisis tried to get early FDA approval for it based on relief of bone pain, but the FDA insisted on a demonstrated survival advantage and asked for a lower dose to improve tolerability. It’s in Phase 3 trials now. Several TKIs have already been approved for other cancers, but none yet for PC. Those could potentially be prescribed “off-label.” However, it is possible that using one now may preclude getting one in a clinical trial later. If it were me, I would wait for Cabozantinib approval, which may not take too long if it keeps performing as it has been. The TKIs that are already approved for other cancers and are in clinical trials now for PC include: Axitinib (Inlyta), Dasatinib (Sprycel), Erlotinib (Tarceva), Gefitinib (Iressa), Imatinib (Gleevec), Sorafenib (Nexavar), Sunitinib (Sutent). PC uses Interleukin-6 (IL6), an immune cytokine, to protect itself, and IL6 seems to interfere with TKIs. Immunosuppressors like mTOR inhibitors (see below) may suppress IL6 and may work synergistically in a cocktail with TKIs. Corticosteroids, which are usually included in these cocktails, may help also.There is a monoclonal antibody in clinical trials, Siltuximab, designed to suppress IL6. In addition to stimulating the ERβ and inhibiting angiogenesis, soy isoflavones may also act as TKIs. mTOR Inhibitors These target a cancer proliferation protein. Three have already been approved for use in cocktails against other cancers, and are in clinical trials for use against prostate cancer. They could potentially be prescribed now off-label. The approved ones are Sirolimus/rapamycin(Rapamune), Temsirolimus (Toresel), and Everolimus (Afinitor). However, Everolimus failed to show any incremental benefit when used with Casodex in a recent clinical trial. Would it work in conjunction with a TKI and/or an GDACI (see below)? The jury is out on that. Note: These are all powerful immunosuppressants used to prevent transplant rejection, and may also cause diabetes-like symptoms. Not something to stay on for a long time. Histone Deacetylase Inhibitors (HDACIs) Valproic Acid (Depakote) is a well-known anti-epileptic and mood stabilizer that was recently discovered to have powerful anti-cancer effects. It may cause PC cells to differentiate; i.e., lower Gleason grade. It and other HDACIs are in clinical trial against prostate cancer. In lab studies, it had a synergistic effect with Everolimus (see mTOR inhibitors, above). Metformin The anti-diabetic drug Metformin seems to have a powerful anti-PC effect. It may only work in conjunction with statins. It’s clinical trials now with statins and with Lupron. Metformin enhances the  antiproliferative and apoptotic effect of bicalutamide in prostate cancer. Statins Statins may slow down the growth of advanced, high grade androgen-independent PC cells. However, this association has been found only in some epidemiological and retrospective studies, and not all of them. Some researchers believe that health-conscious men are both more likely to take statins and to get PSA tested earlier, which would explain why they show up with less advanced disease. Some lab studies support its role. A large controlled prospective study is underway, using red yeast rice as a statin surrogate; the results may provide a more definitive answer. Meanwhile, there seems to be few downsides and many potential upsides to taking low doses as part of the cocktail. COX-2 Inhibitors Although early results in animal models and in small scale trials looked promising, the first large scale, controlled study (the STAMPEDE trial) of celecoxib+hormone therapy vs hormone therapy alone showed no benefit to celecoxib (Celebrex). Whether or not it may have a synergistic effect with other ingredients in a cocktail remains to be seen. Aspirin (which is a mild COX-1 and -2 inhibitor) and other anti-coagulants like Warfarin were associated with reduced mortality in men who'd been treated with RP or RT in a retrospective analysis published this week. It seems like a reasonable supplement unless their are known sensitivities or contraindications. Other I've written in previous posts about how I believe that prostate cancer will only be cured if we look at it as a system of interacting cell types, almost like an ecological niche. If we attack only one cell type, as by androgen deprivation alone, for example, we are sure to cause some other deleterious cell type to take over. I was, therefore, intrigued by an interesting lab study from the University of Rochester (one of my Alma Maters ). They suggest a two-pronged approach.  For the typical androgen-sensitive cancer cell, they suggest an attack with a turmeric/curcumin derivative called ASC-J9. It seems to degrade the androgen receptor without allowing it to find away around the therapy. Interestingly, ASC-J9 is being investigated as an anti-baldness and anti-acne medicine. For the prostate cancer stem cells, they want to accomplish the opposite: repair and stimulate the non-functional androgen receptor. When the androgen receptor on a stem cell is activated, it encourages the cell to differentiate; i.e., become less cancerous. They propose doing this with two substances. One, called 5-AZA, is in a class of of chemotherapeutic medicines called demethylating agents. It fixes old (methylated) DNA. However, although available (sold as Vidaza in the US), it can have some serious side effects. The other agent they tried against the cancer stem cells is gamma tocotrienol, which activates the ERβ receptor (see SERMs above).  In their lab studies they found that this combo suppressed castrate-resistant cancers. Last edited by Administrator; 08-31-2012 at 10:45 PM.

[Sam]

Ann what Allen is saying is true. reason why no-one in the medical world (with the exception of a few) steps out of line with two or even three treatments in a cocktail is the principle of "experimental control": If you allow more than one variable to operate at the same time then you never get to know which variable (agent) has the potential for cure. There are both good and bad sides to this approach. As humans we want a cure, but as scientists we need to keep track of what has been used, in what context and to what degree. I am sure you are familiar with the argument. If anyone wants to take a 'pot-shot' it is there. Thanks for the info. Sam

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Prostate cancer is an exceptionally heterogenous disease. What is good for one man may not be so kind on the next. Be sure to research and test any new supplement or treatment before adopting it - and in any case run it past a medically qualified person for a second opinion.
 
 
 

[Ann]

Hi Sam, I have sent this along to John's naturopath and an Integrative MD who works with her in case there is something there that might "work" for John. I don't make decisions re his treatment…only send along ideas. I am happy that they keep a close eye on his blood work etc.

I was particularly interested in the discussion of SERMs. John's Integrative doc did a lot of blood work last week including various hormones. No results yet but I do wonder about his estrogen levels. Will see. Hormone tests, however, don't tell us anything about ER receptors I would think. As you will remember John did have the test for ER alpha and beta but he was on Prostasol at the time and it really did not tell us anything. Perhaps he should try Genistein. And/or tocotrienols. We will discuss it with them. 

Interesting about the Histone Deacetylase Inhibitors too. 

Patrick is keen on Metformin and statins. John takes a small amount of Metformin (to tolerance) but so far no statins. Maybe another possibility.

And finally...

The other agent they tried against the cancer stem cells is gamma tocotrienol, which activates the ERβ receptor (see SERMs above).

So, yes there is some interesting stuff there. I'd like to come back in 50 years and see what they know then!

Ann

[Sam]

Just an aside really. Where can one obtain gamma tocotrienol in sufficient concentration from a supplementary or pland source. Thanks in advance. Sam.

[Ann]

Hi Sam, I will try to find a source. Have you tried to find one? 

BTW I was looking at one site tonight and extracted this…

I wanted to update on my friend. While he's waiting to get the C11-Acetate PET/CT done next week, he's been taking the gamma-tocotrienol. He said that his PSA doubling rate has been "like clockwork" doubling every month. He said that after one month of taking the gamma-tocotrienol, his PSA velocity has dropped by 40%. He says he's done nothing else differently, so he attributes the improvement only to the supplement.

Ann

[Patrick OShea]

Sammy,

The interesting thing about vitamin E, as found in plants, is the wide range of ratios between any two of the 8 family members.  In fact, I'm not sure that all 8 are ever found together.  LEF, I believe, makes a mistake with one of their products, by trying to build the "perfect" mix:

http://www.lef.org/Vitamins-Supplements/Item00559/Gamma-E-Tocopherol-Tocotrienols.html?source=search&key=vitamin%20e

To do this, they use a tocopherol product + a tocotrienol product (Tocomin).  However, all 8 constituents compete for transporters, & most lose out to alpha tocopherol.

Carotech's Tocomin is derived from palm oil.  About half of the tocotrienols are the gamma form.  I'm sure that most people think it is the best source.  However, it contains a significant amount of alpha tocopherol.

http://www.carotech.net/index/product_range/tocomin.html

A better choice, I believe, is DeltaGold.  It is derived from annatto seeds, which contain only gamma & delta tocotrienols.  Many brands repackage DeltaGold, but avoid those that add other things - particularly tocopherols.

DeltaGold is popular with those concerned with heart issues.  That's because of the research on delta tocotriennol,  DeltaGold is 90% delta & only 10% gamma.

Nevertheless, I feel that it is the best source.  Also, since men with PCa have higher rates of CVD, the delta form might provide significant additive benefit.

I have mostly used:

http://www.iherb.com/A-C-Grace-Company-Unique-Tocotrienol-60-Softgels/12977

Because of the highly competitive nature of tocopherols, I have been using a high gamma tocopherol product with breakfast:

http://www.lef.org/Vitamins-Supplements/Item00759/Gamma-E-Tocopherol-with-Sesame-Lignans.html?source=search&key=vitamin%20e

& DeltaGold in the evening.  However, I have decided to alternate each morning & skip the 2nd dose.

Here is the pecking order for uptake:

alpha T > beta T > gamma T > alpha T3 > delta T > gamma T3 > delta T3  (T3 = tocotrienol)

but here is the order by potency:

delta T3 > gamma T3 > delta T > gamma T > alpha T3 > beta T > alpha T

There is also a rice bran oil product, but there is far too much alpha T.

-Patrick

 

Dx04 @ 56 (DRE nodule 2002) |bPSA 3.3 (0.8 when nodule found)| GS=4+3, RP - no LN, no SV, but PSA nadir-0.3. DT=3 months Salvage RT 2005. Again, nadir=0.3. No HB. Arimidex. AndroDerm.

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From: Sam <georgias...@gmail.com>
To: prostatic-dise...@googlegroups.com
Sent: Tuesday, October 30, 2012 8:31 PM
Subject: Re: [PDT:1233] Interesting summary

[dtc]

Patrick and Sam,

Rice Tocos seem to have more Gamma than Delta, but I
have not been able to find a brand with no or little
Alpha Tocopherol.

Possibly Straight Rice Bran?

Doug


:

[Sam]

I have looked Ann but no-one in the UK as far as I know is aware of the stuff. Sam

[Sam]

Thanks Pat. Nice one.

[dtc]

According to tocotrienol.org, rice bran has 23.6 mg of alpha-tocotrienols and 34.9 mg of gamma-tocotrienols per 100 g. Barley has 67 mg of alpha-tocotrienols and 12.0 mg of both beta- and gamma-tocotrienols. These are much higher amounts than fruits, vegetables and meats have, but neither contain delta-tocotrienols. They're also not a particularly good choice if you're on any kind of low-carb diet, like me.

Doug