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"
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 s
elective ER m
odulators (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.