Some perspective on blocking NF-kB. Retuxan I did not realize was a NF-kB blocker as John was offered that study back in June but we chose another path.
Too Much of a Good Thing: NF-kB Blockade
by Chaya Venkat
My recent article reporting on how "Joe Patient" plans to party on & enjoy his brand new remission using Rituxan got a few personal emails from members. Some speculated that a high dose combination of every available NF-kB blocker out there may shut down this pathway completely, for all practical purposes, and make sure the CLL has no chance of growing back. Is this a possibility, can we take this approach to getting closer to that elusive "cure"??
My answer, in one word, is: No!! Not on your life, you have to be crazy to do something like that. (O.K, that's more than one word, I am busted).
I would not recommend "heavy-duty" NF-kB blockade for CLL patients, or anyone for that matter. NF-kB is a necessary and vital pathway in our bodies, and you would be very foolish if you tried to push it too far out of its natural equilibrium, in either direction.
For example, total suppression of NF-kB in mice studies show that they are not able to mount sufficiently vigorous immune response when subjected to attack by bacterial infections or other pathogens. As we discussed before, NF-kB is the emergency pathway that the body uses to produce fighting troops quickly, when faced with an immune emergency. Mice that have Nf-KB pathway blocked are also more at risk of death from sepsis.
For example, in addition to controlling the functioning of the immune system, NF-kB activity also regulates the proper functioning of our skin. This is the single biggest barrier between ourselves and the rest of the universe out there, some of it decidedly not friendly to us. Mice whose NF-kB pathway has been genetically altered, so that it is shut down to a very large degree have a much higher incidence of squamous cell carcinoma. Even the "heartbreak of psoriasis" is thought to be caused by insufficient NF-kB activation.
NF-kB modulates TNF-alpha (tumor necrosis factor alpha) and many other cytokines. Left unchecked, TNF alpha can do serious damage, as we saw in my recent piece on Crohn's disease. Uncontrolled production of TNF-alpha can cause rheumatoid arthritis, and it can also make you understand the real misery of B-symptoms, as discussed in a recent article on night sweats.
NF-kB activation to some degree is a necessary function in many neural processes, involved in memory, learning and retention. On the other hand, over stimulation of NF-kB is now considered to be one of the root causes of Alzheimer's, and in fact the NF-kB blocker R-Flurbiprofen that I discussed in an earlier article is now in clinical trials for Alzheimer's Disease. Look up this clinical trial at the URL address given for Myriad Pharmaceuticals in my previous Joe Patient article.
Too much food is bad for you, makes you fat and unhealthy, it can create life threatening cardiac problems, increase the risk of diabetes and cancer. There have been a number of excellent studies indicating that slightly reduced calorie intake, keeping the body on tight rations, can increase our life span significantly. But total "blockade of food" will surely kill you of starvation. Messing with NF-kB pathway is sort of like that. Inhibiting it too much is decidedly not a good thing.
Every system in our body is on a push-pull, feedback control mechanism, not a static set-point. That's just engineer talk (we have our jargon too, even if we wear hard hats and not white coats), all it means is that our body systems are more like a pendulum swinging back and forth, constantly changing position and adjusting, never static in one fixed position. Moreover, there is a lot of very complex inter-connections between the various systems, and multiple redundancies that we are just beginning to learn.
Scientists are learning that in general, it really does not help to whack the heck out of any one system, because that is just setting us up for a loophole that the body develops, one that is harder to treat later on. The same theme is reflected in the multiple drug resistance piece I did. Start flooding that old basement with water, and pretty soon the householder goes out and gets himself a nice sump pump to pump out the water. Flood the cancer cells with chemotherapy too many times, and the cancer cells will find a way of pumping out the drug, develop resistance to that particular drug and a bunch more besides.
That is probably why I like immunotherapy approaches like monoclonal antibodies, such as Rituxan. Rituxan therapy uses much of the body's own immune systems to deal with the problem. Sometimes patients are upset that it takes a while for the effects to show up, as much as a couple of months before the full effect of the therapy can be seen, and the kill rate is rarely 100%, even in the peripheral blood. Well, that is also the reason why there is less chance of the CLL developing / transforming into a more refractory cancer, one that no longer responds to this particular drug. Even with Rituxan, my main concern would be development of a CLL clone that has up regulation of complement inhibitory proteins to a degree that makes Rituxan less effective next time around. Necessity is the mother of invention, and this is true for cancer cells as well. It makes sense not to give the body a reason to invent a new mechanism for subverting what you are trying to do.
We are finding out that the subtle detail and complexity of our bodies means we have to use equally subtle and complex therapies to counter cancer. Very few cancers are treated any more with just one chemotherapy drug, but a variety of drugs in a cocktail, in an effort to try and block all the avenues of escape. Just a few years ago, there was a story on the New York Times front page, that a single angiogenesis drug will soon starve all cancers to death, and a cure is just around the corner. We know now that the body has literally dozens of ways of getting around that single puny road block. Dr. Judah Folkman is a pioneer, and my personal hero for this unique and elegant piece of research. But hubris does not last very long in the field of cancer research.
CLL can not (repeat, can not) be cured by NF-kB inhibition. If you tweak the proliferation rate of CLL cells so that it is just a tad slower than otherwise, and you also tweak the ease with which they commit suicide (apoptosis) to be just a teeny bit higher, net result is that the rate of accumulation of the CLL cells (rate of birth, minus rate of death) will slow down, just a little. That means the ALC (absolute lymphocyte count) will not climb as fast as it would otherwise.
How much is "just a little"? I am guessing, but I would be happy if the rate at which the CLL grows back is reduced by only a modest 10%. CLL is an indolent disease, which means the cancer cells do not accumulate too fast. So we can expect to see real differences in length of remissions, even with small changes in the rate of its growth. Even if you had the capability to shut down NF-kB pathway completely, 100%, you would not want to do this, and try to cut the rate of accumulation of CLL cells to zero (i.e., "cure" the CLL). If you do, two things can and will most likely happen: (1) the CLL finds some other way to grow, a redundant system that we have not considered, and keep growing, probably even faster than before. (2) you would be dead because some other truly vital system in your body comes to a screeching halt because NF-kB is shut down 100%. CLL may or may not be cured, but the patient is dead. Not a good scenario.
As in most things in life, moderation is a virtue. In cancer therapy, this is particularly so. One of the reasons why I had my imaginary Joe Patient focus on curcumin and green tea is that both of these are food based products, with a long history of use in ethnic cuisine. They probably are not as potent as synthetic compounds that would do a better job of blocking Nf-KB, and probably safer because of that very fact. But even there, moderation and patience is the watch word.