Cancer and Alzheimer researchers are working at cross purposes

he tale of cancer promoters is the story of how a discovery about cancer transformed Big Pharma from an industry focused on finding drugs, called “small molecules,” into an industry focused on antibodies and in the process wrecked Alzheimer research.

The so-called two-hit theory of cancer says that two separate molecular events need to happen in a cell before it turns cancerous. First, an 'initiator', such as a mutagen or ionizing radiation, causes a DNA mutation. Then, if a 'promoter', a molecule that causes irritation, comes along in the same cell, the cell becomes precancerous. Without the continued presence of the promoter, the damaged cells regress and eventually die, but repeated exposure to the promoter eventually causes it to turn cancerous.

The first promoter found was TPA, a type of molecule called a phorbol ester that's considered a strong irritant. The textbooks tell us that TPA is an activator of protein kinase Cα, an enzyme whose normal function is to cause cell growth.

Two examples of how this works are cigarette smokers who drink and people who are exposed to radon gas who smoke. The effect of radon exposure at the levels you'd find in your basement is not quite zero, but it's so low that it's hard to get an accurate number. Unless, that is, the person also smokes cigarettes. The same synergistic effect caused by the promoter is said to occur if cigarette smokers drink alcohol, which may be why so many studies on alcohol and cancer get different results.

Well, that's what the textbooks say.^[1] There's not enough space in those thousand-page books to convey the true complexity of the story. TPA doesn't just bind to PKCα, but to a dozen other signaling proteins. There are eleven different forms of PKC, each in different organs and each with different biochemical effects. The current theory is that PKCα acts by raising the levels of a protein called NF-κB, which induces the expression of genes that cause cell proliferation, including TNF-α.

People want theories to be simple, but simple theories led to what may be the most destructive idea in biology: the bad molecule theory. This is the idea that some molecules like estrogen and PKC are bad, and so the way to treat the disorder is to get rid of them. But a cautionary tale is TNF-α. TNF-α was originally thought to be a “good” protein because it causes death of cancer cells. Now it's a bad one because it's a tumor promoter. But without TNF-α, your immune system and your ability to fight infection would be seriously impaired.^[2] The FDA is so worried about that it put a black box warning on TNF-blocking drugs. Blocking inflammation is always risky, as the immune system is instrumental in stopping cancer. It also, apparently, causes it.

Growth is good, and also bad

Cell proliferation is good. The body needs cell growth, not just in youth but to counter the effects of aging. Yet steroid hormones (testosterone, estrogen, and progesterone) are considered tumor promoters as well, as is chronic inflammation from any source, such as gallstones or infection. Hepatitis B virus, which causes inflammation of the liver, produces a 98.4-fold increase in the risk of liver cancer. TPA may work by inducing inflammation as well: inhibiting inflammation prevents TPA from being a tumor promoter. But they vary widely in potency. Few are as potent as TPA and hepatitis B virus. What causes those differences and what makes inflammation ‘chronic’ are what science should be studying.

Many of the biomolecules that we want patients to have, like BDNF and growth factors, promote growth in one way or another. If you exercise, some of your muscle cells are damaged by the exercise, so your body initiates a growth / repair cycle to make new ones. When you learn, your brain grows new synapses. As they used to say about greed back in the 1980s, growth is good.

But nowadays virtually everything that induces growth, including many proteins produced by the body and essential for life, is also considered a tumor promoter: glycogen synthase kinase-3 (GSK-3),^[3] SIRT (sirtuins)^[4,5], HMGB1,^[6] TNF-alpha inducing protein,^[7] heme oxygenase-1,^[8] claudins,^[9] all endogenous inhibitors of protein phosphatases 1 and 2a,^[10] PPAR-gamma and PGC-1alpha,^[11] Rnd3 (RhoE),^[12] SYK tyrosine kinase,^[13] TNF-alpha,^[14] PKC,^[15] hyaluronidase,^[16] pleiotrophin,^[17] NF-kappa B,^[18] interleukin 1 beta,^[19] calcium/calmodulin-dependent serine protein kinase (CASK)^[20], O-fucosyl transferase 1,^[21] wnt/beta-catenin signaling,^[22] matrix metalloprotein 11,^[23] Na⁺/Cl⁻-coupled amino acid transporter SLC6A14,^[24] CDK5,^[25] src kinase,^[26] hexokinase 2^[27] and on and on. These aren't rare, exotic enzymes. They're common, essential proteins familiar to any biochemist, and many of them are highly abundant.

Pharmacologists call these enzymes and signaling proteins ‘targets’ because in order to work, a drug has to interact with them. Any molecule that touches any of these particular targets will be shot down by the cancer people. A herd instinct may be at work here: a few papers claim that the protein is “bad.” It quickly becomes dogma, inducing a flood of research designed to support the new theory. Sometimes, as happened with poor old TNF-α, new papers come along saying the opposite and cause a paradigm flip-flop and it becomes a “good” one.

Beta-amyloid

The ultimate bad protein is β-amyloid. Nobody knows why it's produced or what its function is, but the amounts of it correlate roughly with Alzheimer's disease and that makes it a bad protein. The dogma is that it's a useless by-product that's formed all the time and an Alzheimer brain has trouble getting rid of it for some unknown reason. It's virtually impossible to get funding for anything else; NINDS funds less basic Alzheimer research every year, and progress has ground to a halt. Big Pharma has spent billions testing various antibodies in a hopeless attempt to get rid of β-amyloid, the latest being Gantenerumab, which failed as badly as any small molecule drug ever did: a whopping 82% of the patients dropped out. Nasty side effects including ARIA, microhemorrhages, edema, and superficial siderosis were found in 53% of the minority of patients who stuck it out^[28]. The company is spinning it as a success, but it looks more like the best we can say is that there were no treatment-related deaths.

There is no such thing as a bad protein. That goes for β-amyloid as well, as the big pharma companies will eventually figure out. Every molecule your body produces is there for a reason.

Among ordinary chemicals, there are over 500 other molecules that supposedly act as promoters. Some of them you know from the scare stories in the press: asbestos, high fat diet, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), alcohol, glyphosate, coffee, caffeic acid,^[17], and food dyes, with new ones showing up regularly. If they're promoters, they don't cause cancer directly, but only aggravate it by causing inflammation. But the whole bad molecule paradigm is a sign of tunnel vision. Academics get paid for writing papers, and a scary finding is perfect for getting a government grant. Finding a new tumor promoter is easy: just over­express it in cultured cells, add a mutagen to act as an initiator, and you've got yourself a fundable project. That part is easy. Figuring out how it works and giving the public an accurate sense of proportion isn't.

This isn't just theoretical. A few years ago, I invented a promising new drug to treat Alzheimer's disease. You can't have it. You'll never be able to have it, because the grant reviewers at some foundation shot down my request for funding a preclinical trial because there was a paper in the literature that claimed the target was a tumor promoter. My target was found almost exclusively in the brain, so I made the case that this wouldn't be a problem, but it didn't matter. Maybe they thought if it binds to a promoter, it has as much chance getting through the FDA as Rachel Zegler has of getting another starring role in a Disney movie. I don't remember if we ever patented that drug. If not, it's in the public domain and no one will ever test it. If it is, the patent will expire before they get done testing it.

I had a relative who died of Alzheimer's disease. Once, when I was in the hospital, they put me in a room with a guy who had just had a massive stroke. That poor bastard couldn't eat or drink. He had no idea where he was or what had happened to him and he screamed all day and night. If someone offered me a cure for that, I'd take it in a second, even if it had a 100% chance of giving me cancer twenty years later.

We'd like to cure all kinds of things, but people are working at cross-purposes. The bad molecule theory is useless enough for environmental toxins. It's downright harmful when it's applied to human biochemistry, which is insanely complicated. It drives big pharma away from small molecules and toward antibodies, which differ from ordinary inhibitor drugs only in being more fashionable and more profitable.

Like every other class of drugs, antibodies started out as wonder drugs. Antibodies are supposed to be more specific than small molecule drugs, but anyone who's ever run a Western blot knows that's not really true. It's rare to find one that's monospecific. More often they're like the one used in the Western blot shown at right, where a commercial antibody from a reputable manufacturer binds to at least 33 different proteins.

Long lists of things that act as promoters only cause cynicism, legal frenzy-feeding, and fatalism. That's how we got those idiotic California Prop 65 warnings on gauging trowels, bags of cement, electrical switches, and 1½ inch screws. It's easy to make lists. Without a sense of proportion to go with them, they end up killing off other branches of biomedicine.

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