MuTaTo: Is an Israeli company within a year of a “complete cure for cancer”?

I not infrequently write about science communication fails on the part of the mainstream media—more than I would like to have to, in fact. Much of the time, those failures tend to be due to false balance, the most common example of which is a press report having to do with vaccines or autism giving “false balance” by including the comments of an antivaxer alongside the comments of real scientists or physicians, as though the antivaccine view had validity enough to merit being cited this way. Fortunately, this form of false balance seems to be less common than it was when I first started blogging. This time around, though, I’m going to address another form of science communication fail, and it’s one that, quite frankly, leaves me scratching my head over how so many media outlets could have fallen so hard for such obvious self-promotional bullshit. I’m referring to the press reaction to a story in the Jerusalem Post about how Israeli scientists will have a “complete cure for cancer” within a year with their new technology, MuTaTo. (You’ll learn why it got that weird name in a moment.) It’s a story about Dr. Ilan Morad, CEO, and Dr. Dan Aridor, chairman of the board, of Accelerated Evolution Biotechnologies, Ltd. (ABEi), a company founded in 2000 in the in the ITEK Incubator at the Weizmann Science Park in Rehovot.

It didn’t take long after the Jerusalem Post article appeared for headlines to appear like this all over the media, starting with my local news:

I read the article. It was a credulous take on the aforementioned Post article. I’ll explain what’s so horribly wrong with it, and so much of the other reporting about this “cure for cancer” that isn’t

It wasn’t long after that that I started noticing similar headlines appearing all over the news media,. They seemed to start with a New York Post article, We’ll have a cure for cancer within a year, scientists claim, and then to metastasize all over the media, from national to local news outlets. Here afre a few examples:

You get the idea. It’s as though reporters, seeing the Israeli newspaper’s breathless reporting about the promise of a “complete cure for cancer” within a year, turned off all critical thinking abilities. Although I’ll explain in my usual inimitable fashion why Morad and Aridor’s claims are not credible, anytime you see someone claiming a “complete cure for cancer within a year,” you shouldn’t need a detailed understanding of the science involved to realize that it’s hype (and risibly overblown hype), not hope, particularly if the “cure” isn’t even in clinical trials yet.

Hyperbole about an early experimental cancer treatment

There are so many red flags in the original Jerusalem Post article; so let’s begin by looking at some of the hyperbole:

“We believe we will offer in a year’s time a complete cure for cancer,” said Dan Aridor, of a new treatment being developed by his company, Accelerated Evolution Biotechnologies Ltd. (AEBi), which was founded in 2000 in the ITEK incubator in the Weizmann Science Park. AEBi developed the SoAP platform, which provides functional leads to very difficult targets.

“Our cancer cure will be effective from day one, will last a duration of a few weeks and will have no or minimal side-effects at a much lower cost than most other treatments on the market,” Aridor said. “Our solution will be both generic and personal.”

That is the message that most of the articles, including my local news, ran with. The message above was then followed by propaganda so outrageously optimistic and misleading that it’s hard to believe scientists would actually utter such nonsense, other than perhaps to raise venture capital.

Before I explain why, in fairness, I feel obligated to note that a few of those articles let some some skepticism in, but you’d never know it from the headlines shared widely on Facebook and other social media (e.g., surprisingly, the FOX News story), and it was a day or two before headlines started to indicate any skepticism, such as Israeli scientists say cancer cure close; doctors are skeptical:

This story interested me because it gave me just enough information to be pretty sure that ABEi’s claims are unadulterated bullshit. I’ll start out with the reasons I gleaned from the story and then go on. First, ABEi’s claims are based on mouse experiments, nothing more, although the company claims to be ready to start a round of clinical trials. Anyone who’s read this blog before knows just how many results that look promising in mice end up failing in human clinical trials. (Hint: It’s by far most of them.) Indeed, the issue is such that there has been concern (often overblown, in my not-so-humble opinion, but legitimate nonetheless) that there is a problem in preclinical science. Unfortunately, the high failure rate of oncology drugs that pass preclinical studies is an issue that science denialists and quacks often use to attack conventional science. Yes, we can do better, but that doesn’t mean that pseudoscience works. It does mean, however, that any claim for an imminent “cure for cancer” based solely on preclinical studies in cell culture and mice alone should be viewed with extreme caution and skepticism.

Another issue that got my skeptical antennae all a’twitchin’ is that apparently ABEi’s results have only been presented to their scientific peers as presentations at “three separate drug discovery conferences.” There’s nothing inherently wrong with that, of course. It’s how scientists often first present new results being prepared for publication, but what non-scientists often don’t know is that presenting an abstract at a meeting is the least rigorous form of peer review, particularly if the work is a poster presentation. The American Association of Cancer Research (AACR), for instance, accepts literally thousands of posters for its yearly meeting, with very few, if any, being rejected during their peer review process. (I know. I’ve done a fair number of poster presentations there.) That’s why, until a scientist’s results are published in the real peer-reviewed scientific literature where other scientists can take a close look at it, I always reserve judgment. Publication as an abstract at a scientific conference, even a prestigious one, is not enough. Then, even publication in a peer-reviewed journal is not always a guarantee. After all, there are a lot of dodgy, bottom-feeding journals out there, and even top tier journals publish dubious science from time to time, particularly when it’s “frontier science.”

A third aspect of the story that caused my skeptical antennae to start twitchin’ so fast that they threatened to lift me up, as helicopter blades to a helicopter comes from the specific claims being made by the scientists involved with ABEi:

The CEO of the company behind the research told The Times of Israel on Tuesday that it has not published its research in medical journals, as is the norm, because it “can’t afford” to do so, but that the results of its pre-clinical trials have been “very good.” Several Israeli experts contacted by The Times of Israel declined to comment on the claim, some precisely because they were not familiar with the research.

There is only one facepalm big enough for such utterly obvious nonsense:

Godzilla facepalm

Can’t afford to publish the research? Seriously? Presumably the experiments have already been done and the data analyzed; so there should be no additional expense there to publish. Multiple stories say that the company already has patents in the works; so delaying publication based on a patent application is not a valid reason. All it should thus take is for the scientists to write up their results and submit them to appropriate scientific journals. Even if you allow something like a $3,000 publication charge for an open-access journal and that many standard journals don’t require page charges, is Dr. Morad saying that his company can’t afford a sum less than that to publish his results? That doesn’t speak well of the financial health of his company! Alternatively, maybe he knows that the results he has now won’t stand up to peer review and that he needs to do a lot more experiments, which would cost a fair amount of money. (Stay tuned.) In that case, I would be concerned about both the scientific basis of his claims and the financial health of his company! I would also point out that, if he doesn’t have the data to publish and needs to do more experiments, he needs to do those experiments anyway.

MuTaTo: The cure for all cancers?

So let’s take a look at the claims made in the Jerusalem Post story. (I also looked at the ABEi website.) First up, what is this strangely named technology:

Aridor, chairman of the board of AEBi and CEO Dr. Ilan Morad, say their treatment, which they call MuTaTo (multi-target toxin) is essentially on the scale of a cancer antibiotic – a disruption technology of the highest order.

The potentially game-changing anti-cancer drug is based on SoAP technology, which belongs to the phage display group of technologies. It involves the introduction of DNA coding for a protein, such as an antibody, into a bacteriophage – a virus that infects bacteria. That protein is then displayed on the surface of the phage. Researchers can use these protein-displaying phages to screen for interactions with other proteins, DNA sequences and small molecules.

In 2018, a team of scientists won the Nobel Prize for their work on phage display in the directed evolution of new proteins – in particular, for the production of antibody therapeutics.

I hate silly buzzords like MuTaTo. (I say Mu-Tay-To, you say Mut-Tah-To!) I know, I know, the press and investors love them, but come on! Then, of course, because phage display led to a Nobel prize must mean that what this group is doing is equally impactful! This is all marketing, not science.

None of this is to say that phage display isn’t a cleverly designed and highly useful technology that took an existing technology to new heights. Bacteriophages were discovered decades ago and are, simply put, viruses that infect bacteria. Long ago, scientists learned to insert genes into these phages and use them to drive the production of the protein coded for by those genes by the bacteria infected. This is how recombinant insulin, for example, was first developed. Back in graduate school during the early 1990s, I used a precursor to phage display technology, basically a phage library, to look for proteins that bound a specific DNA sequence we were interested in. (Suffice to say, we have much better methods of accomplishing this goal today.) The difference was that the phage simply induced infected bacteria to make the protein, not to display it on its surface. In brief, phage display involves making a library of phage with different consisting of fusions of DNA sequences coding for the desired proteins or peptides with a gene for a protein that makes up the protein coating of the phage. When the phage is reassembled in the bacteria, this recombinant protein leaves the desired peptide sequences “displayed” on the surface of the phage, where they can be more conveniently screened for activity.

In the example of the Nobel Prize winning work, the power of evolution was harnessed to make phage display even more useful. Random mutations were introduced into the gene for an enzyme, after which the mutated genes were packaged in bacteriophages. The altered enzymes were then tested, and those most efficient at catalyzing the desired chemical reaction selected for a new round of mutagenesis and testing, thus “evolving” a more efficient enzyme over several rounds of mutation-phage display-selection. The same process was used to “evolve” stronger antibodies with stronger and more specific attachment to the desired antigen. In the case of ABEi, it sounds as though the company is using this technology to evolve peptides (very short protein molecules) that more avidly and specifically bind to protein targets in cancer cells. It’s clever, as far as it goes, but nothing particularly novel, as a number of groups have been using phage display to develop peptides and antibodies targeting cancer cells for a number of years now, and there are a number of peptides discovered by phage display in clinical trials now. Indeed, adalimumab (Humira) is an antibody-based drug that was discovered using phage display with a “guided selection” method. As Steve Novella noted, there are hundreds of articles indexed in PubMed listing the use of phage display to develop peptide-based cancer therapies going back nearly 20 years.

So, according to ABEi’s scientists, what is the novel and “disruptive” idea behind their treatment? Their first idea is not so novel, namely to link a “strong peptide toxin that would kill cancer cells specifically to their peptide” in order to guide it to the cancer cell and have it not poison normal cells. This is an old idea, and I’ve read more papers and grant applications about such a strategy than I can remember. Of course, a lot depends on the specific antibodies and linked toxins. The very strongest toxins, for instance, can still poison normal cells even if only a little of the peptide to which they’re linked binds to noncancerous cells, even nonspecifically. The specificity has to be quite high for this to work without a fair amount of collateral damage.

More is better? Maybe. Maybe not.

ABEi scientists also appear to have fallen for the “if one target is good, more must be better” line of thinking. In fairness, this is true to some extent; cancers do develop resistance fairly rapidly in most cases to drugs targeting a single protein. However, the more proteins you target, the more problems arise, something that ABEi doesn’t seem to consider:

For starters, most anti-cancer drugs attack a specific target on or in the cancer cell, he explained. Inhibiting the target usually affects a physiological pathway that promotes cancer. Mutations in the targets – or downstream in their physiological pathways – could make the targets not relevant to the cancer nature of the cell, and hence the drug attacking it is rendered ineffective.

In contrast, MuTaTo is using a combination of several cancer-targeting peptides for each cancer cell at the same time, combined with a strong peptide toxin that would kill cancer cells specifically. By using at least three targeting peptides on the same structure with a strong toxin, Morad said, “we made sure that the treatment will not be affected by mutations; cancer cells can mutate in such a way that targeted receptors are dropped by the cancer.”

“The probability of having multiple mutations that would modify all targeted receptors simultaneously decreases dramatically with the number of targets used,” Morad continued. “Instead of attacking receptors one at a time, we attack receptors three at a time – not even cancer can mutate three receptors at the same time.”

Again, this is nothing novel. Combination therapy is a very, very old idea in cancer. Oncologists have long postulated that targeting different molecular mechanisms or different biological aspects of cancer cells can help prevent the evolution of resistance. That’s why nearly all modern cancer chemotherapy is multi-agent. For example, the standard chemotherapy regimen for breast cancer involves three drugs, each with a different mechanism of action. Not surprisingly, in the era of targeted therapies, in which each drug targets a single protein or pathway, simultaneous targeting is also the rage. Indeed, out of curiosity, I did a few PubMed searches and found a whole plethora of articles related to simultaneously targeting two or more molecular targets on cancer; e.g., simultaneous targeting of EGFR/VEGFR and Cyclooxygenase-2 and targeting DNA repair pathways and their backups. Then there are other forms of combined targeted therapy involving targeted therapy plus chemotherapy, targeted therapy plus immunotherapy, targeted therapy plus other targeted therapy. The list goes on and on.

Synergistic activity often equals synergistic toxicity

Here’s probably my biggest question about ABEi’s technology: I’m highly skeptical that anything ABEi does will be as nontoxic as its officers are claiming. If there’s one thing we’ve learned about combination therapy it’s that the toxicities tend to increase more than linearly as more drugs are added to the combination, not that they decrease. Targeting three receptors is far more likely to cause “collateral damage” than targeting two. Then there are off-target effects. No targeted drug, peptide, or antibody is perfectly specific. All will cause effects that are due to something other than the interaction of the drug with its target; i.e., “off-target effects.” The more drugs you add, the more likely off-target effects will be and that the combination of them will result in unexpected toxicity. ABEi’s thinking on this whole issue strikes me as hopelessly simplistic at best:

Morad said their discovery could also reduce the sickening side-effects of most cancer treatments, which stem from drug treatments interacting with the wrong or additional targets, or the correct targets but on non-cancerous cells. He said MuTaTo’s having a combination of several highly specific cancer-targeting peptides on one scaffold for each type of cancer cell would increase the specificity to the cancer cell due to the avidity effect. In addition, in most cases, the non-cancer cells that have a protein in common with the cancer cells do not overexpress it.

Yes, but the difference between expression (making) of the protein in normal cells and overexpression (making a lot or too much of it) is often not huge in terms of fold-differences between normal and overexpressed, which raises the issue of inadequate specificity. If the toxin used is as powerful as Morad describes, then even a small amount of binding to normal cells expressing low levels of the targeted protein could result in significant toxicity. That doesn’t even take into account nonspecific binding; that is, binding not dependent on the presence of the target. There is always nonspecific binding.

I looked at ABEi’s own data in its “proof of concept” published on its website. Let’s just say that the data are promising in one way and completely underwhelming in another. Here’s what I mean. If only normal, cautious, realistic claims were being made, the data would be fine as early preliminary preclinical data for their treatment. However, in light of the claims of a “complete cure for cancer” within a year, these data are massively underwhelming. They show that at best, that there’s a 20-fold difference in uptake of one of its peptides in mouse tumors compared to liver after 24 hours or so. Is that good enough? Maybe it is. Maybe it isn’t. Unfortunately, the same graph also shows that initially its peptide rapidly accumulates in the kidneys and only falls to levels less than 20% of what’s in the tumor. It’s a not unresonable start, but nowhere near specific enough yet, I’ll bet. I also note from the data that the concentrations of the MuTaTo peptide required for killing cancer cells in a dish were not insignificant, requiring micro molar (μM). Here’s a hint: When you’re talking micromolar concentrations of your drug being needed to kill cancer cells in a dish, it is not that impressive. I know this from long personal experience writing grants that have kept resulting in reviewers telling me that my drug’s ability to kill tumor cells at micromolar concentrations is neither very impressive nor very promising.

Riding the hype of precision medicine

So, given that we know that ABEi’s ideas thus far are not particularly novel, what’s unique and revolutionary about ABEi? The news stories would have us believe that it’s this:

The MuTaTo cancer treatment will eventually be personalized. Each patient will provide a piece of his biopsy to the lab, which would then analyze it to know which receptors are overexpressed. The individual would then be administered exactly the molecule cocktail needed to cure his disease.

However, unlike in the case of AIDS, where patients must take the cocktail throughout their lives, in the case of MuTaTo, the cells would be killed, and the patient could likely stop treatment after only a few weeks.

First of all, this is precision medicine (formerly known as personalized medicine), which is not a new idea. Although I personally still think precision oncology based on a tumor’s unique gene expression has great promise, in practice realizing that promise has turned out to be a hell of a lot more difficult than originally predicted. I also can’t help but note that the press has portrayed precision medicine in terms as glowing as it’s used to describe ABEi for far longer. Let’s just put it this way. How one picks the three molecular targets from the results of a genomic profile of a given individual’s cancer will make all the difference in the world, and there is nothing I can find in this article or on the ABEi website that tells me how ABEi does that. I made fun of Stanislaw Burzynski for making claims for “personalized gene-targeted therapy,” and I see little difference here. The message seems to be: Trust us. We’ll know which molecular targets to pick for your cancer. Yet there’s nothing I can find that doesn’t suggest to me that they’re just making it up as they go along and pulling it out of their nether regions when it comes to picking targets based on genomic profiling. That assessment doesn’t even take into account the extreme heterogeneity of cancer, either. Different parts of a given cancer or the cancer and its metastases can have quite different biological characteristics. (It’s why cancer is so damned hard to eradicate.)

And how do Drs. Morad and Aridor know that treatment could be stopped after only a few weeks and the cancer will have been eradicated? They don’t. They pulled that out of their nether regions, too. Their comparison to AIDS therapy is specious as well. Tumor cells can go dormant and recur as new tumors, for instance. Come to think of it, maybe the analogy isn’t that specious. Part of the reason that combination protease inhibitor therapy is needed indefinitely for HIV infection is that the virus can “go dormant” and “hide” in certain tissues, to reactivate later.

MuTaTo: Real science and real promise for cancer or a big con?

Unfortunately, the reaction to the news stories about how “Israeli scientists are on the verge of curing cancer” has been widespread. I was perusing Twitter yesterday, and a friend of mine, a fellow physician, made this point:

Dr. Lipson is Jewish, and this news has gone especially viral among Jewish communities all over, thanks to the Israel connection:

I missed the news report on TV. However, I have seen the Local 4 news story, but oddly enough the video is not linked to it. If it’s anything like all the others I’ve seen, though, I’m guessing it was bad.

Elsewhere, Alison Bateman-House, whom whose acquaintance I made online through our shared activism on “right to try,” summed things up:

Meanwhile, cancer researchers and advocates scrambled to counteract the hype. For instance, Dr. J. Leonard Lichtenfeld, Deputy Chief Medical Officer for the American Cancer Society, wrote A Cure For Cancer? Not So Fast, noting concerns with the reports and how it’s basically impossible for a treatment go go from promising preliminary mouse experiments to full-fledged cure in under a year. The NY Post seemed to backtrack a bit with an article Cancer experts react to claim about finding a cure within a year:

But Dr. Ben Neel, director of Perlmutter Cancer Center at NYU Langone Health, told The Post that “cancer is multiple diseases, and it is highly unlikely that this company has found a ‘cure’ for cancer any more than there is a single cure for infections.”

He said that “more likely, this claim is yet another in a long line of spurious, irresponsible and ultimately cruel false promises for cancer patients.”

Neel added in an email: “Of course, curing cancer is the goal of everyone who comes to work every day at a cancer center — and if this company does, in fact, cure cancer, they will have my congratulations and thanks.”

Mine too. However, based on what I’ve read so far, I highly doubt that I’ll be giving ABEi my congratulations and thanks, at least not any time soon. As for right now, I’m calling them out for, at the minimum, massively excessive hype.

In Israel, the Times of Israel published the article I cited above in which ABEi scientists said they wouldn’t be publishing because it was too expensive. I left this next part out above because it is truly cringeworthy, saving it for the end of the post to drive the final nail in the coffin in which ABEi’s claims rest:

Morad said the team at AEBi chooses to use its scant funds to do more research rather than publishing its research in medical journals

The firm wants to focus on “advancing the research and developing more targeting peptides. It takes a lot of work and we are a small company,” he told The Times of Israel. “We can’t afford it. Publishing an article takes a lot of effort and a lot of funds, and this we can’t afford.

He added: “If we were a big company with a lot of funds, that would be the first thing we would do. If I have $100,000 what do I spend it on?” he asked. “Advancing the research and finding more and more targeting peptides, or doing many experiments to write an article? What would you do, if you had to choose?”

There’s only one thing to do here, and that’s to bring out Godzilla again:

Godzilla facepalm

Or maybe Picard and Riker:

Or maybe even…Jesus:

I laughed out loud when I read Morad’s excuse. The very experiments that “advance the research” would be the ones most interesting to publish. It appears to me that Morad knows his results are too preliminary to publish. However, that means that the research is far more preliminary and thus nowhere near clinical application, much less “less than a year from a complete cure for cancer.”

It’s hard not to wonder whether Morad and Aridor are just grandiose startup executives desperate enough to raise venture capital that they do a bit of creative massaging of the truth, which is all too common among those running startups, or outright con men. (Their excuses for why they haven’t published their results yet made me lean towards the latter.) Regardless of the answer, the best that can be said of them is that they are wildly exaggerating how far long their technology is in development and even more wildly overpromising what it is likely to be able to deliver. In doing so, they’re raising false hope in cancer patients. Let us be clear. Their technology, promising or not, is not a “complete cure for cancer” and will not be a cure for cancer. At best, it probably won’t be a cure for a cancer. (Remember, cancer is not a single disease, but hundreds of diseases, and each cancer can be multiple diseases as well.) It might be a useful therapy. That’s it. It sounds as though it’s worth developing further, but only if Morad and Aridor can show that they have a reliable method to pick their protein targets other than pulling them from their posteriors and that their treatment isn’t too toxic, but I fear that ABEi’s excessive hype might well have doomed it.