What set me off on this rant was the very first comment on the piece that posted on January 31st, “Looking Backward – And a Peek in the Other Direction.”   Here’s the comment:

“Thanks, Doc.

Hope you will comment on the news out of Israel this week:
https://www.jpost.com/HEALTH-SCIENCE/A-cure-for-cancer-Israeli-scientists-say-they-think-they-found-one-578939”

Naturally, I looked, and what I found was an article from the Jerusalem Post,  entitled “A Cure for Cancer?   Israeli Scientists May Have Found One.”   The article quotes Dan Aridor of Accelerated Evolution Biotechnologies Ltd (AEBi) as follows:

“We believe we will offer in a year’s time a complete cure for cancer.   Our cancer cure will be effective from day one, will last 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.   Our solution will be both generic and personal. “

My immediate response was:

“I’ve never heard of that particular one, but a cure for every cancer is exceedingly unlikely. A tiny bit of digging came up with this, published in Forbes:

‘As someone with 10 years of molecular biology and medical experience, I strongly suspect the Israeli scientists…are completely misrepresenting their supposed discovery. But I want so, so badly for it to be true,’ said John Jiao. ‘To my knowledge, there has never been a single published paper which discovered any one protein (peptide) that exists in a large plurality of all cancers, let alone every single one. Of the common ones, they all exist in normal cells as well. So, the idea that these scientists have somehow, without anyone else developing anything remotely close, come up with a cancer cure-all that is not only totally effective but also has no side effects? This looks, sounds, smells and feels like snake oil.’

Sorry to be a wet blanket, but thanks for the well-meant hint.”

The snake-oil invective came from the person quoted in Forbes, not from your mild-mannered friend Doc Gumshoe.   I would not go that far, at least not yet – not before attempting to figure out just what AEBi is trying to do and what they’ve got at this point.

To begin with, they call their treatment Mu Ta To, for multi-target toxin, and characterize it as a cancer antibiotic, “a disruption technology of the highest order.”

Aridor and their CEO, Dr Han Morad, go on as follows:

“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.”

What exactly are SoAP technology and the phage display group of technologies?
Phage display is a well-established technique used to identify molecular entities that may have useful pharmacological activity.   This method of quickly sorting through a large number of potential anti-cancer agents, screening them for specificity, selectivity, and potency, is currently a favored tool in the field of oncology.   

As for SoAP technology, that seems to be what AEBi call their own method of using phage display.   Here’s what they say about it on their website:

1. “SoAP allows AEBi to develop drugs to many illnesses, among them cancer, and is expected to transform the drug discovery R & D phase by significantly reducing the attrition rate of new drug candidates.
2. This breakthrough technology generates very specific lead compounds with greater functionality and improved pharmacological properties.
3. Such lead compounds will allow more effective drugs and fewer side effects.   The need for such technology is acute and pressing for many reasons.
4. The sole external requirement in the screening process is a defined target (usually an illness-related protein).”

And that’s all!   So, what we have so far is that AEBi has (perhaps!) an improvement, or at least a variation, on an established way of getting a quick reading on whether a particular molecule, usually a peptide, has potential cancer-attacking properties.   

Using this screening technique, AEBi claims that it has put together a combination of cancer-targeting peptides plus a specific strong cancer toxin.   In Dr Morad’s words:

“By using at least three targeting peptides on the same structure with a strong toxin, 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 decreases dramatically with the number of targets used.   Instead of attacking receptors one at a time, we attack receptors three at a time. Not even cancer can mutate three receptors at a time.”

This sounds reasonable enough when directed at a particular form of cancer.   Three agents, each taking aim at a different receptor on the cancer cell, linked with a powerful chemotherapy agent of the old kind, a toxin, could certainly be effective against a specific cancer.   But why would the agents that precisely target receptors on a lung cancer cell also work on different cancer cells? The toxin might work on a several different kinds of cancer – poison is poison.   But cancer cells are all quite different, and targeted therapies work on only one fairly narrowly-defined type of cancer.   So how in the world is that going to lead to “a complete cure for cancer”?

What else do we know?

Thus far, AEBi has tested their universal cancer drug on mice which have been inoculated with “human cancer.”   What type of cancer, they do not say. In fact, none of their research has been published anywhere. Questioned about this, Dan Aridor, Chairman of AEBi, answered that “they could not afford to publish.”   Sorry, but this is rubbish. Medical journals do not charge fees for publishing original research. The fact that AEBi has gone this far – even though, in reality, a single mouse study is not very far – without publishing any data at all and without peer review, is certainly cause for skepticism.    

According to AEBi, their mouse study was successful.   Does that mean that their agent is likely to be successful in humans?   Based on the success rate in humans of agents that have been effective in mice, the answer isn’t even “maybe.”   The answer is, “it’s a really long shot.”

And in those words we have a hint about what AEBi might really be up to.   Another clue comes from the second comment to that last piece. After the first commenter suggested that I look into the Israeli cure for cancer, the very next commenter said:

“Interesting article out of Israel – any way for Americans to invest in this company?”

When the Jerusalem Post piece came out, there was apparently a good deal of internet comment – some skeptical, some evincing signs of open-mouthed wonderment, and some “wait and see.”   Lots of people were of one mind with John Jiao when he said “I so very badly want it to be true.” And probably lots of people thought that, yes, this complete cure for cancer is a long shot, but sometimes a long shot is worth a small wager.   

And remember that making a bet on the stock market is not like making a bet on a horse race.   It’s more like making a bet on who will win a beauty contest. It’s not who you think is the most beautiful, it’s who you think the judges will think is the most beautiful.   If enough people think that the Israeli cure for cancer is a possible winner and plunk down their money on AEBi stock, the stock will rise, and if you also plunk a bit of your own money on their stock, your stake will rise along with it.   If the long shot hits the gold, you could win really big. But in the meantime, as long as there aren’t too many skeptics (like Doc Gumshoe) letting air out of the balloon, the ride could be profitable. You could get out before the balloon deflates.  (I need to add here that hopping on for a short ride on a venture with the expectation that you can bail before it tanks is by no means a recommended investment strategy.)

But that, I think, is what AEBi is figuring.   They may or may not have an effective drug, at least for one type of cancer.   But in the meantime, they’ll attract a lot of investors and get rich themselves.

On the other hand, is it possible that when AEBi talks about “a complete cure for cancer” what they really mean is that using phage display and their SoAP technology they will quickly develop a large number of distinct drugs which as a group will constitute a complete cure for all cancers?   And that they will have it ready in a year’s time? Identifying the receptors and developing agents that target all those receptors, testing the agents, running clinical trials, and getting those new drugs to patients…. Sounds like many, many years of hard work. No, I think they really want people to believe that they are going to come up with a single drug that will cure every cancer – and come along for the ride.

Why is it that Doc Gumshoe, along with anyone who knows anything about how cancer grows and spreads, thinks that it’s somewhere between exceedingly unlikely and outright impossible for one drug to cure all cancers?   

Cancer is not a single disease, but a group of diseases with a few common features

Cancer cells grow from stem cells, just as do normal cells.   But cancer cells possess key differences from normal cells, and it is these differences that lead to the disease processes that are damaging and can be ultimately fatal to the host organism.   The most important might be that normal cells have a built in characteristic called apoptosis, or programmed cell death.   Apoptosis is an important survival trait for the host organism.  Healthy human cells grow and divide as needed to maintain necessary function.   When these normal cells are damaged or can no longer perform their function, they die, and new cells replace them.   In a healthy organism, most cells are young and healthy, and apoptosis keeps them that way.

Programmed cell death does not take place in cancer cells.   Thus, cancer cells grow and divide unchecked. They can form solid tumors, which occupy space, crowding out and damaging normal cells, and causing severe pain.   They steal nutrients that would normally sustain the healthy cells, and in that way damage the organism. And they can travel to other parts of the body, establish new colonies there, and attack the host organism on another front.   This process is termed metastasis.

The cause of the changes that result in the formation of cancer cells has traditionally been thought to be random errors in the transcription of genetic material in stem cell division, such as mutations, which can result in the loss of the genes that suppress tumors, or in the over-expression of the genes that promote cancer cell growth, termed oncogenes.   The frequency of stem cell divisions in different organ systems and tissue types in the body is highly correlated with the incidence of cancer in those locations.  Every time a stem cell divides, there is a chance that a mistake will occur, such that the “offspring” cells are not exact copies of the “parent” cell. These inaccurate cell divisions are essentially random mutations, and the great majority of these mutations will be meaningless – the new cells will simply die or fail to replicate.   In a few cases, the mutations will be beneficial, conferring some evolutionary advantage to the host, and these mutations may become part of the species genome. But in some cases, the mutation will lead to cancerous cells, which continue to replicate and increase in number.

Characterizing the mutations as “random errors” does not mean that they occur spontaneously with no cause.   The radiation that we are all constantly exposed to can lead to mutations, as can a huge number of external substances that enter our bodies – in what we eat, drink, breathe, and absorb through our skins.   The mutations themselves are nonetheless random – the external cause, whatever it is, just messes up the way the genetic material is transcribed. However, because the mutations take place as the stem cells are beginning the process of becoming mature cells in various parts of our bodies, the cancer cells themselves are individually different.   Let’s say a stem cell is maturing, on the way to becoming a lung cell. When a mutation occurs, triggered by an exterior cause such as tobacco smoke, the stem cell goes on to become a lung cancer cell – not just a miscellaneous cancer cell, but specifically a lung cancer cell. Even within the lung cancer category, there are several subtypes – small cell and non-small cell lung cancers, and within the non-small cell category there are more subtypes: adenocarcinomas, squamous cell carcinomas, and large cell carcinomas.   And treatment works best when it is targeted to the specific subtype of cancer.

Cancer cells have some characteristics in common.   We’ve mentioned the absence of apoptosis, which is basically what makes them cancer cells.   But they also have the characteristic of being greedier than normal cells. These common characteristics have made it possible to develop some drugs that are effective against a broader range of cancers, although by no means effective against all cancers.   Those common characteristics, and the types of drugs that address those characteristics, are described below.

Inhibiting cancer cells from promoting vascularization

Cancer cells need nutrients to survive, and they get them by inducing the growth of blood vessels (angiogenesis) to deliver those nutrients to the growing cancer cells.   They accomplish this by releasing vascular endothelial growth factor, or VEGF, in amounts far greater than normal cells. A drug that targets angiogenesis through the release of VEGF is bevacizumab (Avastin, from Genentech/Roche).   It binds to the VEGF molecule in such a way that VEGF cannot interact with its receptor on endothelial cells. Avastin is FDA-approved for a number of cancers, including colon, kidney, brain, and lung cancer; however, the FDA recently recommended that it no longer be used to treat breast cancer.  Nevertheless, Genentech/Roche are not giving up on Avastin for breast cancer. Currently, 2,427 clinical trials are under way with Avastin, including 212 in patients with several forms of breast cancer at various stages; most of these are in combination with other drugs. Several other VEGF inhibitors are also on the market.   These include pazopanib (Votrient, from Novartis); sunitinib (Sutent, from Pfizer); cabozantinib (Cabometyx, from Exelixis; and sorafenib (Nexavar, from Bayer).

In one form of breast cancer that is especially difficult to treat, tumor growth is fostered by another type of growth factor, termed HER2, which stands for human epidermal growth factor type 2.   In turn, release of HER2 is triggered by tyrosine kinase in another of its cancer-related roles. Some drugs have been developed specifically to target tyrosine kinase in HER2 breast cancer, including lapatinib (Tykerb, GlaxoSmith Kline) and trastuzumab (Herceptin, Genentech/Roche).

Inhibiting cancer cell replication

All cells, whether cancer cells or healthy normal cells, reproduce by splitting, or mitosis.   As noted above, the crucial difference is that normal cells have a built-in program that eventually kills them off – apoptosis, which serves the valuable function of making way for new cells, so that most of the cell population in our bodies consists of young and healthy cells.   Cancer cells, not being subject to apoptosis, will go on reproducing endlessly, growing and spreading – that is, unless something prevents them from doing so. A number of drugs can inhibit this process, and these have demonstrated great clinical benefit in some cancers. Many of these drugs were initially derived from a substance found in the bark of the Pacific yew tree, called taxol.   These include paclitaxel (Taxol, Bristol-Myers Squibb), docetaxel (Taxotere, Sanofi-Aventis), another formulation of paclitaxel (Abraxane, Celgene). Capecitabine (Xeloda, Genentech/Roche) also prevents cell replication, but by inhibiting DNA synthesis.

Another mechanism through which cell replication may be inhibited is targeting telomerase in cancer cells.   (We mentioned telomeres in the discussion of the Mediterranean diet, which has been found to protect telomeres and thus extend the lifetime of healthy cells.)   Telomerase is an enzyme that protects telomeres, which are the ends of genes, so targeting telomerase is a way of attacking cancer cell replication.

An agent that has shown some promise in that approach is imetelstat, from the biotech company Geron, which did much of the basic research into the role telomerases play in cancer. The 2009 Nobel Prize for Physiology or Medicine was awarded to two Geron collaborators, Elizabeth H. Blackburn and Carol W. Greider, along with Jack W. Szostak for the discovery of how chromosomes are protected by telomeres and the discovery of the enzyme telomerase.   

Several natural substances are being studied for their possible effects as inhibitors of telomerase in cancer cells.   These include curcumin, quercetin (found in many fruits including apples, grapes, berries, and citrus fruits), tannic acid, and berberine (from the roots of a number of plants).   At this point, there is no clinical evidence for the effectiveness of these natural substances in preventing cancer cell replication.

Some drugs in the class called tyrosine kinase inhibitors also inhibit cancer cell replication.   Tyrosine kinase is an enzyme which can play a number of roles, including stimulating the growth of new blood vessels, but is also active in cell replication.   In healthy cells, tyrosine kinase activates a kind of “on-off” switch that makes it possible for cells to reproduce, but in cancer cells, tyrosine kinase turns the switch on and keeps it on, so that cells just keep reproducing without cease.   Imatinib (Gleevec, Novartis) is a cancer-cell specific tyrosine kinase inhibitor which is used to treat one form of chronic myelogenous leukemia (CML) and also gastrointestinal stromal tumors (GIST). CML median 5-year survival has nearly doubled since the approval of imatinib, from about 31% to about 59% currently, and median survival in patients with GIST is also currently about 5 years.

Killing cancer cells with oncolytic viruses

The curious fact that some viruses preferentially attack cancer cells has been observed since early in the 20th century, and research into the possibility of putting this into therapeutic use began about 50 years ago, but only now are the first oncolytic virus-based treatment attaining approval.   BioVex, a small biotech outfit, developed a drug called OncoVex, based on the herpes simplex virus, for the treatment of melanomas. In 2011, Amgen made a deal with BioVex worth in total about $1.1 billion for development of the drug, talimogene laherparepvec, initially called T-Vec, which Amgen has renamed Imlygic.   Clinical trials with Imlygic have been highly promising. The virus-based drug is injected directly into melanomas which are deemed to be not appropriate for treatment by surgery. One of the most impressive findings in the clinical trials with Imlygic is the relatively high durable response rate, meaning that melanomas treated with this agent tend not to recur, unlike melanomas treated by other means, which do tend to recur.   Imlygic, along with some other oncolytic viruses, launches a two-pronged attack on cancer cells – not only does the virus lyse (destroy) cancer cells directly, but it prompts the patient’s immune system to attack the cancer cells as well. Imlygic received FDA approval in October of 2015 – the first FDA-approved drug based on an oncolytic virus.

A Canadian firm, Oncolytics Biotech, has an agent, Reolysin (pelareopep), based on one of the reoviruses, which is now in Phase 3 trials against head and neck cancers and is being studied in lung, colorectal, and pancreatic cancers.    Reolysin has received FDA fast track designation in metastatic breast cancer on May 8, 2017. And an Australian biotech, Viralytics Ltd, has a couple of agents in clinical trials, based on the Coxsackie virus, against ovarian, lung, gastric, and pancreatic cancers.    An advantage of some of these agents is that they don’t have to be injected into the tumor cell, but can be given intravenously.

Other oncolytic viruses currently under investigation include a recombinant adenovirus to target bladder, breast, ovarian, colon, and prostate cancers, from Cold Genesys, Inc, in California.   Another California outfit, Genelux, is looking at attenuated vaccinia viruses, which have shown effectiveness in head and neck tumors and advanced solid tumors. (The vaccinia virus is used to vaccinate people against smallpox.)

All of these viruses have to be modified in some form so that they target cancer cells only and limit their potential for causing disease in the patient.   A challenge for the developers of virus-based therapies will be to convince patients that it is safe to be treated by a pathogen which would otherwise make them sick.

But is it possible, all the same, that AEBi might be on to something?

Remotely possible, yes.   Perhaps there is yet one more shared characteristic of cancer cells in addition to their lack of apoptosis, permitting them to divide and spread without limit, their capacity to induce the growth of blood vessels to bring them nourishment, and their attractiveness to viruses which may attack and kill them.   And perhaps AEBi, through their SoAP-modified phase display technique, has identified an agent that would target that shared characteristic. And perhaps the statement that they cannot afford to publish their research means that if they did, an unscrupulous band of rogue researchers would steal their idea and beat them to the finish line.   All of those are remotely possible. But Doc Gumshoe remains highly doubtful.

Postscript: More About the Opioid Quandary

I thought I had said quite enough on this subject after the two Doc Gumshoe posts in October of 2017, in which I discussed at considerable length the conflicting positions about the need for chronic pain management, on the one hand, and the effort to reduce the number of opioid overdoses and resulting deaths.   To restate the main points of those pieces, I pointed out the following:

• 18 million of us in the US rely on opioids for the management of long-term pain.
• Fewer than 8% of chronic pain patients become addicted.
• Medical opioid prescribing is down by a third since 2011.
• At the same time opioid overdose deaths are soaring – heroin overdoses by 500% and fentanyl overdose deaths by 600%.
• By a huge margin, people who abuse opioids do not obtain them through a legitimate medical prescription, but through illicit means.

Despite the fairly clear evidence that the major part of the opioid abuse problem is not medical over-prescribing, but diversion and street drug peddling, the attention of the news media has largely focused on such matters as Purdue’s marketing of OxyContin and the misdeeds of the Sackler family.   Those issues are real, but the reaction of the CDC and other government agencies has, in the opinion of many specialists in pain management, resulted in policies and guidelines that have caused great harm to many persons in severe chronic pain.

A long, well-written Op Ed piece in the Times of 10 February, “When the Cure Is Worse Than the Disease,” by Maia Skalavitz, made some of those same points.   But more telling, the piece recounted the stories of several patients who had relied on opioids for the management of their extreme chronic pain, and when their opioids were withdrawn due to those guidelines, could no longer tolerate their pain, and committed suicide as their only way to free themselves from the pain that made their lives intolerable.

The Doc Gumshoe pieces mentioned above discussed the issue that physicians, as well as pharmacists, are keenly aware that they may be viewed with strong disfavor and even in some cases sanctioned for “over-prescribing” opioids, which may lead them to prescribe opioids with great reluctance, even to patients in obvious need.   The Times piece noted that 10% of physicians have stopped prescribing opioids altogether.

Another guideline-directed practice is forced opioid tapering.   An article in Pain Medicine (Darnall B., 11/20/18) says the following:

“We, the undersigned, stand as a unified community of stakeholders and key opinion leaders deeply concerned about forced opioid tapering in patients receiving long-term prescription opioid therapy for chronic pain. This is a large-scale humanitarian issue. Our specific concerns involve:

• rapid, forced opioid tapering among outpatients;
• mandated opioid tapers that require aggressive opioid dose reductions over a defined period, even when that period is an extended one.

Rapid forced tapering can destabilize these patients, precipitating severe opioid withdrawal accompanied by worsening pain and profound loss of function. To escape the resultant suffering, some patients may seek relief from illicit (and inherently more dangerous) sources of opioids, whereas others may become acutely suicidal. Regardless of one’s view on the advisability of high-dose opioid therapy, every thoughtful clinician recognizes rapid tapering as a genuine threat to a large number of patients who are often medically complex and vulnerable.”

The article, by the way, has 119 signatories.

The current trend in attempting to quell the opioid overdose epidemic appears to treat the drug abusers as victims who must be protected, at the expense of the many persons living with acute pain who rely on opioids as their sole remedy.   Opioid tapering, forced by decree on patients with severe pain and no real alternatives, is in no way even close to a solution to the problem of opioid abuse. Making these patients carry the brunt of the pain and distress, even to the extent of losing their lives, will have a minimal effect on the drug abusers, who will continue to get their drugs by illegal means.   There will be no diminution of overdoses and overdose deaths as a result of forced tapering.

* * * * * * *

To Gumshoe citizens who have made suggestions as to what they would like to see in these diatribes, I’m trying to keep track of them and hope to get to them before too much longer.   Best to all and keep the comments coming! Michael Jorrin (aka Doc Gumshoe)

[ed note: Michael Jorrin, who I dubbed “Doc Gumshoe” many years ago, is a long-time medical writer (not a doctor) who opines on topics in health and medicine for our readers a couple times a month. He does not typically discuss investments directly, but has agreed to our trading rules. All of his past columns and commentary can be found here.]