March 30, 2013

An Antibiotic for Cancer by $PVCT's Craig Dees

(c. 2007)

Many people often ask me, “Why isn’t there a cure for cancer like an antibiotic?” This is almost immediately followed by their idea why there isn’t.

Lay Theories on Lack of a Cancer Cure. Having the job I do, I hear numerous theories on why there isn’t a cure for cancer. The well-meaning but off-the-wall hypotheses come from people in all walks of life from billion dollar fund managers in New York, a nuclear physicist at a National Lab, and from the plumber currently working on our air conditioner.  Once someone finds I work on cancer, they have to test the truth of their belief on the cancer “expert” as the opportunity presents itself.

“There is a wide spread belief that there is a far-reaching conspiracy by all those associated with the treatment for cancer hiding a cure or preventing one from being found.”

My favorite theory was one from a nuclear physicist. This physicist having an epiphany late at night felt the need to call me a little after midnight and share his insight. While sleepily listening to a convoluted explanation of cancer involving strong and weak intranuclear forces at the atomic level, I broke laughing saying, “ Cancer isn’t a mystery just a hard problem to solve for a number of reasons.”  I continued, “The causes of cancer at the molecular level doesn’t need any obtuse quantum mechanical explanations.” The physicist seemed genuinely surprised my assertion that cancer isn’t mysterious and listened to quite a lecture from me on the known causes of cancer and why its been hard to treat. It kept me amused to educate such a bright individual who was a good “hard” science type into the complexity of biology and biochemistry that we call life. Debatable if any good I did was worth the loss of sleep but to change misperceptions that are ride ranging…I’ll settle by correcting misperception and ignorance one individual at a time as I can.

However, the most common assertion that you might have already surmised or believe yourself, is the conspiracy theory.  Most often presented to me is the belief that large companies, doctors, hospitals and the entire healthcare industry including our academic institutions etc. are in collusion to prevent a cure from cancer reaching the market to protect profits from treatments that still remain for the most part highly toxic, poorly effective and generally very expensive.  Assertion of the conspiracy theory along these lines is an almost daily occurrence. So I have to conclude that it is a very widespread, prevalent belief. Additionally, and goodly number of cancer conspiracy theorists are convinced the “cure” has already been found and is being hidden. A much more sinister conspiracy than just preventing or hindering forward progress in the battle against this dreaded disease.

The assertion of a conspiracy almost always causes me a good laugh. The assertion of a conspiracy also allows me to follow my early career dreams of being a professor and teacher in the footsteps of my father.  I get to teach of lot of biochemistry and biology to a receptive audience who started the interaction with the “cancer guy”.

Why It Took So Long to Find the Anticancer Antibiotic 

When I get to debunk the conspiracy theory, before I launch in the “science” and biological origins of cancer, I start with more practical considerations. I generally laugh and say, “If someone at a big company was hiding a cancer cure it would be impossible to keep secret.”  Second, I say, ‘It would be impossible to keep secure.” Some secret that big would be too tempting a target for someone not to leak it and more likely steal it. All they would have to do is take it, get funding for a new start up company (which would be easy to do) and off to the races. What’s the one who had been hiding the “cure” going to do? Admit they have been hiding a cure and letting hundreds of millions suffer and die?  I think not. The risk of an angry mob at your facilities alone with torches set to burn the place would be way too much. So a hidden cancer cure would be too much of target for even the janitor to make off with.  Even if the conspirator came forward and took the risk of disaster by an angry populace, the value of the “cure” would be still well worth the ownership fight to come.
As a fresh out of postdoctoral studies Director of Research for a medium sized pharmaceutical and biologics company, I rapidly learned who knew all the secrets in the company. You didn’t get early and confidential information from my fellow upper management who had a vested interest to keep many things quiet.  There are lots of things not good to be spread around among the rank and file. For example, we were doing poorly during the recession in the agricultural industry. One good way out was to either sell off divisions of the company or the whole company itself. Even this strategy was never talked about even at my management level. Why? First, it was a public traded company and there are rules about disclosure about events with such significance to shareholders. Second, one doesn’t want to start a panic of the help causing them to dive off the ship in a division that might be sold by taking jobs with the competitors. Worse yet, causing worried employees to leave in divisions that might be affect.
 However, as an employee it was in my best interest to know these things well ahead of time. After the take over that eventually did happen, we managers were all summoned to Kansas City for a big group meeting with the company that did the buy out. When the first words out of the new CEO’s mouth were “All of you hear still have your jobs” a huge collective sigh of relieve went through the giant auditorium.
 So how did I find the most confidential information?  I learned that the janitor knew everything including everything from the Corporate Headquarters in another state, to the far-flung divisions, offices and production facilities around the world. He knew information almost immediately even though the confidential things might have just been decided.  The breadth and speed of his knowledge was uncanny.  Being an inquisitive scientist I had to figure this out and under took my own investigation. First, the janitor went into every office locally as did those in corporate headquarters. Its amazing how ignore the janitorial staff as an insentient piece of furniture and what they will say in front of them. The janitorial staff in each distant division was inconstant touch with the others. One of the information pipelines was very unique. Most of our facilities had laboratory animal colonies. Trucks delivering lab animals arrived daily. The janitors of one facility told the crew of the trucks that passed the information on to our janitor who, once I learned this information highway, told the head of R&
I also point out that it would be difficult for any individual to give up the lasting fame as being the “discoverer” of a the cure for cancer. Especially since one can have the fame and a huge financial gain too. It’s hard for me to conceive of an individual with so little ego hiding something with an impact that will echo down centuries.

So just common sense considerations alone argue against a cure “hiding” somewhere out there. It’s just not a practical thing to believe in considering the nature of economics and human behavior.

The Hard Problems of Cancer that Make a Cure Difficult

The very first problem is that cancer is not one disease. It is many diseases with multiple different causes. It occurs in many different tissue types with differing biochemistry and in multiple different organs with their own unique physiology. The anatomical locations of tumors again add problems of how to address the multiplicity of “diseases” that are lumped under the description of “cancer. So just on the anatomical level the complexity of the problem is huge which inhibits finding a “cure” for all cancers.  Secondly, cancer is caused by many different things that include infection by oncogenic viruses, exposure to toxic materials or radiation, aging and failure of anticancer defenses, and inborn errors on the genetic code blue print that details what each of us are. If I think a little bit more, I’m sure I can add to this short list.  So adding this second series of things to the anatomical barriers to a broad-spectrum cure for cancer, the difficulty is already almost insurmountable and there are plenty more barriers.

Lack of Unique Targets is the One Big Hurdle. A year or two ago, I was privileged to be invited to the annual meeting of the Prostate Cancer Foundation. One talk specifically stuck in my mind as defining the whole problem of cancer etiology and treatment. One investigator was using techniques with absolutely huge genetic arrays for gene expression. Some of the most beautiful work I have ever seen performed. The technology and size of the gel arrays being performed was able to quantify expression of thousands of genes. The investigator’s conclusions after looking at very large numbers of genetic markers were interesting. He said, “ Nothing is unique, things that you would expect to be up are for the most part up and down things are mostly down.”

For lay people I often explain one factor in the lack of unique targets and specific treatments by saying, “Cancer isn’t caused by an alien invader like bacteria or viruses entering the body.”  I say, “Cancer is like a misbehaving immature teenager running with the wrong crowd, disobeying orders, and being in the wrong place.”  “Cancer is difficult to treat because thing that will kill the teenager will kill both teenagers that are behaving and children and adults too.” The lack of unique targets that comes with an alien invader like a bacterium, is what limited us in finding a treatment similar to an antibiotic.”

Similarly the root cause of finding a wide-ranging “antibiotic-like” treatment for cancer is the lack of unique biochemical targets in cancerous cells. Unique biochemical pathways in bacteria like that for folate that exist in bacteria but not humans allows use to make antibiotics like the triple sulfa types that have broad-spectrum activity. Similar very specific targets in cancer cells have been hard to find. 

So to date, most of our treatments are horribly toxic compounds most often horrific carcinogens themselves with little differentiation of effects between healthy and normal cells. One prominent cancer investigator gave me his opinion that the majority of our current cancer therapies like radiation were on 1.1-1.2 times more effective on cancer cells than they were on normal. Even if this investigator’s numbers aren’t correct, the concept tied to his assertion is true. There is very little difference for our older cancer therapies on cancer cells and normal tissue. Therefore, as one should expect there is very poor efficacy and a high level of side effects.  Since many of the older treatments have been targeted at our genetic blueprint so an almost universal side effect of our treatments is a potential for a new cancer later due to the effects of the treatment.

In addition to finding tumor-specific targets to attack, the target has to be universal to many or all cancer types for a broad-spectrum antibiotic like treatment.  The target when “hit” has to have a major effect in bringing about the destruction of the cancer cell…Not only does the target have to unique to cancer cells but it has to be and “Achilles Heel”.

So to date this complex combination of factors that include anatomical, physiological, molecular and cellular barriers has made the discovery of a compound that acts like a broad-spectrum antibiotic hard to find. Not a large conspiracy among those trying to cure the disease.

The Cancer “Antibiotic”

Currently there are many new potential treatments for cancer that attack the problem using the idea of making the treatment more specific. Since the “attack” on cancer cells is more specific the safety is greatly improved, as should be the efficacy. One of these is Reolysin™ a modified Reovirus that has increased specificity for cancer cells. There are new more specific inhibitors of protein kinases that are elevated in cancer cells under investigation. Therefore, the potential of the new treatments is much more likely to perform like an “antibiotic” against cancer.

One other approach also incorporates a specific attack on the “Achilles Heel” of cancer cells. Recently it has been shown that cancer cells appear to have a common “Achilles Heel” that when attacked can cause the specific destruction of cancer cells while leaving a normal cell right next to it unscathed. The Achilles Heel of cancer cells is the subcellular structures called lysosomes. Lysosomes can be visualized as little bags of degradative enzymes that can destroy large molecules that living cells are constructed of and use as “food” and building materials. Within the lysosomes are a wide variety of these enzymes that function under acidic conditions (i.e. acid hydrolases). Cancer cells, like a fast running combustion engine, and that are growing at an abnormal rate required large amounts of “fuel”, air and building materials and are highly dependent on the acid hydolases within the lysosomes. Therefore, attack on these “bags” of enzymes is the downfall of cancer cells. When the lysosomes are damaged or ruptured, the enzymes are released into the interior of the cell and kill the cell by “digesting” the cancer cell components.

Recently, a common red dye, PV-10, under the right conditions was demonstrated to specifically localize into tumor tissue. Once in the tumor tissue, PV-10 partitions into the diseased cellular membranes while staying out of normal cells. Once inside, PV-10 enters the very acid environment of the lysosome and causes it to leak or rupture. This releases the acidic degradative enzymes into the interior of the cancer cells.  PV-10 functionally causes the cancer cell to “eat” itself. So PV-10 attacks cancer by not only very specific targeting of only diseases cells but hits them in a critical spot that results insults in their immediate self-destruction. Further, this critical spot appears common to all cancer cells. Table 1 shows that PV-10 kills every cancer cell tested to date including cancer cells (e.g. lung cancer cells) that have strong resistance to a large number of chemical chemotherapy agents. Clinical trials now in Phase II testing have also shown that PV-10 is capable of resolving melanomas previously treated with radiation or chemotherapy and are resistant.

Therefore, PV-10 surpasses the previous barriers at the anatomical, physiologic, and molecular levels that inhibited the finding of an “antibiotic” for cancer. It specifically attacks a critical target seemingly common to all cancer cells while leaving normal cells intact. Early stage clinical trials testing for efficacy and safety in human breast cancer and melanoma support this assertion. As more types of cancers are treated, judgment that this is the closest to anticancer agent for cancer will be confirmed.

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