Richard D Feinman

Merci. Parmi les nombreuses raisons qu’encourage l’optimisme, nous avons un nouveau collaboration avec Dr. Matthew R. Pincus qui a précédemment développé un agent anticancéreux très prometteur.

Figure: Acetoacetate sensitizes SW-480 (colon cancer) cells to the effect of rapamycin. See next comment for details. https://www.dropbox.com/s/i6cz92pbo5gwwyn/AcAc_SW-480_Rapamycin%20.png?dl=0

We do have some interesting results. On the cellular end we are addressing two major questions. The most straightforward has to do with pharmacology. There are many anti-cancer drugs but often they are very toxic. We had previously shown that acetoacetate, one of the ketone bodies, slowed the growth and reduced energy state of several cancer lines and we wanted to know if, as a consequence, ketone bodies might sensitize cells to the cytotoxic drugs. The long-range hope is that patients could take smaller doses if they were on a Ketogenic diet and thereby avoid side effects and toxicity. We focused on two cell lines, MCF-7, a breast cancer line and SW-480, a colon cancer line. We studied three drugs, rapamycin, methotrexate and PNC-27. Rapamycin is a metabolic inhibitor -- most people have heard of mTOR, the mammalian Target Of Rapamycin. Methotrexate inhibits the folic acid pathway which indirectly slows DNA synthesis (thymidine, the T in the TGAC bases of DNA, depends for its synthesis, on a folic acid reaction and the idea is that cancer cells which are multiplying rapidly will be preferentially knocked out. Finall, PNC-27. is a peptide that represents a piece of p53, a tumor suppressor , that was developed by Matthew Pincus who is collaborating with us. We found that lower concentrations of the toxic drugs are required if administered to cells in the presence of acetoacetate. This was true for both MCF-7 and SW-480. For example, after a 72 hour incubation, we killed 70 % if MCF-7 cells with less than 1 nM rapamycin if acetoacetate was present. In the absence of the ketone body, it took more than 5 nM. We want to emphasize that this has to be considered a very preliminary result. It has been reliable and reproducible but you never know with tissue culture because of all the details involved and, obviously, it is very much only a model for a whole human. We always cite Albert Szent-Györgyi (who discovered vitamin C): "Today we celebrate. Tomorrow we do the controls." I will try to post some graphics. The second question is what's going on in the Warburg effect -- the reliance of cancer cells on glycolysis ai. Here the approach is more technically complicated and also preliminary. I will try to explain it, possibly on a blog.

My recollection is that Cahill told you personally that he knew about the misinterpretation But that he felt it was too late to fix. Is that accurate memory?

I think that our big problem rests with academic medicine and the NIH and other public and private health agencies which are very conservative and very slow to change. One of the likely outcomes of our research is that a ketogenic diet may be a valuable adjunct to pharmacology allowing drugs to be used at much lower doses thereby reducing side-effects and toxicity. We need the help but, in the end, we may be helping big pharma. (This is not our main goal -- they have no trouble finding a way to make a profit). We are also trying to get them to help us although they are also very conservative on what they like to fund. We are, again, very grateful for the backing from this community.

Explaining the diagram, Part II. GLYCOLYSIS glucose ---------> pyruvate. Pyruvate can be converted to many things. Some cells -- many bacteria and other microorganisms, rapidly exercising muscle cells and red blood cells -- use only glycolysis for energy. Those cells convert pyruvate to other things like alcohol or lactic acid (fermenting bacteria produce ethanol and lactic acid bacteria are the cultures in yoghurt). Such cells are said to have an anaerobic energy metabolism because glycolysis does not require oxygen. Looking ahead, many cancer cells are said to be "glycolytic" because they only use glycolysis even in the presence of oxygen while the normal cells from which they derive run glycolysis but further process the glycolysis using oxygen. Of importance, the Warburg effect refers to Otto Warburg's observation that cancer cells were producing lactic acid. One of the products that aerobic (oxygen-requiring) cells produce is acetyl-CoA. (You can just remember it as a name or, if you took freshman chemistry, you may recognize it as a derivative of acetic acid). Acetyl-CoA is the substrate for oxidative metabolism. A combination of processes (Krebs cycle, electron transport) referred to as respiration is where most energy is obtained in most human cells and requires oxygen. Details of respiration to be discussed in part III but the take-home message here is that the compound acetyl-CoA is the big player in oxidative metabolism. It is not only produced from glycolysis but also (primarily if you are on a low-carb diet) from fat in a process called beta-oxidation, and also from some amino acids from protein. Ketone bodies also produce acetyl-CoA. Ketone bodies are made in the liver and provide acetyl-CoA to other tissues. Part III will explain why and how. Figure summarizing info so far: https://dl.dropboxusercontent.com/u/37202414/EXPERIMENT-II_SEPT_23.png

The diagram was, of course, technical, but I think the take home message is important so I will give a basic explanation (Biochemistry 101). There are chemical names but I don't discuss the chemistry so you can just learn them as names. Part I. All cells, all organisms, use the same mechanism to process glucose. The process is called glycolysis. The name tells you that it is the lysis (breaking) of glucose. Glucose is a six carbon compound and the lysis gives you two molecules of a three carbon compound called pyruvic acid. (In biochemistry acids are indiscriminately called by the acid name or by an "ate" name. "Pyruvate" and "pyruvic acid" are two names for the same molecule.) so: glucose ---------> pyruvate is the process of glycolysis ( although it has many steps). Part II when i get to real computer.

I would add an optimistic note to Gene's comment. We have ignorance on our side. What I mean is that the subject is so poorly investigated and the potential is very clear. We think that we know how to ask the right questions we are confident that we will get something of value. And, again, grateful for the backing.

Jennifer, I would add to Gene's comment that one of our goals is to see whether we can develop ketogenic diets as a therapeutic adjunct so that chemo or other modalities can be carried out at less toxic levels.

I would add to Gene's comments that researching this question and seeing the lack of information show us just how little information there is on diet at all in cancer therapy. There is some meaning in this in that ketogenic diets are the most reasonable approach and this was not on anybody's radar. That is why we think that results with cancer may actually point the way to better therapy for diabetes and other metabolic disease.

I would not say 'never.' One of the great promises in the ketogenic approach is that it can be used as an adjunct for drugs which may target cellular elements but which are too toxic or have very serious side-effects. We think, for example, that based on the results with diabetes where there is substantial reduction in need for medication on low-carb diets, that all drug studies should have two drug arms with and with carbohydrate reduction. We think this would make the drugs look better and help the patient. This is in a drug company's interest. Experience tells us that they will be slow to see the value in this -- were are trying to obtain funding for such studies and it is slow enough -- but I think that we can do better than 'never.'

We are really grateful and, of course, the research is our main goal but it suddenly hit us that these donations and comments constitute an antidote to all the BS that we have to tolerate.