The History of Cancer Metabolism

 

Otto Warburg and the Nobel Prize in 1931

Dr. Warburg was a physician and a scientist in Germany. Warburg earned his doctorate of chemistry in Berlin in 1906 and doctorate of Medicine in Heidelberg in 1911. He started his work as a professor at the Kaiser Wilhelm Institute for Biology.

Warburg investigated the metabolism of cancer cells. Warburg knew that cancer cells grew much faster than normal cells. He did not know, however, how the cancer cells generate the large amount of cellular energy the cells need to sustain the abnormally high rate of growth.

Eventually, Warburg discovered that cancer cells turn on certain enzymes in the cell to generate more energy. In normal cells, energy is generated by breaking down the glucose. This process is known as the glycolysis. Glycolysis is usually a slow process. Warburg noticed that the rate of glycolysis is much faster in cancer cells. Digging further, he discovered enzymes that are normally “off” in glycolysis are “on” in cancer cells. Warburg named his observation the “Warburg effect.”

Medical Application of Warburg effect

 

Medical Imaging

One of the medical applications of the Warburg effect is cancer imaging. To detect cancer cells, a patient is injected with radioactive glucose. A CT or NMR machine can detect radioactive signals emitted by radioactive glucose molecules. Upon injection, the cells in the body take up the radioactive glucose molecule. Because of the Warburg effect, cancer cells take up a lot more radioactive glucose molecules than normal cells. Observing the different rate of radioactive emissions, a CT or NMR scan distinguishes cancer cells from normal cells.

 

Current state of anti-cancer drug

For most of the 20th century, the Warburg effect has been overlooked and ignored as a possible strategy to kill cancer cells. Instead, drug companies exclusively focused on developing anti-cancer drugs that target DNA replication. DNA replication is an essential step of cell division. Drugs that disrupt DNA replication kill the cells because cells commit suicide when DNA replication fails. These drugs were effective in killing cancer cells. Unfortunately, these drugs also killed normal cells by indiscriminatingly disrupting all manners of DNA replication, whether it was for normal cells or for cancer cells. These drugs had huge side effects by killing fast dividing normal cells, e.g., hair cells, gut cells, liver cells, immune cells, and blood cells. The outcome was, and has been, that the battle against cancer is won, but the battlefield is ravaged, and the patient dies from complications and organ failures due to the death of normal cells. Unfortunately, most mainstream chemotherapy drugs to this date are still DNA replication inhibitors.

There have been other drugs targeting specific enzymes that have gone rogue (by mutation). For example, Gleevac targets a very specific mutant of a cellular enzyme. These drugs work well for cancers caused by a very specific mutation. The downside of these drugs is that cancer cells continue mutating, and render these drugs ineffective. Just like a new flu vaccine is needed every year because of rapid mutation of flu virus, drugs that target specific mutations stop working because cancer cells mutate over time.

In the late 20th century, drug companies switched to a new strategy, targeting cancer cells using antibodies. Antibodies specifically trained to kill only cancer cells reduced the side effects significantly, as the antibodies only kill the cancer cells. These drugs were, however, extremely expensive to manufacture and took very long time to develop. Because of the huge upfront development costs, drug companies have been reluctant to develop antibody drugs unless there is a broad enough market to justify billions of dollars or more in sales.

 

Anti-cancer drug targeting cancer metabolism

The next generation anti-cancer drugs take advantage of the Warburg effect. More than a handful of enzymes specifically associated with the Warburg effect, that is, enzymes only turned on in cancer cells, but not in normal cells, have been identified. Theoretically, shutting down these enzymes will either slow the growth of cancer cells or kill the cancer cells by implosion.[1] A Pubmed search of medical literature resulted in more than 800 research papers, reporting on various effects of shutting down the cancer metabolic pathways. These observations include laboratory studies, animal studies, and certain human clinical trials. There are biotech startups developing the next generation drugs targeting cancer metabolism.

 

MetabloxTMuntitled-55

Metablox is a formulation that specifically kills cancer cells by shutting down the cancer metabolism. Metablox is administered by intravenous injection. Upon injection, key ingredients of Metablox are taken up by cancer cells. They then stick to the enzymes necessary to maintain high levels of energy production, and impair them. In response, the cancer cells, due to the loss of their energy production mechanism, trigger apoptosis and die.

 

What types of cancer can Metablox treat?

As Metablox targets cancer metabolism, which is common to any and all forms of cancer, Metablox can be used for any types of cancer in theory. As an experimental drug, it has only been offered to terminal cancer patients who ran out of standard FDA-approved options. As terminal stage patients, these patients had advanced metastasis. Thus, treatment follow-ups through imaging were focused on controlling metastasis in the liver and large tumors pressing against vital organs. A list of cancers that Metablox have been used, and found effective, includes cancers of the lung, including SCLC and NSCLC, colon, ovary, pancreas, and kidney (renal carcinoma). Other types include sarcomas in various regions, glioblastoma, and astrocytoma.

 

What are the side effects of Metablox?

The side effects of taking Metablox are minimal as compared to traditional anti-cancer drugs. Of the patients so far, no serious adverse reaction was observed. There was one case of grade 1 anemia, one case of erythema, and five cases of mild nausea that required no further treatment. In certain patients with very large tumor burden, laboratory signs of tumor lysis syndrome (TLS) were observed. TLS is now treated prophylactically by giving the patient a dose of anti-TLS medicine, and since adding this to the protocol, no TLS has been observed.

 

How many have tried Metablox so far?

About 50 from U.S. and Europe.

 

What are the clinical outcomes of the patients who have tried?

We have not documented their outcomes in a systematic way other than their survival. More than 90% of the patients have lived and are still living beyond their doctors’ prediction. More importantly, because of almost nonexistence of side effects, the patient’s quality of life has been dramatically improved.

 

How long is the treatment?

The treatment is an intravenous infusion. A patient goes through five infusions per week for three weeks. After having one or two weeks break, the three-week cycle is repeated twice more. As a total, a patient goes through nine-week treatment roughly over three months.

 

Where can I get Metablox?

Dr. Kevin Bethel, and his staff are doing Phase 2 clinical trials with Metablox and can be contacted here.

[1] Cells have a mechanism, known as apoptosis, that commit suicide when something is wrong with them. Disrupting energy supply of a cell is one of the ways known to trigger apoptosis.

 

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