important discovery from Harvard --leading to new selective targeting of cancer

[Lani]

Attacking Cancer's Sweet Tooth Is Effective Strategy Against Tumors Mice Lacking Sugar-Metabolizing Pathway Outlive Four-Month Experiment [Harvard Medical School]
BOSTON, MA-An ancient avenue for producing cellular energy, the glycolytic pathway, could provide a surprisingly rich target for anti-cancer therapies. A team of Harvard Medical School (HMS) researchers knocked down one of the pathway's enzymes, LDHA, in a variety of fast-growing breast cancer cells, effectively shutting down glycolysis, and implanted the cells in mice. Control animals carrying tumor cells with an intact glycolytic pathway did not survive beyond 10 weeks. In striking contrast, only two of the LDHA-deficient mice died, one at 16 weeks, another at just over 18 weeks. Eighty percent of the mice outlived the four month experiment. The findings by Valeria Fantin, Julie St-Pierre, and Philip Leder appear in the June Cancer Cell.

"This is an exciting contribution that reveals a surprising Achilles heel in cancer cells. It also adds to our sense of opportunity for new avenues of cancer therapeutics," said Stuart Schrieber, Morris Loeb professor and chair of the Department of Chemistry and Chemical Biology at Harvard University.

As a tumor grows, cells crowd one another and may be cut off from oxygen-carrying blood vessels—a distinct disadvantage since most cells require oxygen to produce the bulk of their energy-storing adenosine triphosphate (ATP). In the 1920s, Otto Warburg proposed that some cancer cells evolved the ability to switch over to an ancient, oxygen-free route, the glycolytic pathway. What is more, they continue to use this pathway even when access to oxygen is restored. Though the so-called Warburg effect has since been confirmed, the role played by glycolysis in cancer has been largely ignored. Few have attempted to attack specific points along the glycolytic pathway to gain a therapeutic effect.

"LDHA could be one weak point that we could attack but maybe, if we understand exactly all the steps involved, we could devise alternative strategies to attack the same pathway," said Fantin, who was an HMS research fellow in genetics when the study was performed. She is currently a research scientist at Merck & Co.

What may excite the growing band of researchers who are studying the Warburg effect, and cancer metabolism more generally, is the way the study resolves a long-standing debate about how and why cells switch to glycolysis in the first place. Warburg speculated that cancer cells change over to glycolysis, which occurs in the cytoplasm, because the mitochondria, where oxygen-dependent ATP synthesis occurs, are defective. But the mitochondria of cancer cells appear to be mostly intact, which led many researchers to minimize the importance of the glycolytic switch.

The mitochondria do display an intriguing difference, however. Normally, mitochondria turn glucose into ATP through the oxygen-dependent process of oxidative phosphorylation (OXPHOS). This results in the expulsion of protons, which lowers the mitochondria's membrane potential. Curiously, the mitochondria of cancer cells exhibit a high membrane potential. Researchers suspected that was because the cells have switched to an alternative means of producing ATP, namely glycolysis, but it was not clear if the glycolytic and mitochondrial pathways were connected in this fashion.

It appears the two pathways are reciprocally linked. Fantin and her colleagues found that by shutting down the glycolytic pathway (through the knock down of LDHA), they could lower the mitochondrial membrane potential of tumor cells. What is more, oxygen consumption increased in the knockdown cells, suggesting they were reverting to the mitochondrial OXPHOS pathwayÑa kind of Warburg effect in reverse.

"The findings provide us with an insight into a mechanism that had been suspected in the last six or seven decades," said Leder, John Emory Andrus professor and chair of the Department of Genetics at HMS. Knocking out the glycolytic pathway could deliver a big blow to tumor cells.

"LDHA could be one weak point that we could attack but maybe, if we understand exactly all the steps involved, we could devise alternative strategies to attack the same pathway," Fantin said.

What makes the prospect of anti-glycolytic therapies even more attractive is their potential safety.

Healthy cells meet 90 percent of their energy needs through OXPHOS. People who lack the LDHA enzyme appear to function normally though they cannot be pushed toward anaerobic exercise.

"They have muscle destruction because they lack an alternative route for producing energy," Fantin said. It is not clear whether they have a lower indidence of cancer.

Also appealing is the idea of combining anti-glycolytic therapies with anti-angiogenic ones.

"If you have a molecule that is very stable you could think about delivering it first, obliterating the glycolytic pathway," said Fantin. Angiogenesis inhibitors would wipe out blood vessels and the oxygen supply with it, leaving the cells with no way to cope. "There is definite potential to combining these things," she said.


ABSTRACT: Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance [Cancer Cell; Subscribe]
Alterations in cellular metabolism are among the most consistent hallmarks of cancer. Herein we have investigated the relationship between increased aerobic lactate production and mitochondrial physiology in tumor cells. To diminish the ability of malignant cells to metabolize pyruvate to lactate, lactate dehydrogenase A (LDH-A) levels were knocked down by means of LDH-A short hairpin RNAs. Reduction in LDH-A activity resulted in stimulation of mitochondrial respiration and decrease of mitochondrial membrane potential. It also compromised the ability of these tumor cells to proliferate under hypoxia. The tumorigenicity of the LDH-A-deficient cells was severely diminished, and this phenotype was reversed by complementation with the human ortholog LDH-A protein. These results demonstrate that LDH-A plays a key role in tumor maintenance.

[CLTann]

Would someone translate to the simple daily language from above? Can we simply say that if our diet is free of sugar, we will be better off? How about starch, which quickly converts into glucose in our body? Those high-sounding words just confuse me.

The above also suggests that exercise is good for us, is that right?


Ann

[Lani]

I would therefore hope you wouldn't run away from big words and abbreviations

Also, that you would remember from your basic biochemistry (mine was 34 years ago) that all food sugar,starch, fat, protein is broken down to glucose before it can be used.

There are two ways the body can use glucose for energy--one pathway uses oxygen to burn it (oxidative phosphorylation) and the other is only used when not enough oxygen is available (in a runner who runs past their aerobic capacity or a tumor cell which has outgrown its blood supply).

This article does not advocate or even address whether exercise is good for cancer.

Sorry to sound so School-marmish, but many if not most of those who read these posts have FAR LESS FORMAL EDUCATION IN THE SCIENCES THAN YOU.

Those faced with recent diagnoses, recent recurrences or just plain fear of the unknown have many justifiable reasons to wish to avoid reading posts with too much scientific lingo or concepts. Many just don't have the background.

Many put a LOT of effort in and become self-taught and do REMARKABLY WELL understanding the complicated biology of new findings regarding breast cancer.

I posted this in the main forum as it was a major change to how cancer may be attacked.

I have been asked to, and previously provided, "translation" of abstracts which were deemed too technical and have done so. In this case, I provided the general article from the press along with the abstract, hoping the medical writer would know how to provide knowledge at a level helpful to all.

I often feel oncologists don't want to be scientists but rather go the easy way and follow a "recipe" unaltered ie, give a for b, c for d, e for f without modification or engaging their mind as if there might be a better treatment for any individual patient.

Your attitide--don't give me long words, just tell me what to do--is the patient's equivalent--don't give me details or reasons, just tell me what to do. This is perilous in the case of cancer, as dogmatic "knowledge " frequently proves wrong a few years later, making understanding of science (which helps one understand whether something intuitively "makes sense") all the more important in decision-making. ie, since more is unknown than known, educating yourself about recent discoveries helps when time comes to make decisions.

Perhaps you are just fed-up today, perhaps you had some bad news. I really think this article is GOOD NEWS. See if you can get past the "high-sounding words" and realize that this article has nothing to do with what you should or shouldn't eat, rather it shows the way to how to develop drugs which will effect only the cancer cells (AS NORMAL CELLS ONLY USE THIS PATHWAY 10% OF THE TIME) IN SUCH A FUNDAMENTAL WAY, THAT IT IS HIGHLY UNLIKELY THEY WILL FIND A WAY TO MUTATE TO GET AROUND THE TARGETTED ATTACK.

AGAIN, I am sorry to "lay it on" but many put lots of effort into trying to understand this disease and I had hoped your background would make this less of an effort in your case than in that of the majority.

[RhondaH]

I appreciate them.

Rhonda Hoffman
Personal Lines Underwriter

[CLTann]

Lani,

I do appreciate your postings and made an effort to understand the important implication of the Harvard research work. However, even with my meager pharmacist training and educational background, I frankly have difficulty in grasp the whole picture. From the view of an average population of this group, I tried to write you for easy and simple clarification.

The title of the article is very clear. Sweet tooth route is now found to be a clue for cancer amplication, leading death to many mice in that group. As we go into the article further, I got lost in the development of confirmation of the hypothesis. Thats where I ask for a simple clarification.

It is the very point that I believe this article is very significant and should be read with care that I made my request so that others less exposed to medical terms can see its importance. Hopefully, we all can immediately benefit from the conclusion, admittedly not well established conclusion.

If staying away from sugar will benefit all of us, why wait for several years before its confirmation? That step is not a difficult and harmful one anyway.

I do see the merit of your argument and the complexity of the disease, but if a simple advice can be added now, why not?


Ann

[Mary Anne in TX]

I love reading all the information, no matter how technical. I find if I just keep reading that I eventually get it! Maybe it's the ol' librarian in me loving to do research! But thanks a million for any and all information. It feeds my hope in large doses!

[CLTann]

Further thought on the subject.

If glucose is the culprit in the disease process, as the article implies, I am wondering how can anyone avoid to have this life supporting intermediate in one's system. As we all know, all foods go through our body and convert into glucose. Then, how could any experiments be conducted while maintaining the nutrition requirement of the animals?

Ann

[Christine MH-UK]

There has been some very promising work on mice using 3-bromopyruvate, which interferes with glycosis in liver cancer, and this article I just found on the internet from the May 2006 edition of Science Magazine mentions a few others that interfere with the energy dynamics in cancer cells. These drugs are at various stages of development, including some already in clinical trials. At one point it quotes two scientists who say that glycosis seems to be a factor in the survival of tumors rather than the origins of tumors. Unfortunately, it also makes clear that not all cancers are glycolytic, only about 60% to 90%, so won't cure all cancer patients, even if it works really well.


http://www.usuhs.mil/alumni/energydereg.pdf

[MJo]

"If glucose is the culprit in the disease process, as the article implies, I am wondering how can anyone avoid to have this life supporting intermediate in one's system."

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I'm wondering too, since I already live without estrogen. LOL. MJO

[Christine MH-UK]

This is from the Science article and shows how drugs might use a cancer cell's dependence on glycolysis against it. I have highlighted a sentence that I think is very important, since it shows that they are trying to find substances that make it difficult for cells to use glucose.

"Drugs targeting tumor bioenergetics are on the way. Most exploit a tumor's increased reliance on glycolysis. Threshold Pharmaceuticals Inc., a biotech company in South San Francisco, California,is already testing two such drugs in cancer patients: a chemotherapy compound conjugated to glucose, and a glucose analog that cannot be metabolized, thus shutting down glycolysis. Hexokinase, because it catalyzes the first step in glycolysis and can block cell death, is another key target. Hay, for example, proposes that drugs causing hexokinase to separate from mitochondria could treat cancer, by both damping down glycolysis, indirectly blocking a signaling enzyme is another strategy. In 2004, Johns Hopkins researchers reported that a hexokinase inhibitor, 3-bromopyruvate, completely eradicated advanced glycolytic tumors in all mice treated. Chemists at the M. D. Anderson Cancer Center in Houston, Texas, are now developing 3-bromopyruvate analogs for eventual clinical trials. Other potential drug targets exist. Last year, Thompson identified an enzyme, ATP citrate lyase, that allows cancer cells to overcome a natural check on glycolysis. Inhibiting it blocks growth of tumors in mice. And this March, Dang and Nicholas Denko of Stanford University in California separately reported that another enzyme, pyruvate dehydrogenase kinase (PDK), acts to shut down mitochondrial respiration and protect cells in low-oxygen conditions. "One can imagine that by blocking PDK activity we can actually trigger cells to commit suicide," Dang says. Compounds that limit glycolysis would, in theory, kill cancer cells while sparing normal cells, which can burn amino acids and fatty acids for energy. "When [cancer] cells are engaged in highthroughput aerobic glycolysis, they become addicted to glucose," says Thompson. "So if you suddenly take away their ability to do high-throughput glucose capture and metabolism, the cell has no choice but to die.""