Metabolic management of cancer

[AlaskaAngel]

On 2/2/07, eric posted a question about DCA (dicholoroacetate) that was interesting. Following that thread, meredith posted another on 3/9/07, and then Christinemhk posted another on 10/4/07.

I too have been interested in the possible metabolic management of cancer, and have initiated threads about recent information regarding the use of metformin for its effects on the mitochondria.

Because of the further posts by Rich that included more info about DCA and other possible clues regarding cancer and metabolic management, I thought I would post this update on DCA that I found. I don't have the current status of DCA, but for those who wonder if the DCA idea "died" as being "too far out" and "too kooky" in comparison to the standard treatment with chemotherapies, or whether the research into DCA has continued to slowly make progress, this is something of an update on DCA.

This research over time into DCA also provides some insight into the controversies about obstruction in the development of better treatments, and whether the system we have for recommending treatments now is self-perpetuating in favoring more toxic treatments, due in part to our desperation at time of diagnosis and our tendency to want to rely on treatments that hit cancer "as hard as possible".

http://scienceblogs.com/insolence/20...oroacetate.php

Because the discussions in those earlier threads were also interesting, here are some of them over time:

http://her2support.org/vbulletin/sho...&highlight=DCA

http://her2support.org/vbulletin/sho...&highlight=DCA

http://her2support.org/vbulletin/sho...&highlight=DCA

http://her2support.org/vbulletin/sho...&highlight=DCA

One way to make better progress with such work as the metabolic management of cancer would be to train endocrinologists to focus specifically on metabolic management of cancer and to sit as members with full authority to make recommendations for treatment on each of our tumor boards. It could provide more humane and less expensive solutions for the generations to come.

AlaskaAngel

[Rich66]

That was an interesting video clip. I was unaware that it took them 2-3 months to get DCA up to a "therapeutic" level.

I had kind of soured on this after coming upon toxicity concerns. But perhaps a slow, gradual introduction helps avoid that. I had also come across info suggesting a range of cancer cell susceptibility to glycolysis approaches..the studied brain cancer being at the top.

Anyway..more here:
DCA Dichloroacetate (glycolysis, research, sources, DNA meth inhib to increase effect/reduce neuropathy)
http://her2support.org/vbulletin/showthread.php?t=26768

And another controversial approach:
3 bromopyruvate (glycolysis inhibitor of high efficacy/controversy, decreases ATP, increases ROS, intra-arterial app)
http://her2support.org/vbulletin/showthread.php?t=41654


And Metformin:
http://her2support.org/vbulletin/showthread.php?t=39740

[Rich66]

Came across this recent article related to DCA:
http://medicalxpress.com/news/2011-1...-cravings.html

[AlaskaAngel]

This seems to be the official site for the Alberta DCA research updates, and the last one seems to have been from May, 2010, but it does give some additional info about what they have been planning for their next steps, pending achieving enough independent funding:

http://www.dca.med.ualberta.ca/Home/FAQS/

[ElaineM]

Personally I think Metformin shows great promise. I have done alot of reading about this. Unfortunately oncologists may not want to give up a piece of the action to other specialists.

[gdpawel]

AlaskaAngel

Ironic that you posted this today. Just the other day, someone on the Inspire board posted about ChemoFit. Chemofit looks like a typical "cell death" assay (which is good), based on flow cytometry (also good).

They obtain fresh "live" specimen (good again) and placed in a formulated sterile collection/transport medium. Looks like it keeps the specimen viable up to 72 hours at room temperature (don't know if it's 3D analysis).

And for optimal results, patient should not have had chemotherapy or radiation therapy within 3 weeks of specimen collection.

They can test conventional drugs singlely and in combinations. Don't see any "targeted" drugs listed (JM Hyatt et al. A Cancer Chemosensitivty Assay. Presented at . Am J Obstet Gynecol 189(5): 1301-7, 2003).

Medicor Cancer Centres (Canada’s first integrated private cancer treatment clinic, which works with DCA in Canada), utilizes ChemoFit.

http://www.medicorcancer.com/dca-therapy.html
http://www.medicorcancer.com/chemofit.html

Greg

[Rich66]

Are the usual suspects aware of Chemofit?
I wonder if they can test DCA on a sample.

[gdpawel]

Other cell-death assay labs in the US have been testing DCA for several years. However, they've never been overly impressed in it being an active agent.

Are you aware of any clinical trials, even presented at a meeting with an abstract? It's getting to be an old drug by now and all there seems to be are anecdotes, to my knowledge. I can't find a single publication of a clinical trial. Am I missing it?

I understand ChemoFit is not 3D analysis. If they're measuring with flow cytometry, it's got to be single cells. And I don't know exactly about their transport medium they are using.

In cell-based functional profiling assays, polypropylene is the stuff that cell culture plates are made out of. Polypropylene keeps the tumor clusters in a 3D conformation. With typical cell culture plate plastic, the cells would attach and spread out into a 2D conformation.

[Rich66]

I wonder if DCA is more like endocrine therapies...takes too long to work for cell death assays oriented toward chemo effects.

Seems DCA has had $$ problems in terms of pursuing large trials.

Observational DCA Data
For the first time in the world, on Dec 7, 2007 we publicly shared our observational data from the treatment of 118 cancer patients with DCA. We updated our data in 2009 from treating over 347 patients. This can be found here. As of Oct 2011, we have treated over 800 cancer patients with DCA, the most of any center in the world. Since clinical trial data is now emerging, we are no longer collecting observational data. Instead, we are focusing our efforts on publishing our findings in reputable peer-reviewed medical journals. Our first publication is: "Use of Oral Dichloroacetate for Palliation of Leg Pain Arising from Metastatic Poorly Differentiated Carcinoma: A Case Report." This can be viewed here.

Medicor mentions using DCA with other treatments:

We have noted that DCA by itself does not appear to be as effective (or curative) compared to combination therapy. When we initially started DCA therapy, most patients took DCA by itself. We observed that in patients who showed a positive response initially, DCA had to be stopped either due to side effects or because it started to lose its effectiveness. By adding supplements like alpha liopic acid, adjusting the dose and having a non-continuous DCA regimen we have managed to reduce the side effects to a more tolerable level. While patients started experiencing more tolerable and reversible side effects, the loss of effectiveness of DCA was troubling. Change in dose was not able to reverse this effect for long leading us to discontinue DCA treatment. However, when we started combining DCA with other treatments like TM therapy, we found that treatment could be continued for much longer and was more effective.
We have now started using DCA more in combination with other treatments (e.g. chemotherapy, TM, ribavirin, radiation therapy etc.) and have observed more favorable responses. For combination with chemotherapy we strongly recommend a ChemoFit test to determine effectiveness. While there are no general criteria to predict if patients will respond to DCA or a combination therapy with chemo, a ChemoFit test can provide very sensitive and specific response information for the individual patient.
Our two cases of complete remission both took combination therapy. More information about these cases are available on the Case Reports pages.

[gdpawel]

Rich

They've treated 800 patients and the best they have is a case report? And the report is pain palliation? You can palliate pain by giving morphine. And the only way they can get real responses is by combining it with real chemotherapy?

What I'm getting from US cell-death assay labs is DCA really doesn't work. They gave it a good honest effort, but the drug has no activity. I remember giving them the suggestion of trying DCA and where to obtain it.

I recall that the first inkling of activity was that it was supposed to produce cell death in the "Yale Apoptosis Assay" (caspase expression). But the paper was a dud. The drug is a dud. They treated 800 patients and got a total of 2 CRs and those patients also got "real" chemotherapy.

A dud is a dud. It's like that molecular profiling research study from 2010. They got a grand total of 3 actual responses (actual, significant tumor shrinkage) out of about 66 patients treated and close to 85 assayed. If any other assay-directed clinical trial did that badly, they'd have been out of work 20 years ago. However, they were able to do and publish an actual clinical trial, courtesy of a $5 million gift. You have to give them credit for their philanthropy!

Greg

[Rich66]

Perhaps you are focusing too much on assays which may not show results from a metabolic (or endocrine) approach.

Did you watch the video clip on glio? Here they mention it taking months to achieve therapeutic dosing...far longer than a cell assay would track.

Did you look at this: http://www.medicorcancer.com/dca-data.html

You brought attention to the fact that medicor does both assay as well as DCA work. Perhaps they have some thoughts on this intersect.

Seems it might be premature to call duds.

[gdpawel]

Perhaps! But it has come up a dud in cell function analysis.

[Rich66]

Maybe snapshot vs movie............

[AlaskaAngel]

I appreciate the discussion, wherever it leads.

"Standard therapy" continues to require massive amounts of human and economic resources, and is not even available to so many cancer patients throughout the world.

As long as there is no therapy to offer that is predictable and measurable in effect on an individual basis, a careful and more complete understanding of the conversion of energy in fueling cell development and death makes sense to me, whether it involves DCA or something like metformin--or even both.

A.A.

[gdpawel]

A.A.

In regards to DCA (the subject), it wasn't originally purported to be some sort of growth factor intercepting agent, it was supposed to induce apoptosis (cell death), as determined in a short term assay (like cell death assays). At the time these labs were testing it, this was how it was purported to work. They never found it to have meaningful activity. Not so much as a single case where it worked well. I was surprised, but at least they took the effort to look into it.

Greg

[Rich66]

Greg,
seems like current cell tests are suggesting activity:
http://www.ncbi.nlm.nih.gov/pubmed?t...0acid%20cancer


AA,
Targeting more than one metabolic mechanism seems to have merit: http://www.ncbi.nlm.nih.gov/pubmed/22093145

CONCLUSION:

This study is the first to demonstrate that targeting two key metabolic hallmarks of cancer is an effective anti-cancer strategy with therapeutic potential.

An evolving approach to speed up identification of possible therapies..found a fair amount of candidates in diet drugs:
http://www.hemonctoday.com/article.aspx?rid=90966

although a small quantity (12%) of antineoplastic drugs showed activity in the thyroid cancer cells, more than 25% of anti-obesity and cardiotonic drugs demonstrated potent activity.

[Rich66]

Int J Cancer. 2011 Mar 1;128(5):1001-8. doi: 10.1002/ijc.25728. Epub 2010 Dec 7.
Anticancer drugs that target metabolism: Is dichloroacetate the new paradigm?

Papandreou I, Goliasova T, Denko NC.

LINK

Source

Department of Radiation Oncology, Division of Radiation and Cancer Biology, Stanford University School of Medicine, Stanford, CA, USA.

Abstract

Recent findings in the fields of oncogenic regulation of metabolism, mitochondrial function and macromolecular synthesis have brought tumor metabolism and the Warburg effect back into the scientific limelight. A number of metabolic pathways that seem to be important for tumor growth are being touted as novel targets for anticancer drug development. One of the candidates in this class of drugs being investigated is dichloroacetate (DCA), a molecule used for over 25 years in the treatment of children with inborn errors in mitochondrial function. This pyruvate mimetic compound stimulates mitochondrial function by inhibiting the family of regulatory pyruvate dehydrogenase kinases (PDK1-4). The stimulation of mitochondrial function, at the expense of glycolysis, reverses the Warburg effect and is thought to block the growth advantage of highly glycolytic tumors. Interestingly, some of the recent in vitro findings have shown very modest "antitumor cell activity" of DCA when cells are treated in a dish. However, several studies have reported "antitumor activity" in model tumors. This apparent paradox raises the question, how do we evaluate cancer drugs designed to target tumor metabolism? Traditional approaches in cancer drug development have used in vitro assays as a first pass to evaluate potential lead compounds. The fact that DCA has better in vivo activity than in vitro activity suggests that there are unique aspects of solid tumor growth and metabolism that are difficult to recapitulate in vitro and may be important in determining the effectiveness of this class of drugs.
Copyright © 2010 UICC.

[gdpawel]

Rich

Those are all just studies showing some perturbation of non-clinical laboratory systems. You can find the same sorts of stuff on pomegranate juice and garlic (or just about anything that you care to think about, e.g. see below).

The proof of the pudding is that they treated 800 patients and got 2 (two) CRs and both of those patients got real chemotherapy, in addition to DCA and that DCA only produces "benefits" in patients who also receive real chemotherapy.

That's the track record of every quack remedy which gets promoted for cancer use. It wasn't a quack remedy until they treated their first 25 patients, but it's certainly a quack remedy after they've treated 800 and only got what they now admit that they got.

e.g.

http://www.ncbi.nlm.nih.gov/pubmed?term=garlic%20cancer

http://www.ncbi.nlm.nih.gov/pubmed?t...anate%20cancer

http://www.ncbi.nlm.nih.gov/pubmed?t...tract%20cancer

http://www.ncbi.nlm.nih.gov/pubmed?t...20oil%20cancer

http://www.ncbi.nlm.nih.gov/pubmed?t...otein%20cancer

http://www.ncbi.nlm.nih.gov/pubmed?t...20tea%20cancer

http://www.ncbi.nlm.nih.gov/pubmed?t...elion%20cancer

This paper suggests that not only does DCA not work very well, it also has the ability to antagonize the activity of real chemotherapy drugs which do work.

http://www.ncbi.nlm.nih.gov/pubmed/20502900

The conclusion remains the same. The drug is a dud.

Greg

[Rich66]

Understanding CR is not the only criteria of benefit and just so we're referencing the same info:

106 patients (60%) showed a positive response to DCA. Similar to our previous analyses, we have divided the positive responses into the following five categories based on the degree of clinical benefit. The categories below are not mutually exclusive since patients may have had a combination of positive responses while on DCA. For example a patient who had a reduction in tumour size and symptomatic improvement is counted in both categories 1 and 4. For this reason, the numbers below do not add up to 106. This presents an overall picture of the responses to DCA.

• Category 1: Reduction in tumour size/complete tumour regression. Seen in 21 patients (12%). We are very excited to report that in 2 patients (1%) we have seen complete remission of metastatic cancer. The other 19 patients (11%) had measurable tumour reduction which was demonstrated by imaging studies and/or direct tumour measurement.
• Category 2: Reduction in tumour markers. Seen in 16 patients (9%). These patients had a reduction in markers such as CEA, CA-125, CA19-9, CA15-3 or AFP. These types of blood markers are typically used to monitor certain cancers such as colon, ovarian, prostate, pancreatic, lung, liver, or breast.
• Category 3: Improvement in blood tests. Seen in 12 patients (7%). These included improvements in hemoglobin, liver enzymes, albumin, and other tests indicating reduced tissue damage or reduced cancer activity that could not be explained by other events or medications.
• Category 4: Symptomatic improvement. Reported in 52 patients (29%). This included significant pain reduction, relief of bowel obstruction, weight gain, improved appetite and improved energy level. These improvements were sustained for a period of more than 4 weeks, thus making it unlikely to be a result of placebo effect.
• Category 5: Disease stabilization. Seen in 61 patients (34%). In these patients, there was no evidence of cancer progression while taking DCA, where progression would otherwise have been expected.

Consider most patients likely exhausted conventional therapies. And the concession to rapid evaluation:

the 4 week cutoff likely underestimates true DCA response. We have seen patients improve only after 8 weeks of DCA treatment in some cases.

By the way, if something is only beneficial in combination..if the net benefit is greater..that's still worth pursuing.

And similar to "real chemotherapy", the particular makeup of the cancer cell (dependence on glycolysis) may make a huge difference..as in the gliomas mentioned in the presser. I suppose Michelakis et al could be complete frauds making up the results to keep their labs funded. But some of this reminds me of how Herceptin nearly got written off.

[gdpawel]

DCA only produces "benefits" in patients who also receive real chemotherapy.

The primary reason for Her2/neu testing in breast cancer is to determine who is most likely to benefit from Herceptin, which is directed against the Her/neu protein. However, the potential benefits and risks of Herceptin have renewed concerns about the reliability of Her2/neu testing and oncologists should be concerned about it. Some studies have shown that the test produces false positives as often as 26% of the time, and may also carry some risk of false negatives.

Aetna and United Healthcare put out an announcement a few years ago that said if there’s uncertainty about the accuracy of a test that breast-cancer patients get, the insurer will cover a do-over. The insurers were trying to draw more attention to the issue. They certainly were trying to promote awareness of the problem, and if there is uncertainty, then repeat it.