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/2010/05/evangelos_michelakis_on_dichloroacetate.php

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

http://her2support.org/vbulletin/showthread.php?t=26946&highlight=DCA

http://her2support.org/vbulletin/showthread.php?t=27423&highlight=DCA

http://her2support.org/vbulletin/showthread.php?t=27622&highlight=DCA

http://her2support.org/vbulletin/showthread.php?t=30369&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/2011-12-enzyme-flips-cells-sugar-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 (http://www.medicorcancer.com/dca-data.html). 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 (http://www.liebertonline.com/doi/pdfplus/10.1089/jpm.2010.0472).


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 (http://www.medicorcancer.com/dca-reports.html).

[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 (http://scienceblogs.com/insolence/20...oroacetate.php) 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?term=Dichloroacetic%20acid%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. (http://www.ncbi.nlm.nih.gov/pubmed/20957634#) 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 (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Papandreou%20I%22%5BAuthor%5D), Goliasova T (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Goliasova%20T%22%5BAuthor%5D), Denko NC (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Denko%20NC%22%5BAuthor%5D).

LINK (http://dx.doi.org/10.1002/ijc.25728)

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?term=pomegranate%20cancer

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

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

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

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

http://www.ncbi.nlm.nih.gov/pubmed?term=dandelion%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 (http://scienceblogs.com/insolence/2010/05/evangelos_michelakis_on_dichloroacetate.php). 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.

[Rich66]

That's interesting info about Her2 testing. But what part of the site says only patients receiving "real" chemo have benefit? I found this (http://www.medicorcancer.com/dca-data.html) which is not so clearcut:

We are treating more patients with combination therapy (DCA + 1 or 2 other drugs) and feel more confident now that DCA works better in combination with other agents than by itself over a prolonged time period.I believe the glioma cases (http://scienceblogs.com/insolence/2010/05/evangelos_michelakis_on_dichloroacetate.php) were monotherapy.

Regarding the interference with chemos, even within platinums, seems there are studies on both sides of the issue.

http://www.springerlink.com/content/a570v5561073g130/

multicellular spheroidal growth, as observed in the H835 cell line and pulmonary tumourlets, seems to increase chemoresistance markedly. The activity of carboplatin and JM118 is significantly and specifically increased in combination with the apoptosis sensitiser DCA that promotes mitochondrial respiration over aerobic glycolysis. In summary, among the novel platinum drugs satraplatin has the potential for treatment of lung carcinoids and DCA potentiates the cytotoxicity of selected platinum drugs.

[gdpawel]

One way to tackle a tumor is to take aim at the metabolic reactions that fuel their growth. But a report in the February Cell Metabolism, a Cell Press Publication, shows that one metabolism-targeted cancer therapy will not fit all. That means that metabolic profiling will be essential for defining each cancer and choosing the best treatment accordingly, the researchers say.

The evidence comes from studies in mice showing that tumors' metabolic profiles vary based on the genes underlying a particular cancer and on the tissue of origin.

"Cancer research is dominated now by genomics and the hope that genetic fingerprints will allow us to guide therapy," said J. Michael Bishop of the University of California, San Francisco. "The issue is whether that is sufficient. We argue that it isn't because metabolic changes are complex and hard to predict. You may need to have the metabolome as well as the genome."

Just as a cancer genome refers to the complete set of genes, the metabolome refers to the complete set of metabolites in a given tumor.

The altered metabolism of tumors has been considered a target for anticancer therapy. For instance, tumors and cancer cell lines consume more glucose than normal cells do, a phenomenon known as the Warburg effect. There has often been the impression that such changes in metabolism are characteristic of cancers in general, but cancer is a genetically heterogeneous disease. The team led by Bishop and Mariia Yuneva wondered how metabolism might vary with the underlying genetic causes of cancer.

They found in mice that liver cancers driven by different cancer-causing genes (Myc versus Met) show differences in the metabolism of two major nutrients: glucose and glutamine. What's more, the metabolism of Myc-induced lung tumors is different from Myc-induced liver tumors.

"Our work shows that different tumors can have very different metabolisms," Yuneva said. "You can't generalize."

Bishop and Yuneva say their findings also highlight glutamine metabolism as a potential new target for therapy in some tumors, noting that the focus has been primarily on glucose metabolism. Interestingly, the data shows that a version of a glutaminase enzyme normally found in kidney cells turns up in cancerous liver cells. That means there might be a way to attack the metabolism of the cancer without damaging normal liver tissue.

"We shouldn't lose sight of the rather immediate therapeutic potential," Bishop said.

The researchers will continue to inventory metabolic variation in mouse models. Ultimately, they say it will be important to catalogue the metabolic variation in the much more complex, human setting.

References: Cell Press

[Rich66]

Perhaps teh two states are anabolic and catabolic. Maybe existing drugs can address both: Metformin and Chloroquine
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272257/?tool=pubmed

Uncoupling parasitic cancer metabolism. Drugs such as chloroquine (which inhibits autophagy) and metformin (which inhibits lipolysis), will prevent energy transfer to cancer cells and tumor growth.


the anticancer activity of metformin may stem from its antimitochondrial activity, thereby preventing cancer cells from using the energy-rich onco-metabolites (L-lacate, ketones, glutamine and fatty acids) derived from the tumor stroma.

[gdpawel]

Dr. Robert Nagourney
Medical and Laboratory Director
Rational Therapeutics, Inc.
Long Beach, California

In many ways the era of targeted therapy began with the recognition that breast cancers expressed estrogen receptors, the original work identified the presence of estrogen receptors by radioimmunoassay. Tumors positive for ER tended to be less aggressive and appear to favor bone sites when they metastasized. Subsequently, drugs capable of blocking the effects of estrogen at the estrogen receptor were developed. Tamoxifen competes with estrogen at the level of the receptor. This drug became a mainstay with ER positive tumors and continues to be used today, decades after it was first synthesized.

Recognizing that some patients develop resistance to Tamoxifen, additional classes of drugs were developed that reduced the circulating levels of estrogen by inhibiting the enzyme aromatase, this enzyme found in adipose tissue, converts steroid precursors to estrogen. Despite the benefits of these classes of drugs known as SERMS (selective receptor modulators), many patients break through hormonal therapies and require cytotoxic chemotherapy.

With the identification of HER-2 amplification, a new subclass of breast cancers driven by a mutation in the growth factor family provided yet a new avenue of therapy – trastuzumab (Herceptin). For HER-2 positive breast cancers Herceptin has dramatically changed the landscape. Providing synergy with chemotherapy this monoclonal antibody has also been applied in the adjuvant setting offering survival advantage in those patients with the targeted mutation.

Reports from the San Antonio breast symposium held in Texas last December, provide two new findings.

The first is a clinical trial testing the efficacy of pertuzumab. This novel monoclonal antibody functions by preventing dimerization of HER-2 (The target of Herceptin) with the other members of the human epidermal growth factor family HER-1, HER-3 and HER-4. In so doing, the cross talk between receptors is abrogated and downstream signaling in squelched.

The second important finding regards the use of everolimus. This small molecule derivative of rapamycin blocks cellular signaling through the mTOR pathway. Combining everolimus with the aromatase inhibitor exemestane, improved time to progression.

While these two classes of drugs are different, the most interesting aspect of both reports reflects the downstream pathways that they target. Pertuzumab inhibits signaling at the PI3K pathway, upstream from mTOR. Everolimus blocks mTOR itself, thus both drugs are influencing cell signaling that channel through metabolic pathways PI3K is the membrane signal from insulin, while mTOR is an intermediate in the same pathway.

Thus, these are in truest sense of the word, breakthroughs in metabolomics.

[Rich66]

The link where you can comment and subscribe as well:
http://robertanagourney.wordpress.com/2012/03/03/a-new-target-in-breast-cancer-therapy/

[gdpawel]

According to Dr. Neil Love's Research To Practice, it used to be that the formal publication of an important new oncology data set generally took a year or more with snail mail peer review and revisions. These types of delays still occur, particularly when the authors and reviewers disagree on the meaning of the data. However, in 2012 things seem to be usually a lot different, as seen in this past December New England papers reporting the full results from the CLEOPATRA trial evaluating pertuzumab in HER2-positive metastatic breast cancer (mBC) and the BOLERO-2 study of everolimus plus exemestane in ER-positive mBC. Both appeared in press almost simultaneously with their presentation in San Antonio.

[Jean]

So at the end of the current day doctors are offering what they know in trials to be working or not working depending on the patient and their own personal
genetic response to treatment. While I believe all of us want a non toxic treatment that works and does the job
I can't help but consider this thought.

Years prior to the development of many of our current chemo drugs - when patients were dx. with the cancer it was a death sentence. Today we have patients surviving stage 4 cancer.

When it comes to options for cancer treatment, chemotherapy is often at the top of the list. Although the process is often life-saving, it does not come without its share of side effects. Many of the side effects of chemotherapy generally stop once treatment has completed; however, some side effects may take longer to heal, or may not heal at all. According to the National Cancer Institute, the severity of each side effect generally depends on what type of chemotherapy drugs are being used, and the schedule in which chemotherapy is administered.

Not all side effects of chemotherapy are temporary. For example, permanent heart damage can be done with the use of anthracycline drugs for chemotherapy. The chemo drug bleomycin can cause permanent damage to the lungs. Other chemotherapy drugs raise the risks of permanent damage to the reproductive organs. Not everyone will suffer permanent side effects, but it is important to discuss with your doctor the side effects of the particular chemotherapy drugs they choose to use for your treatment.

There is such a great amount of fear for the newly dx.
and at the very least it is important to understand while
we are aware of the down side of treatments there is also the opposite side...those that are NED due to our current treatments. Hopefully the near future will hold
better and less toxic treatments - It is such a complex
issue. Just consider how long it took Dr. Salmon to do the research with Herceptin and he almost lost the funding
for that research. It was only fast tracked after the evidence of the trial proved to be so outstanding.
Plus it still took years for herceptin to be approved for early stage patients.

I was discussing with my onc. recently the complex issues of our cells and the constant change that occurs
within our bodies each day which makes the cure for cancer such a challenge. The chemistry of our bodies continues to be a mystery.

[Rich66]

I was discussing with my onc. recently the complex issues of our cells and the constant change that occurs within our bodies each day which makes the cure for cancer such a challenge.

Hmmm..and what did they say?

[Hopeful]

Re: chemotherapy, here is a link to an article I posted yesterday in the Articles Forum: http://her2support.org/vbulletin/showthread.php?t=53357&referrerid=1173

TAKE-HOME MESSAGE

In this retrospective analysis, chemotherapy, but not trastuzumab, was associated with increased loss of HER2-positivity in metastases in patients with HER2+ breast cancer, and this discordance was associated with a poorer prognosis


Hopeful

[gdpawel]

Hope

This seems to confirmed the retrospective analysis presented at the 2011 European Multidisciplinary Cancer Congress by the Karolinska Institute, Sweden that tumor hormone-receptor and HER2 status can change in breast cancer patients during the course of their disease. And because these changes can significantly influence survival and can completely change the patient's clinical management, these patients should undergo regular biopsies.

For example, they saw that 32.4% of breast cancer patients had altered ER status and 40.7% had altered PR status and 14.5% of patients change HER2 status during the course of disease. A similar pattern was seen in patients who experienced multiple consecutive relapses, 33.6% in ER status, 30.2% in PR status and 15.7% in HER2 status. Treatment options that were effective in the primary cancer might not be optimal for the relapsed/metastatic disease.

Findings published in the Annals of Oncology (2010; 21:1254-1261) showed a much higher proportion of changes in these key receptors than has been previously reported; differences between nodal tumor tissue and primary breast cancer was seen in 46.9% of patients with metastatic disease. In addition, many of the differences in expression between the primary tumor and the node were large-magnitude (>5-fold) changes.

Changes in molecular phenotype between primary and metastatic breast cancer have been recognized in phenotype analyses. The endpoints of molecular profiling (genotyping analysis) are gene expression, examining a single process (pathway) within the cell or a relatively small number of processes (pathways) to test for theoretical candidates for targeted therapy. The endpoints of functional profiling (phenotyping analysis) are expression of cell-death, both tumor cell death and tumor associated endothelial (capillary) cell-death (tumor and vascular death), and examines not only for the presence of the molecular profile but also for their functionality, for their interaction with other genes, proteins and other processes occurring within the cell, and for their actual response to anti-cancer drugs (not theoretical susceptibility).

In other words, pheotype (functional profiling) analyses, which measure biological signals rather than DNA indicators, provides clinically validated information and plays an important role in cancer drug selection. The data that support phenotype analyses is demonstrably greater and more compelling than any data currently generated from genotype analyses.

Greg

[fullofbeans]

Many scientific experiments (not many on human) are advocating fasting (not starving) as a metabolic management of cancer. short burst say 5 days.. DCA is meant to simply reproduce this effect i.e. stop glcolysis. but indeed some cancer do feed perfectly well on fatty acid too

http://www.economist.com/blogs/babbage/2012/02/fasting-and-cancer

http://www.ncbi.nlm.nih.gov/pubmed/22391012

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2815756/

http://www.ncbi.nlm.nih.gov/pubmed/22391012

http://www.medicalnewstoday.com/articles/241518.php

[R.B.]

Hi FullofBeans - great to see you are still posting your thoughts here (-:

And AA _ I mailed you some material on metabolism - I do not know if you got it.

A complex thought provoking subject.

Fats shorter than 12 carbons long (medium chain triglycerides +MCT) are metabolized 'differently' by the mitochondria, than longer fats, including because they are more readily taken up by mitochondria.

So the effects of fat intake on tumor growth may depend on which fats you look at - and the effects are further complicated as Omega 6s in excess and imbalance with Omega 3 arguably increase the risk of cancer growth by metabolism independent pathways, as well as metabolism dependent pathways, as discussed in the Omega 3:6 'Greek diet' thread.


This paper is though provoking

http://altcancerweb.com/alternative-cancer/ketogenic/ketogenic-diet-case-reports.pdf

As is this

http://ukpmc.ac.uk/abstract/MED/6583457

Tumor promotion by dietary fat in azoxymethane-induced colon carcinogenesis in female F344 rats: influence of amount and source of dietary fat.
(PMID:6583457)

The promoting effect of dietary corn oil (CO), safflower oil (SO), olive oil (OO), coconut oil (CC), and medium-chain triglycerides (MCT) on azoxymethane (AOM)-induced colon tumors was studied in female F344 rats. The animals were fed low-fat diets containing 5% CO, 5% SO, or 5% OO 2 weeks before, during, and 1 week after sc injection of 20 mg AOM/kg body weight. One week after the AOM treatment, groups of animals were transferred to high-fat diets containing 23.52% CO, 23.52% SO, 23.52% OO, and 23.52% CC, or 5.88% CO + 17.64% MCT; the remaining animals were continued on 5% fat diets. All animals were fed these diets until the termination of the experiment. Body weights and intakes of calories, protein, and micronutrients were comparable among the various dietary groups. The incidence of colon tumors was increased in rats fed diets containing high-CO and high-SO compared to those fed low-CO and low-SO diets, whereas the diets containing high OO, CC, or MCT had no promoting effect on colon tumor incidence. There was a significant increase in the excretion of fecal deoxycholic acid, lithocholic acid, and 12-ketolithocholic acid in animals fed the high-CO and high-SO diets and no difference in these secondary bile acids excretion in animals fed the high-OO and high-CC diets compared to those animals fed their respective 5% fat diets. This study thus indicates that not only the amount of dietary fat but also the fatty acid composition (type) of fat are important factors in the determination of the promoting effect in colon carcinogenesis.


This follows a similar theme


http://w09.biomedcentral.com/1471-2407/8/122

Growth of human gastric cancer cells in nude mice is delayed by a ketogenic diet supplemented with omega-3 fatty acids and medium-chain triglycerides


Methods

Twenty-four female NMRI nude mice were injected subcutaneously with tumour cells of the gastric adenocarcinoma cell line 23132/87. The animals were then randomly split into two feeding groups and fed either a ketogenic diet (KD group; n = 12) or a standard diet (SD group; n = 12) ad libitum. Experiments were ended upon attainment of the target tumor volume of 600 mm3 to 700 mm3. The two diets were compared based on tumour growth and survival time (interval between tumour cell injection and attainment of target tumour volume).
Results

The ketogenic diet was well accepted by the KD mice. The tumour growth in the KD group was significantly delayed compared to that in the SD group. Tumours in the KD group reached the target tumour volume at 34.2 ± 8.5 days versus only 23.3 ± 3.9 days in the SD group. After day 20, tumours in the KD group grew faster although the differences in mean tumour growth continued significantly. Importantly, they revealed significantly larger necrotic areas than tumours of the SD group and the areas with vital tumour cells appear to have had fewer vessels than tumours of the SD group. Viable tumour cells in the border zone surrounding the necrotic areas of tumours of both groups exhibited a glycolytic phenotype with expression of glucose transporter-1 and transketolase-like 1 enzyme.
Conclusion

Application of an unrestricted ketogenic diet enriched with omega-3 fatty acids and MCT delayed tumour growth in a mouse xenograft model. Further studies are needed to address the impact of this diet on other tumour-relevant functions such as invasive growth and metastasis.


More here

http://books.google.com/books?hl=en&lr=&id=xY9mnvCdueQC&oi=fnd&pg=PA241&dq=MCT+oil+cancer&ots=1KhVDfY35P&sig=GQBxZoAy9VHpB6CmxrY7CIcMu7E#v=onepage&q=MCT%20oil%20cancer&f=false


As on a wider basis is this, which ties in with other papers looking at the enteral use of Omega 3.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1235121/