Metabolic management of cancer

[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 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 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/arti...7/?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.co...ancer-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/sho...eferrerid=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/babba...ing-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-...se-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&...cancer&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/