Saturday, 23 December 2017

Erenumab and other CGRP receptor antagonists- potential for action against brain tumours?

At the moment I'm keeping an eye on trial results and emerging research of this relatively new medication (Erenumab) for episodic migraine to understand how it could have anti-cancer activity against angiogenesis in malignant brain tumours.

Furness and Wookey, 2012

Erenumab is a human monoclonal antibody against the calcitonin gene-related peptide receptor (CGRP receptor) and its primary use is for the prevention of migraine.

This simply means that it acts as an antagonist for the CGRP receptor. CGRP comprises of 37 amino acids and is produced in the peripheral and central neurons. The main function of this peptide is to transmit pain. Early studies in humans have shown that the drug could prevent migraines by up to 50% in phase 2 clinical trials (8) so wider spread use and future applications would be interesting to see. Long term safety requires further study as this is a relatively new drug.

Research into CGPR receptor antagonists have been in development over the last few years with limited success, but this new drug has been hailed as a significant breakthrough with greater potency shown in clinical trials.

Before the introduction of these newer drugs, the last time a promising drug came on to market specifically for migraine relief was in the early 1990s. This came in the form of a class of drugs called triptans, which act as selective serotonin receptor agonists to treat migraines and cluster headaches.

These drugs are typically administered by migraineurs at the onset of attack. The main difference with these drugs and CGPR receptor antagonists in terms of symptom relief is that triptans are not preventative, they are what is termed 'abortive treatment'. Its kind of like putting a plaster over a wound. Imagine if we could stop the wound forming in the first place or at least reduce the swelling and pain before it becomes a major problem.

The Role of CGRP and its Antagonists in Migraine (14)

I noticed that similar promising drugs targeting this receptor had some limitations. For example, Oicegepant has to be administered intravenously which isn't very practical, and further development of Telcegepant was suspended following phase III clinical trials after some studies indicated there was some liver toxicity after 3 months of use (12). Despite having had to be discontinued for a number of reasons, these drugs are generally tolerable with well established safety profiles. One very favourable aspect of Erenumab so far is that toxicity is low and as such it is more tolerable at therapeutic doses over time. Longer term safety has not yet been completely quantified but early signs are promising due to its increased potency at lower doses.

You would take Erenumab as an injection only once a month. Access to the drug would likely be difficult to get hold of for other purposes, but we can use all of this information to ask ourselves about other drugs or natural agents we may use that have similar mechanisms of action. There is also some possibility of using biofeedback to control these processes.

Mechanisms of Erenumab and other CGPR receptor agonists against brain cancer:

Erenumab's potential role in halting brain cancer cell replication and growth sparked my interest, as well as the ability to potentially monitor its effectiveness by assessing production and/or activity of calcitonin receptor in brain cells. Brain tumours could therefore be treated more effectively or even prevented at an earlier stage of development by administering an effective amount of the compound that binds to the calcitonin receptor to inhibit the growth of, or kill, brain tumour cells in the patient.

Furness and Wookey, 2012

What is CGPR and why is it an important drug target?

CGPR is one of several neuropeptides found in the human trigeminal sensory neurons and is a potent dilator of cerebral and dural vessels. It is also involved in meningeal dural vasodilation.

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Erenumab is unique because previous medications for migraine, apart from triptans, are usually indicated for other conditions eg. anticonvulsants and more general anti-inflammatory agents such as the NSAIDS paracetamol, aspirin, ibuprofen, naproxen. Typically these drugs are only partially effective at best for such severe headaches (1) and their effects don't last long enough for episodic migraines.

Links between aetiology of episodic migraines and pathogenesis of brain cancer:

Episodic migraines can be described as one of many forms of epilepsy, and brain cancer patients can suffer migraines, as well as general neuropathy for several reasons. This can even take the form of neuroinflammation as a result of the standard of care for brain cancer, so even from a quality of life perspective this drug is worth investigating in my opinion.

The headlines have been rather sensational with the drug being described as a 'miracle', a 'breakthrough' and 'groundbreaking' but sadly this is common when many new drugs come on to the market and they rarely live up to this promise in reality. With that being said, I do believe this drug is unique and has an interesting target for a number of conditions, which also includes breast cancer.

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So often, most of the hype behind these new drugs tends to fizzle out until the next week's 'breakthrough drug'. There is always hope however, and this drug does indeed look very useful and efficacious for a number of reasons, which is why I have decided to do more research to understand the mechanisms of action, potential side effects short and long term, and its potential anti-cancer mechanisms specifically for brain cancer (the obvious application). This drug target is definitely on my list of back up plans in case I ever have a recurrence of my tumour.

My first thought when reading more about this class of drugs is that it could be even more effective for meningioma brain tumours, at least for symptom control, as this type of tumour is more often associated with migrainous activity with or without an 'aura'.

Small meningiomas can be asymptomatic until they grow and spread, usually causing seizures and headaches. As with migraines, where up to 85% of sufferers can be female (9), the majority of patients with meningioma brain tumours are female (over 2.5x more frequency compared to males) (11). I am not sure why this is, it could possibly be a hormonal reason, but it is very interesting.

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A meningioma is a type of brain tumour that forms from the meninges, layers of tissue that surround and protect the brain and spinal cord. These tissues are comprised of three layers known as the dura matter, arachnoid matter and pia matter. Even general observation can show you how migraines could be a serious concern as the tumour grows, and of possible surgical complications.

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Even if Erenumab could reduce the need for steroids to reduce brain swelling for these patients and/or associated symptoms, that would provide tremendous relief for these patients I'm sure. Let's not dismiss quality of life.

As part of a drug cocktail approach to manage cancer:

I am a huge fan of a drug cocktail approach using non toxic, repurposed drugs with key targets on signalling changes associated with malignant brain tumours. Perhaps most important, as an adjuvant treatment, I believe it is very vital to consider use of certain non-toxic agents whilst undergoing chemotherapy to aid drug delivery to the brain.

Chen, Y. and Liu, L., 2012

This is without a doubt the major hurdle of temozolomide and other chemotherapeutic agents for brain cancer. The main reason they don't work is because they cannot cross the blood brain barrier at appreciable doses to target cancer stem cells without significant toxicity to healthy brain cells. A few interesting agents that may aid drug delivery to the brain to enhance the effects of chemotherapy for brain cancer are detailed below.

There are many other proposed agents, but I think this is a nice brief summary of a few I have looked into most. The main action is to modulate the expression of efflux transporters. In a nutshell, efflux transporters play a vital role in drug absorption, ensuring it can be directly delivered to the intended site of action. One key target for high grade gliomas specifically, would be monocarboxylate transporters.

Why? Well, if you understand the Warburg Effect, you will understand that the high glycolytic nature of malignant gliomas describes their propensity to metabolise glucose to lactic acid at an elevated rate. This is a survival mechanism that has parallels with Darwinian evolution. Cancer is very clever and doesn't want to die so in order to survive, these neoplasms efflux lactic acid to the tumour microenvironment through transmembrane transporters- monocarboxylate transporters (MCTs). It has been suggested therefore that inhibition of MCT function could impair the glycolytic metabolism and effect both glioma invasiveness and survival (3)

Furness and Wookey, 2012

Anti-angiogenic benefits for malignant brain tumours:

The take home message here is that CGRP can become a major therapeutic target for brain cancer as we understand that endogenous CGRP facilitates tumour-associated angiogenesis and tumour growth (13). We have established that CGRP may be derived from neuronal systems, including primary sensory neurons and these neuronal systems exhibit numerous biological activities involved in brain cancer formation, survival and its ability to adapt and thrive.

I am currently investigating more natural ways to target this receptor by possibly using different frequencies of UV light. I understand, for example, that it is possible to use green light to combat neuroinflammation (10). I believe we could potentially use green light to not only to treat migraine photophobia, but also reduce neuroinflammation and silence peripheral nociceptors to alleviate both the inflammatory and neuropathic pain. It is noticeable that many who experience these types of migraines and pain exhibit a degree of photophobia. I don't think we can ignore this fact and how this all links together.

Rodrigo et al. 2017


1. Affaitati, G., et al., 2017. Use of Nonsteroidal Anti‐Inflammatory Drugs for Symptomatic Treatment of Episodic Headache. Pain Practice17(3), pp.392-401.

2. Chen, Y. and Liu, L., 2012. Modern methods for delivery of drugs across the blood–brain barrier. Advanced drug delivery reviews64(7), pp.640-665.

3. Colen, C.B., Shen, Y., Ghoddoussi, F., Yu, P., Francis, T.B., Koch, B.J., Monterey, M.D., Galloway, M.P., Sloan, A.E. and Mathupala, S.P., 2011. Metabolic targeting of lactate efflux by malignant glioma inhibits invasiveness and induces necrosis: an in vivo study. Neoplasia13(7), pp.620-632.

4. Dickerson, I.M, Brown E.B. Methods of treating cancer using an agent that modulates activity of the calcitonin-gene related peptide ("CGRP') receptor. In: University of Rochester. 2011. (ISBN No. US 20110189205 A1

5. Durham, P. L., & Vause, C. V. (2010). CGRP Receptor Antagonists in the Treatment of Migraine. CNS Drugs24(7), 539–548.

6. Furness S, Johns T, Wookey PJ. Diagnosis and treatment of brain tumors. In: Welcome Receptor Antibodies Pty Ltd; 2012. (ISBN No. WO2012000062 A1)

7. Evans, R.W., Timm, J.S. and Baskin, D.S., 2015. A left frontal secretory meningioma can mimic transformed migraine with and without aura. Headache: The Journal of Head and Face Pain55(6), pp.849-852.

8. Goadsby, P.J., Reuter, U., Hallström, Y., Broessner, G., Bonner, J.H., Zhang, F., Sapra, S., Picard, H., Mikol, D.D. and Lenz, R.A., 2017. A Controlled Trial of Erenumab for Episodic Migraine. New England Journal of Medicine377(22), pp.2123-2132.

9. Migraine Research Foundation. (2017) . Accessed online: 09 Dec. 2017

10. 7. Rodrigo N. et al. (2017). Green light alleviates migraine photophobia. Neurology. Apr 2017, 88 (16 Supplement) S47.005;

11. Schneider, J.R., Kulason, K.O., White, T., Pramanik, B., Chakraborty, S., Heier, L., Ray, A.E., Anderson, T.A., Chong, D.J. and Boockvar, J., 2017. Management of Tiny Meningiomas: To Resect or Not Resect. Cureus9(7).

12. Tepper SJ, Cleves C. Telcagepant, a calcitonin gene-related peptide antagonist for the treatment of migraine. Curr Opin Investig Drugs. 2009;10 (7):711–20.

13. Toda, M., Suzuki, T., Hosono, K., Hayashi, I., Hashiba, S., Onuma, Y., Amano, H., Kurihara, Y., Kurihara, H., Okamoto, H. and Hoka, S., 2008. Neuronal system-dependent facilitation of tumor angiogenesis and tumor growth by calcitonin gene-related peptide. Proceedings of the National Academy of Sciences105(36), pp.13550-13555.

14. Image credit: The Role of CGRP and its Antagonists in Migraine- Peripheral Actions of CGRP: Neurogenic Inflammation;; Web December 2017;

Sunday, 26 November 2017

WORTH REPEATING!- Drug cocktail approach against cancer stem cell-like cells

'Mitochondrial ROS and H2O2 production may be a trigger, for driving mitochondrial oxidative stress, ultimately leading to increased mitochondrial oxidative metabolism in CSCs. Pharmaceuticals, chemical inhibitors, or natural products that we have identified to target CSCs, which interfere with a specific metabolic process or function, are shown in BLUE.'

Sunday, 8 October 2017

Evidence for use of Stiripentol and other agents to effectively inhibit cancer stem-like cell activity.

A few months ago (in March, in a previous post in my blog), I theorised that stiripentol (the 'ketogenic diet pill') may be of use as an anti-cancer agent for brain cancer and perhaps others due to inhibition of Lactate Dehydrogenase activity. I think I have just found recent evidence that this theory may be valid.

Stiripentol by Diatomit enhances beneficial effects of therapeutic ketosis for cancer management by inhibiting lactate dehydrogenase and offers neuroprotection and increased seizure threshold by enhancing central GABA neurotransmission.
Here is an extra from the paper with reference to stiripentol and complimentary agents that could possibly offer a safe, synergistic therapeutic benefit.
'We have now identified a variety of clinically-approved drugs (stiripentol), natural products (caffein acid phenyl ester (CAPE), ascorbic acid, silibinin) and experimental pharmaceuticals (actinonin, FK866, 2-DG), that can be used to effectively inhibit cancer stem-like cell activity.'
The study can be found here:

Saturday, 7 October 2017

Probiotics experiment- VSL#3. Gut dysbiosis and cancer, epilepsy.

I am currently on day 5 of a 30 day experiment using myself as a human guinea pig to test these high potency probiotics from Visibiome.

I first heard about this product from Dr. Rhonda Patrick and I trust her judgement. She stated how Visibiome contains 8 strains of live bacteria in concentrations of 450 billion bacteria per packet and I had this confirmed by the company that produces it. 

Why is this so important?

This is impressive as many probiotics only contain about 100 million bacteria (often dead as they should ideally be kept cold). I decided to investigate further and try these probiotics myself to see if I may benefit so I contacted the sister company based in the U.K. (Vivomaxx). 

The gut micro biome. You are only 10% organically human. (9)

Let's begin...

I received them promptly in pill l form, placed in an ice packed package. I chose the capsules because the carbohydrate content is negligible so should not interfere with my ketogenic diet to manage my epilepsy. I could experience some 'turbulence' as I adjust to it, which may or may not result in increased seizure activity temporarily. I have no idea, but I'm prepared for anything. So far so good.

The formulation used in these products is said to be the same as VSL#3, a probiotic that has been the subject of over 60 human clinical trials as a medical food in the dietary management of gastrointestinal and liver disorders.

From reading about the capsules, I found that they contain 112 billion bacteria per tiny capsule, and you can take up to 4 a day! It is said that these quantities are necessary to properly colonise the gut, which contains up to 10-100 billion bacteria/ml of faeces material. Optimal conolisation is achieved in 2-3 weeks so I have personally chosen to do this for 30 days, consistent with some interesting studies I have read. More information on the product can be found here: 

I became interested further by studies suggesting novel mechanisms of action accounting for deficiencies of the endocannabinoid system (which is implicated in several chronic conditions) to regulate inflammation. It has also been established that endocannabinoid signalling is a key regulator of synaptic neurotransission throughout the brain (7), allowing for improvements in seizure control if you are able to target the appropriate receptors.

'The endocannabinoid system plays an important role in regulating inflammation in several chronic or anomalous gut inflammatory diseases. In vivo and ex vivo studies showed that 30 days treatment with a probiotic mix activated the endocannabinoid system in zebrafish.' (4)

The endocannabinoid system controls a variety of gastrointestinal functions. (10)

I decided to attempt to replicate this protocol in similar fashion, for 30 days. Obviously I am not a zebrafish, but I know that they are commonly used in research as they posess a similar genetic structure to humans. They share 70 percent of genes with us and 84 percent of genes known to be associated with human disease have a zebrafish counterpart. (5)

Orthologue genes shared between the zebrafish, human, mouse and chicken genomes, using orthology relationships from Ensembl Compara 63. (1)

Back to the experiment:

I began with just 1 capsule in case I experienced any gastrointestinal disturbance and from day 3, I had begun to take 2 capsules with food as I seem to tolerate it well. 

My main curiosity with this experiment in general, is to see how taking these probiotics may affect my epilepsy- positively, negatively, or no change. Personally I'm not sure if there will be any difference, but my general health may be improved. I will have a stool sample analysed after the experiment.

I also suffered a brain haemorrhage as a result of the tumour and have had brain surgery so it was interesting to find research on how the gut micro biome becomes altered as part of the inflammatory response, impacting both short and long term recovery. The simplest explanation I found came from this study on the inflammatory response to stroke in the Journal of Neuroscience. (12) A brain haemorrhage is not too dissimilar to a stroke, especially if the blood brain barrier integrity has been further affected by having had brain surgery. I still have invisible disabilities as a result of the assault on this area of my brain and I am able to control it to a large degree with diet and lifestyle adjustments but I am always looking to improve this.

Schematic showing how stroke alters gut microbiota,
which primes the immune system to exert further damage. 
I realise that the gut and brain have a complex, fascinating connection through these trillions of bacteria, that is only just starting to be understood at a higher level. This is exciting and provides us with so many opportunities to learn more and investigate all posibilities. 

The gut brain connection is facilitated via the vagus nerve, which is very important to note for individuals with epilepsy. The vagus nerves are a pair of nerves running from the brain throughout the body to send electrical messages around all physiological systems. The central nervous system can become spontaneously overstimulated with epilepsy, but it is possible to attempt to regulate these electrical impulses with Vagal Nerve Stimulation or with microbial and/or nutritional stimuli.

'...distinct microbial and nutritional stimuli activate the vagus and the nature of the signals transmitted to the brain that lead to differential changes in the neurochemistry of the brain and behaviour.' (2)

Vagal Nerve Stimulation (VNS) device (13)

I am now probably a little too aware of how every thought we have and every action we make impacts on gut health in profound ways as a 2 way feedback system between the gut and brain via the vagus nerve.

It is interesting to think how many individuals suffering with drug resistant epilepsy will attempt to put an end to their suffering with Vagal Nerve Stimulation (VNS), by which a small electrical device similar to a pacemaker is implanted under the skin to the left vagus nerve in the next with the aim of reducing seizure activity. Its pretty invasive and only appears to give significant, but partial relief at best, with a review stating that of those who responded (54%), there was a reduction in seizure frequency of around 45-63%. (3)

This is significant, but frustration will remain for these patients, especially the non responders. I wonder if we could find kinder solutions to this complex electrical circuitry that makes up our brain and central nervous system through modulation of the gut microbiome. Could probiotics help us to find some kind of solution here for non responders and perhaps even in combination with VNS for the responders?

Gut dysbiosis and cancer:

As a secondary aim of my investigation, I would like to learn more about the clear association between gut dysbiosis and a number of cancers (17), focusing on the brain and central nervous system of course.

I have recently transitioned into a more 'mediterranean' style ketogenic diet so that the probiotics have more of a variety of prebiotics to feed off. I have also increased amounts of ginger and turmeric in my diet, which should help, theoretically at least. 

I still have ghee because it is high in butyric acid, a short chain fatty acid which the microbes love. It is at a high concentration in this food, but is also produced in the intestines by bacteria that ferment non-digestible carbohydrates. (8) I feel it would be helpful for people to remember this fact when discussing carnivorous ketogenic diet ('zero carb') approaches. It has been suggested that high levels of dietary fat decrease levels of butyric acid, but this information would shed some doubt on these findings when viewed in different contexts.- how much fat, what source, what is 'high fat', what is carb/fat ratio, etc. 

I knew early on that the ketogenic diet acts partly by shifting the gut microbiome to result in favourable changes in the gut and brain chemistry, and I attempted to optimise this effect in creative ways when I was on a 'zero carb' ketogenic diet- eg. entomophagy (insect fibre), adding specific supplements, digestive enzymes.

I read an interesting study recently revealing how the ketogenic diet is able to mitigate symptoms of epilepsy at least partly by correcting an imbalanced gut microbiota in epileptic infants. (15)

I also looked at effects of how other fasting mimicking diets, including intermittent fasting and time restricted feeding, will also alter the composition of microbiota, specifically in relation to cancer, but this was harder to find. Maybe we are still learning.  

How we might determine the composition of the microbiota in patients with cancer compared to healthy volunteers. (16)

My conclusion is that, in light of the data, from what we know and what we have yet to understand, it would not be unfeasible to suggest that taking probiotics at appropriate times may help to reduce risk of recurrence of a high grade glioma. I understand (in basic terms), the close relationship between the vagus nerve and microbiome-brain-gut-axis communication and so this may have an additional or stand alone benefit for epilepsy management and improved quality of life. Its fascinating stuff.- most of the more interesting research I found is on colon cancer, but there are obvious potential applications for a host of other cancers. Its a new area to look into, we can't make any definitive conclusions, but I'm looking forward to learning more.


1. Collins, J. E.White, S.Searle, S. M. & Stemple, D. L. Incorporating RNA-seq data into the zebrafish Ensembl genebuildGenome Res. 2220672078 (2012)

2. Forsythe, P., Bienenstock, J. and Kunze, W.A., 2014. Vagal pathways for microbiome-brain-gut axis communication. In Microbial Endocrinology: The Microbiota-Gut-Brain Axis in Health and Disease (pp. 115-133). Springer New York.

3. García-Pallero, M.A., García-Navarrete, E., Torres, C.V., Pastor, J., Navas, M. and Sola, R.G., 2017. Effectiveness of vagal nerve stimulation in medication-resistant epilepsy. Comparison between patients with and without medication changes. Acta neurochirurgica159(1), pp.131-136.

4. Gioacchini, G., Rossi, G. and Carnevali, O., 2017. Host-probiotic interaction: new insight into the role of the endocannabinoid system by in vivo and ex vivo approaches. Scientific Reports7.

5. Howe, K., Clark, M.D., Torroja, C.F., Torrance, J., Berthelot, C., Muffato, M., Collins, J.E., Humphray, S., McLaren, K., Matthews, L. and McLaren, S., 2013. The zebrafish reference genome sequence and its relationship to the human genome. Nature496(7446), p.498.

6. Lewis, T. (2016) Stroke Alters Gut Microbiome, Impacting Recovery. The Scientist Magazine. From URL: Accesed online, 07 Oct 2017.

7. Ludányi, A., et al., 2008. Downregulation of the CB1 cannabinoid receptor and related molecular elements of the endocannabinoid system in epileptic human hippocampus. Journal of Neuroscience28(12), pp.2976-2990.

8. Maness, L.R., 2016. The Effect of Butyric Acid on GLUT4 and IRS1 Expression in Human Preadipocytes in vitro.

9. image adapted from The Sociable Scientist.  

10. Pinto, L., Capasso, R., Di Carlo, G. and Izzo, A.A., 2002. Endocannabinoids and the gut. Prostaglandins, Leukotrienes and Essential Fatty Acids (PLEFA)66(2-3), pp.333-341.

11. Schwabe, R.F. and Jobin, C., 2013. The microbiome and cancer. Nature Reviews Cancer13(11), pp.800-812.

12. Singh, V. et al., “Microbiota dysbiosis controls the neuroinflammatory response after stroke,” The Journal of Neuroscience, doi:10.1523/jneurosci, 2016.

13. Vagus nerve stimulation. Epilepsy Society. from URL: Accessed online, 07 Oct 2017.

14. Vivomixx. from URL: Accessed online, 07 Oct 2017.(12)

15. Xie, G., Zhou, Q., Qiu, C.Z., Dai, W.K., Wang, H.P., Li, Y.H., Liao, J.X., Lu, X.G., Lin, S.F., Ye, J.H. and Ma, Z.Y., 2017. Ketogenic diet poses a significant effect on imbalanced gut microbiota in infants with refractory epilepsy. World Journal of Gastroenterology23(33), p.6164.

16. Zitvogel, L., Daillère, R., Roberti, M.P., Routy, B. and Kroemer, G., 2017. Anticancer effects of the microbiome and its products. Nat Rev Microbiol15, pp.465-78.

17. Zitvogel, L., Galluzzi, L., Viaud, S., Vétizou, M., Daillère, R., Merad, M. and Kroemer, G., 2015. Cancer and the gut microbiota: an unexpected link. Science translational medicine7(271), pp.271ps1-271ps1.

Friday, 6 October 2017

Biochemical individuality. Thoughts on the effectiveness of dichloroacetate as an anti-cancer agent from DNA testing and analysis

I have been using Prometheus to extract raw data from my 23andme raw data in an attempt to personalise my approaches moving forward. You can find out more here:

Interestingly, following on from my post about DCA, I decided to determine what SNPs I had relating to specific nutrients, metabolic therapies, and drugs. I have explored this before, but not in as much depth as I have recently.

From pouring over the exhaustive amount of data detailed in my Prometheus report I found that I appear to be a slow metaboliser of DCA, which is interesting for a number of reasons.

DCA is an interesting chemical compound, because it can be a chlorine byproduct from chlorinating swimming pools and tap water, and the 'poison' could be in the dose, with some arguing that it may be a major environmental hazard, or a 'panacea for human ills'- This has not yet been proven definitively either way, as the study below has concluded, but perhaps never will be because it seems to be either helpful or harmful depending on the context. 

I came across this study when investigating if being a slow metaboliser could allow me to have greater harm from drinking chlorinated water, or, conversely, derive less potential benefit from treatment with DCA if I ever go down this route as a back up plan should I have a recurrence. In that case I may benefit more from intravenous DCA or I may not benefit significantly at all! Its interesting, harmful or helpful? Or both? Here is what I found...

And my own personal conclusion? Well, I often say with these things that whenever we have seemingly extreme views, the truth often lies somewhere in between and this seems to be the case with DCA.

There is biochemical individuality with any drug, diet, or drug, whether it be 'natural' or synthetic. This is why I value genetic testing and a personalised approach to any treatment protocol. It is also why I chose to discontinue chemotherapy a few years ago not long after starting. It was a personal decision based on the fact that my tumour was not chemosensitive and I was unlikely to benefit from progression free survival. Even if you believe cancer is a metabolic disease, it is our genetics that can help us to determine what might potentially be the most beneficial approaches for us as individuals. You are as unique as your cancer and we are all different despite the many things we can have in common.

So with all this in mind, what is your view of DCA? Effective for some but not all? Personalised application and dosages? Breakthrough effective metabolic cancer treatment or major environmental hazard? The truth probably lies somewhere in between these two main ideas. 

Wednesday, 23 August 2017

DCA and glioma

Human glioblastoma patients require at least a 6.25 mg/kg oral, twice-a-day dose of DCA (Dichloroacetate) to inhibit PDK (Pyruvate dehydrogenase kinase) and kill cancer cells as indicated in the study below (5).

A reliable source of DCA can be found here:

It comes in tablet form as well as a powder.

The main problems I see here is that you would need to have enough of the product to get the appropriate therapeutic dose and it is not cheap!

Simple background as to why DCA might be useful:

As many reading this will already know, most tumours display unique metabolism described as the 'Warburg Effect' which has long been associated with the resistance to apoptosis which characterises cancer. Even in tumours where glucose is maybe not the primary fuel, it appears to still play a key role as a major energy source. 

the Warburg Effect (9)

Cancer is clever, there are parallels with Darwinian natural selection (1), meaning it can adapt to use different fuels in the absense of others. With this in mind, I believe it is key to note that the best result is unlikely to come from a monotherapy approach. Nevertheless, this glycolytic phenotype in most cancers appears to be a common denominator and gives reason as to why all these molecular abnormalities occur, and as a result lead to defective mitochondria. The good news is that research suggests this suppression of mitochondrial function we see in cancer may be reversible with DCA at therapeutic doses.

Mitochondrial physiology (8)

DCA exerts its anti-cancer effects by inhibiting an enzyme called PDK (Pyruvate Dehydrogenase Kinase), a mitochondrial enzyme that is activated in a variety of cancers. Inhibition of PDK with DCA shifts the metabolism of cancer cells from glycolysis to glucose oxidation (7). As a result we would hope to see restoration of normal mitochondrial function and suppression of mitochondrial dependent apoptosis.

As I say, typically nothing works as effectively in isolation as with a multi-modal approach. Personally I would recommend a low carb, fasting mimicking diet, time restricted feeding and/or longer periods of just water fasting alongside DCA. 


Well, I get lots of people asking about how some tumours appear to be able to use fatty acids for energy after reading certain studies showing up regulation of lipogenic enzymes in cancer cells (4). It is well established that deregulated lipogenesis plays an important role in tumour cell survival (3) and as a result, FASN (fatty acid synthase) is also a therapeutic target. However... 

I wouldn't worry about this in the context of a continuous ketotic state or through implementation of a low carb diet and I will tell you why. Despite the fact that this phenomenon exists, research shows that the expression of FASN is highly dependent on nutritional conditions in lipogenic tissues. 

'FASN-catalysed endogenous FA biosynthesis in liver and adipose tissue is stimulated by a high carbohydrate diet, whereas it is suppressed by the presence of small amounts of FAs in the diet and by fasting.' (2,6) 


1. Greaves, M. and Maley, C.C., 2012. Clonal evolution in cancer. Nature481(7381), p.306.

2. Katsurada, A. et al. Effects of nutrients and hormones on transcriptional and post-transcriptional regulation of fatty acid synthase in liver. Eur. J. Biochem190, 427–433 (1990).

3. Mashima, T., Seimiya, H. and Tsuruo, T., 2009. De novo fatty-acid synthesis and related pathways as molecular targets for cancer therapy. British journal of cancer100(9), p.1369.

4. Menendez, J.A. and Lupu, R., 2007. Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nature reviews. Cancer7(10), p.763.

5. Michelakis, E.D., Sutendra, G., Dromparis, P., Webster, L., Haromy, A., Niven, E., Maguire, C., Gammer, T.L., Mackey, J.R., Fulton, D. and Abdulkarim, B., 2010. Metabolic modulation of glioblastoma with dichloroacetate. Science translational medicine2(31), pp.31ra34-31ra34.

6. Sul, H. S. & Wang, D. Nutritional and hormonal regulation of enzymes in fat synthesis: studies of fatty acid synthase and mitochondrial glycerol-3-phosphate acyltransferase gene transcription. Annu. Rev. Nutr. 18, 331–351 (1998).

7. Sutendra, G. and Michelakis, E.D., 2013. Pyruvate dehydrogenase kinase as a novel therapeutic target in oncology. Frontiers in oncology3.

8. Wallace, D.C., 2012. Mitochondria and cancer. Nature reviews. Cancer12(10), p.685.

9. Vander Heiden, M.G., Cantley, L.C. and Thompson, C.B., 2009. Understanding the Warburg effect: the metabolic requirements of cell proliferation. science324(5930), pp.1029-1033.