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.

Image src: http://www.neurologyadvisor.com/reconsidering-the-vascular-hypothesis-of-migraine-pathophysiology/slideshow/3738/

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.

IMG src: https://www.theguardian.com/science/2017/nov/30/migraine-drug-erenumab-could-halve-the-length-of-attacks-study-shows

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.

Image src: https://en.wikipedia.org/wiki/Meningioma

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.

Image src: https://en.wikipedia.org/wiki/Meninges

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


References

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. http://doi.org/10.2165/11534920-000000000-00000

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) http://migraineresearchfoundation.org/about-migraine/migraine-in-women/ . 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; Flipper.diff.org; Web December 2017; http://bit.ly/PsCR70



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