Urine Recipe Published!


Sorry for the long hiatus.  August was a very busy vacationing month for me.  Now back to the science…!

Some great news out of the University of Alberta today!  Biology researchers, specifically Dr. David Wishart and his team, have tabulated, analyzed and sorted out over 3000 separate metabolites found in human urine and published the entire database online for other researchers to use!  This news was reported to the public by the CBC on Thursday, September 5 20131 (http://www.cbc.ca/news/canada/edmonton/story/2013/09/04/edmonton-urine-uofa-study.html) and to the scientific community through the online scientific journal PLOS One2.

Now what is a “metabolite” and why would it be important to know the metabolites found in human urine?


As defined by Webster’s online dictionary, a metabolite is a product of metabolism (http://www.merriam-webster.com/dictionary/metabolite).  And for those who have never taken a biology class, metabolism is the term used to define all the chemical reactions and chemical pathways that our cells perform to create energy and “function” within our body.  Some commonly known metabolites found in urine, such as creatine, urea and uric acid, come from the metabolism of proteins ingested in our diet.  Since this is a database of the metabolites found in urine, naturally they are the waste products generated from metabolism in our body.

The Metabolome

The formal collection and cataloguing of over 3000 metabolites into the urine metabolite database (being called a Urine “Metabolome” by scientists – combining the words metabolite and genome) has created a powerful tool that scientists and doctors worldwide can now refer to when making discoveries through their own research projects.  From this long list identifying and measuring the normal amounts of metabolites found in healthy urine, new discoveries and ultimately new diagnostic tests can be developed to test for any number of human diseases including cancer.

Think of this accomplishment as discovering the recipe for the greatest punch you’ve ever had and then sharing that recipe for others to use!  Now think of diseases, such as certain cancers, being able to slightly alter or completely change that punch recipe.  If scientists now have the recipe for a healthy punch, they will be able to find disease conditions that are able to alter this recipe.  After discovering the alteration, they can begin creating tests to routinely find these recipe deviations in patients.  Testing urine would, in most cases, be less expensive and less painful than collecting blood or tissue biopsies to test for cancer and other conditions.  Now of course, all of this is still mostly hypothetical but it would be really difficult to do if scientists and doctors didn’t know the healthy recipe in the first place!

At this point you may already be thinking that this is old news and urine tests already exist.  And you would be right, but the goal of the Urine Metabolome is to support the ongoing development of more and cheaper tests and discoveries that will ultimately add to our understanding of the human body.

This comprehensive metabolite list, and other lists that are currently being produced for other bodily fluids and tissues, will be instrumental in helping to further discoveries in disease metabolic states and hopefully creating future test kits for them.

Here is a link to the Urine Metabolome website: http://www.urinemetabolome.ca/


1)      CBC News; U of A scientists test the water on urine; http://www.cbc.ca/news/canada/edmonton/story/2013/09/04/edmonton-urine-uofa-study.html; Sep 4, 2013.

2)      Bouatra S, Aziat F, Mandal R, Guo AC, Wilson MR, et al; The Human Urine Metabolome. PLoS ONE 8(9); 2013: e73076. doi:10.1371/journal.pone.0073076


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Gilotrif can stop EGFR from ruining a good game of Telephone

News reported by the Associated Press on July 12, 2013 is that the American Food and Drug Administration has approved the sale of Gilotrif (science name: Afatinib), made by Boehringer Ingelheim, used to treat about 10% of patients with non-small cell lung cancer (NSCLC)1.

But how does is this fabulous new drug work to help us live longer and treat one of the deadliest forms of cancer?

First off, Gilotrif is a small molecule compound developed by Boehringer Ingelheim chemists.  It is designed to recognize and fit itself into a portion of a larger protein to prevent it from sending a message down the line.  Think back to kindergarten and the exciting game of “telephone”.  Imagine how hard it would be if something was designed to go over your mouth and prevent you from talking!  Your ear still works and you can hear the message but you can’t pass it on!  The game would end very quickly and the message wouldn’t be able to get down to the end of the line.  This is exactly how this small molecule is designed to work.


Chemical structure of Afatinib

Another important thing to know about this small molecule is just which protein it is designed to recognize and prevent from passing on a message.  The protein family it inhibits is called the Epidermal Growth Factor Receptor (EGFR) family and they are normally found at the surface of cells and function by receiving signals from outside the cell and transmitting that message to the inside to initiate the growth and division of the cell which leads to the replenishment the epidermal tissue2.  Epidermal tissue is the outer layer of tissue that separates the body from the outside world (skin, cells lining the exterior walls of the gut, and lungs).  And from this information we can see that the cancers that this drug could potentially treat are limited to cancers that come from these tissues.  Important to know; the originating cells of a cancer will mostly determine the overall lcharacteristics of the tumours.

So what is wrong with the EGFR family of proteins and why are they causing tumours?

Epidermal Growth Factor Receptors

(In case you were wondering, members of this family of receptors include the HER1, HER2, HER3, HER4 proteins.)


Normally, when these proteins receive an “it is time to grow and divide” signal from the outside, they relay that message to the inside of the cell through tyrosine-kinase activity.  This is the scientific way of saying that this protein has the ability to add a flag (phosphate) to the amino acid tyrosine, found in many other proteins in the cell which starts a cascade of activity that eventually leads to the growth, survival and division of the cell.

However, in the case of cancer, the tyrosine kinase ability of the EGFR proteins have gained the ability to start the growth/division communication cascade within the cell without the need to recognize a signal from the outside of the cell.  Think back to the game of telephone.  This would be the same as one person in the game, without receiving a message, constantly passing on a message to their partner anyways.  The whole game would be taken over by this message that was created by someone not following the rules!  In cells, these unregulated messages can have profound, harmful consequences such as uncontrolled cell growth which can form a tumour mass.

So how does this protein become a rogue player in the game of telephone?  A random mutation to this protein can cause it to send messages uncontrollably.  These mutations often affect the “mouth” or tyrosine kinase sections of these proteins.  Mutations can be caused by the usual cancer risk factors such as too much sun (UV rays), smoking, obesity, etc.  There is also evidence that this mutated protein could be genetically linked.  However, it is still not known if any real increase in cancer risk exists if you inherit these mutations (since there hasn’t been a study on this yet).  But it is known that in most cases of non-smoking , non-risk factor associated lung cancers, this mutation can be found.  On average this accounts for about 10-15% of lung cancers in Caucasian and about 50% of Asian patients2.  This finding alone, suggests a possible link to genetics but it is not known for sure.

Benefits to blocking EGFR

Luckily for lung cancer patients, it has been found that in most EGFR mutated cases, the tumour growth and progression is completely dependent on EGFR signaling.  That means if doctors and scientists can stop EGFR signaling then they can stop the growth of the tumours and stop cancer progression.  They have done this in the past using tyrosine kinase inhibitors designed to plug up the “mouth” of the protein and prevent it from phosphate flagging the proteins in the cell.  But the first generation of inhibitors used did not function as permanently as Gilotrif has been designed to.  The older generation simply plugged the mouth but could easily fall out and EGFR would become active again.  This new drug, Gilotrif, has been designed to plug up the mouth permanently by binding on very tightly to the tyrosine kinase site and never letting go.  The only way for the cancer cells to grow again would be to make new EGFR and hope the drug Gilotrif is not present!

This is similar to plugging the mouth of a rogue telephone player and preventing them from passing on any message in the game.

Limitations and potential consequences

So as you could imagine, removing such an essential protein involved in the communication of epidermal cell replenishment could cause some problems.  Common side effects are related to the fact that the cells in these tissues can not regenerate and make new tissue.  Not replenishing gut cells results in stomach cramps, diarrhea, and nausea.  Skin cells that do not grow can result in the formation of rashes, dry skin, and acne.  And it has been reported that the incidence of side effects was quite high, upwards of 90% of treated patients2.

Another limitation highlights the resiliency of cancer and provides a micro-model of evolution at work.  It has been reported from doctors that some cancers in patients receiving the first generation EGFR inhibitors can mutate further and continue to grow.  This has been suggested to altering the tyrosine kinase area to prevent the first generation inhibitors from recognizing and plugging it up.  This could also be a mutation that somehow bypasses the EGFR pathway and allows the cells to grow again.  And just like evolution, if a mutation is beneficial to the survival of the cancer, these mutations are selected for and the cancer can continue to grow, resistant to first generation tyrosine kinase inhibitors.  This resistance has also been detected in laboratory animal models of cancer receiving Gilotrif.  This indicates that Gilotrif could cause these evolutions in a patient’s cancer as well.

Scientists and doctors hope to overcome this resistance by giving drug cocktails that target different pathways which support cancer growth.  The hope is that by blocking multiple pathways, the cancer cells can’t gain all the required mutations at once to allow it to survive and continue to grow.

The development of this drug highlights the need to better understand cancer and hopefully future research can identify other cellular pathways crucial to the growth of cancer.  That way, scientists and doctors can continue to develop drugs designed to specifically shut down these pathways and control the growth of cancer.  Also, understanding the activity of the drugs allows improvements such as permanent binding to be made to upgrade our similar, existing drugs.


1)      AP Staff;  FDA approves drug to treat advanced lung cancer; July 12, 2013. (http://www.nbcnews.com/health/fda-approves-drug-treat-advanced-lung-cancer-6C10620068)

2)      Valerie Nelson et al.; Afatinib: emerging next-generation tyrosine kinase inhibitor for NSCLC; OncoTargets and Therapy 2013; Issue 6 135–143.

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Invitro-fertilization: A new meaning for “Ménage à trois”

It was reported on June 28, 2013 by The Guardian science correspondent Ian Sample that the British government would be further supporting efforts to develop and adopt Invitro-fertilization (IVF) technology that allows for the creation of embryos from three separate parents1.  If parliamentary approval is reached, the treatment could be offered to prospective parents in as early as 2014.

So what exactly are we talking about when we are discussing 3-parent embryos?  Well first off, the procedure in question is commonly referred to as “Mitochondrial Transfer” and has been used successfully in mice and other research animal models for many years.  The treatment is designed to treat maternal genetically-linked diseases (genetic diseases only passed down from the mother).

Now why would doctors and scientists want to perform a mitochondrial transfer on a fertilized egg?

To understand this, we need to further understand the role and characteristics of the mitochondria within our cells.


Just as a quick disclaimer, this review will stay away from obvious ethical questions raised by genetic manipulation of an embryo and playing “god”.  The review, like all my other reviews, will focus on the scientific rationale that led to the development of this treatment for treating human disease.


The mitochondria are commonly referred to as the “power plants” of our cells.  They are organelles (organ of a cell) found in our cells that are responsible for cellular respiration and producing large amounts of the energy unit: ATP.  The food that we consume, in the form of carbohydrates, protein and fat, are used in the components of the Citric Acid Cycle located in mitochondria to produce ATP.  Adenosine Tri-phosphate (ATP) is consumed by the cell to power its many different functions.  For example, in muscle cells, the ATP is used to power the contraction of the individual cell.  Without mitochondria, our cells would not have enough ATP to function properly and life (as we know it) wouldn’t exist.

Now you may be wondering, how an organelle that acts as a power plant has anything to do with a genetic disease.  A genetic disease by definition is a disease that is linked to our genes or DNA!

Well here’s a concept they didn’t always tell you about in high school biology classes.  Mitochondria have their own DNA!  This DNA is kept separate from our own DNA found in the nucleus.  It is in addition to those 46 chromosomes that we always hear about (23 from dad, 23 from mom).

As an aside, the presence of DNA in mitochondria has given rise to the evolutionary theory that mitochondria were once separate living organisms which invaded another cell and together they formed a cellular system that was superior in their ability to create and utilize energy2.  This ability allowed the new symbiotic relationship to out compete other systems and led to the creation and evolution of the eukaryotic cells which gave rise to all the plants and animals.  They have entire units within evolutionary biology courses in University based on this very story!

Today, mitochondria DNA, in addition to maintaining mitochondrial health, help to encode all those factors that are important in cellular respiration.  If any of these genes are mutated then the mitochondria will have limitations concerning its ability to take part in cellular respiration and maintaining a healthy cell.  If a cell loses its energy reserves then it loses its ability to function which can lead to all sorts of diseases ranging from debilitating neurodegenerative disorders to blindness or deafness and even death as an infant3.

Just imagine if your muscles lost the ability to efficiently make more ATP, your muscles wouldn’t be able to contract and you’d lose the ability to move (muscular dystrophy)!  Or what if the lack of functional mitochondria afflicted your nerve cells?  Then your nerve cells will lose the ability to utilize ATP to power its ion pumps which are important in sending action potentials (electrical impulses) throughout your body (neurodegenerative)!

The presence of healthy mitochondria is very important in maintaining the energy stores within the cells of a healthy person.

Concept of Mitochondrial Transfer

In a case where familial diseases have been traced to mitochondria DNA gene mutations the concept of replacing the mitochondria during invitro fertilization treatments was proposed.

We inherit our mitochondria from our mothers because mitochondria are present in the woman’s eggs whereas men sperm don’t really transfer their mitochondria onto the ovum during fertilization.  Doctors and scientists in fertility clinics therefore proposed replacing the mitochondria from the eggs of women known to have mitochondria linked genetic diseases with the healthy mitochondria from another woman’s donated eggs.  The hybrid egg is then fertilized by the prospective father’s sperm and the new, 3-parent embryo is implanted into the mother. 

3 parent babies

Making a hybrid egg

Issues (other than moral)

This technology is still highly experimental, and to date, this author is not aware of a person who has been conceived utilizing the 3-parent embryo technique.  There are also a host of medical and scientific questions left to be answered through clinical trials (which invariably would require a person be conceived and be subjected to life of medical monitoring).  The ability of this treatment to successfully treat a mitochondrial disease has also yet to be determined.  It also has to be determined if any unremoved, unhealthy, contaminating mitochondria in the egg can interfere with the success of the treatment.  It should also be scientifically determined if similar results could be obtained by using mitochondria from another source, such as from the father’s other cells.

Despite the controversial nature of this medical science technology, this research has been able to elucidate the origins of certain diseases.  Understanding the genetic and cellular connections of mitochondrial diseases can eventually open the doors to other proposed treatments for those already born with these diseases.  In any case, the future should prove to be an interesting one!


1)      Ian Sample; Three-person IVF: UK government backs mitochondrial transfer; The Guardian, Friday 28 June 2013. (http://www.guardian.co.uk/science/2013/jun/28/uk-government-ivf-dna-three-people)

2)      Michael W Gray et al.; The origin and early evolution of mitochondria; Genome Biology; Volume 2(6); 2001.

3)      Francoise Baylis; The ethics of creating children with three genetic parents; Reproductive Biomedicine Online; Volume 26, 531– 534; 2013.


Filed under Medical Technology

Tamoxifen: The very old drug intended for this but now used for that


Other known alias:

Nolvadex, Istubal, Valodex, ICI 46,474


On June 25, 2013 the Scottish Parliament announced that Tamoxifen will now be available for women at high-risk of developing breast cancer1.

So what is Tamoxifen and how does it reduce the risk of developing breast cancer?

First off, Tamoxifen (or initially called ICI 46,474) is a fairly old drug which has been around since the 1960’s when Dr. Dora Richardson of ICI Pharmaceuticals (now AstraZeneca) first chemically synthesized it and Dr. Arthur Walpole pushed for its continued development.  Being such an old drug has allowed it to develop quite the colourful past and highlights the importance of “looking outside the box” when developing new drug treatments.

When it was designed and created, scientists were busy trying to produce an anti-estrogen compound (something that could block the function of estrogen).  They intended to use this drug as a Morning-after pill.  However, in a glaring example of how success in animals does not always translate into success for humans…the drug worked as intended in rats but failed to prevent pregnancy in early human trials.  In fact, it was later discovered to increase the fertility of human females by increasing ovulation!  (This is why clinical trials are important to prove that a drug that works in animals actually works as intended in humans!)

To this day, Tamoxifen is still being actively researched and considered a potential drug for use to treat women who have problems with ovulation termed anovulation or Polycystic ovary syndrome2.  How it actually works to promote increased ovulation is still not really understood.  Looking at the scientific literature, there seems to be evidence that Tamoxifen can interact with both the ovaries and pituitary gland, thereby playing around with hormonal levels to increase the development of mature eggs and their release per cycle.  This research is still ongoing even after 50 years of development!  This is because the medical community and ICI Pharmaceuticals moved on with the development of Tamoxifen and began looking at other indications where blocking estrogen could be a benefit.

Breast Cancer

As with all cancers, the developing tumours take on some characteristics of the bodily tissue/organ that gave rise to the tumour.  This is why certain cancer drugs can only be used to treat specific cancers originating from specific tissues of the body.  In the case of breast cancer, the presence of estrogen receptors would be expected since the originating tissue would normally respond to estrogen (unless medical tests reveal the cancer is estrogen receptor negative).

Estrogen is a hormone, and like all hormones act as messengers that travel throughout the body to deliver its instructions.  For breast tissue, estrogen, which is mainly released from the ovaries, signals the development and maintains the health of breasts.  However, in the case of breast cancer, the estrogen normally found in the body can act as a signal to the tumour cells to divide and grow.  Finding a way to block the ability of estrogen to send this signal could, in theory, block a growth signal in the tumours.

Enter Tamoxifen!  Originally created to block estrogen in the hopes of preventing pregnancy, doctors have been using it for over 20 years to prevent breast cancer cells from growing.  Tamoxifen mimics the shape of estrogen and binds those same estrogen receptors found inside breast cells, but unlike normal estrogen it does not send a signal to the cell to divide; kind of like a key that fits into a lock but cannot turn the lock to unlock it, while still preventing the real key from unlocking the lock!

Unlike other cancer drugs, Tamoxifen does not kill the cancer cells, which is why it is termed oncostatic (“onco” meaning cancer, “static” meaning standing still) and not oncolytic (“onco” meaning cancer, “lytic” meaning to lyse, blow up or kill cells – like Lysol which kills bacteria) like other common anti-cancer drugs.

For cancer prevention in high risk populations, like the aforementioned Scottish population, Tamoxifen is designed to prevent any young cancer cells from receiving estrogen growth signals and becoming a tumour.  People deemed to be “high-risk” often have a long family history of breast cancer and often through genetic testing have revealed indications that they will develop breast cancer within their lifetime.  Tamoxifen, in these cases, would hopefully holds all those young, almost cancer cells, static and prevents them from growing and forming a tumour.

Consequences and benefits

As you may be aware up to this point, the risks of using Tamoxifen are related to preventing estrogen from performing its regular activities.  People on Tamoxifen often suffer from hot flashes and other menopausal-like symptoms!  Also, the use of Tamoxifen during pregnancy is not recommended by many scientists and doctors.  Pregnancy normally results in large changes to the hormonal balance within a woman’s body, all of which are perfectly designed to ensure the promotion of a healthy uterus and ultimately the safety of the developing fetus.  Messing around with an important hormone like estrogen can have consequences during the pregnancy.  And this is proven by many clinical studies where pregnant women currently receiving Tamoxifen to control their cancers had a greater chance of having a baby with birth defects3!

I realize the irony of this since I already mentioned how Tamoxifen increases the fertility of women!  Here we have one drug that can prevent the growth of cancers but can promote pregnancy in anovulating women!

To answer this paradox we must keep in mind the difference in these cases and the timeframe where Tamoxifen is prescribed.  For women with difficulty ovulating, Tamoxifen was given at the start of their cycles for only 5 days, by the time of conception Tamoxifen would be eliminated from their bodies and the normal pregnancy timeline can continue without interruption.  Compare this to the cases where Tamoxifen led to an increased chance of birth defects, the drug was present throughout pregnancy in an effort to protect the woman from breast cancer.  Clearly, the presence of an estrogen blocking drug during pregnancy would not be advised.

Another glaring consequence of Tamoxifen relates to the fact that it does not kill breast cancer cells, only stops them from growing.  It is theoretically possible that over time, the cancer cells can develop mutations that allow them to grow without the need of estrogen – thereby becoming resistant to Tamoxifen.  This is why doctors may prescribe a variety of drugs in a “cocktail” to prevent the cancer from developing a resistance to the drugs (If one drug can’t get it, the other will!).

In the end, Tamoxifen has been used successfully in many instances to control the growth of breast cancer and prevent breast cancer recurrence.  Its presence and longevity in the marketplace even after going off patent protection speaks to its success as a cancer drug.  And continued research may yet reveal other estrogen dependent diseases that can treated by blocking estrogen with Tamoxifen.  Due to its success and a bright future, we may continue to see this drug for many years to come!


1)      New drug that can half risk of breast cancer developing to be available to Scots women; Daily Record; June 25, 2013. (http://www.dailyrecord.co.uk/news/health/new-drug-can-half-risk-1990976)

2)      Lakhbir Kaur Dhaliwal et al.; Tamoxifen: An alternative to clomiphene in women with polycystic ovary syndrome; J Hum Reprod Sci. 2011 May-Aug; 4(2): 76–79.

3)      Geert Braems et al.; Use of Tamoxifen Before and During Pregnancy; Oncologist. 2011 November; 16(11): 1547–1551.

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Eylea (Aflibercept): inhibiting VEGF to prevent leaky eyes


The general pathway to age-related macular degeneration.


Eylea or also known by the scientific trade name “Aflibercept” is being touted by its maker, Regeneron Pharmaceuticals, as a treatment for those with age-related macular degeneration.  Age-related macular degeneration is one of the leading causes of blindness in older peoples.

Before I go into describing how the makers have intended for Eylea to work, I will first discuss the biology behind macular degeneration.

Age-related Macular Degeneration

The culprit of age-related macular degeneration has been identified as a build up of what the professionals call “Drusen” within the layers of the retina in the eye.  The retina is the tissue at the back of the eye that receives all the focused light and transmits that image via the optic nerve to the brain, kind of like the film in a camera.  Drusen has been described as fatty deposits that appear yellow-whitish within the retina and is actually one of the things that an eye doctor screens for when they look deeply into your eyes.

What makes up Drusen?  Well, the ingredients that make up Drusen have been described by scientist Lan Wang and her colleagues to be a combination of fats, proteins and cholesterol1.  The proteins present within Drusen are particularly interesting because she identified the presence of immune system proteins called “complement” (particularly C5 and C8 – for those who wanted to know).  These proteins are normally found in your blood stream floating along and have the ability to signal the rest of the immune system, including all the different kinds of white blood cells, to the presence of an infection and in some cases kill bacterial invaders themselves through the “complement cascade” (more about complement will be talked about in future drug reviews or an in-depth review can be found here: http://youtu.be/vbWYz9XDtLw).  However, in this case they aren’t alerting to the presence of an infection, they are just caught within the mix of ingredients that make up Drusen.  It is the presence of these immune proteins that are being blamed for triggering inflammation within the retina and in particular the release of vascular endothelial growth factor (VEGF) into the surrounding tissue and blood stream2.

Role of Vascular Endothelial Growth Factor (VEGF) in Macular Degeneration

VEGF as the name suggests was first discovered to kick start the process in building new “vasculature” or blood vessels within tissues3.  One of the reasons a tissue may need more blood vessels is if its current oxygen supply and waste management needs aren’t being met.  As an aside to this article, VEGF is actually produced fairly commonly by tumours which require new blood vessels to connect it to the body.

In addition to forming new blood vessels the protein is also responsible for “loosening” the walls of blood vessels, and making them leaky, enabling white blood cells and fluids to squeeze through and potentially infected organs or body tissue.

In the case of macular degeneration, the presence of the infection signaling proteins (C5 in particular) is enough to stimulate parts of the retina to produce VEGF, thereby making the retina blood vessels leaky and allowing the influx of fluids into the back of the eye which interferes with the normal functions of the retina and causes sight problems2.

To combat the loss of eyesight in people identified with age-related macular degeneration, scientists have proposed controlling the protein that starts the “loosening” of blood vessels, which is VEGF.  That is why the drug Avastin, which was designed to fight cancer by actually sweeping up all the VEGF produced and preventing tumours from developing blood vessels (ultimately hoping to starve the tumours to death) have been used successfully to control macular degeneration.


Eylea is another drug designed to sweep up and eliminate VEGF produced by the retina.  However, it is designed much differently than Avastin and therefore could potentially allow both to be used together to treat age-related macular degeneration.  Unlike Avastin which is a monoclonal antibody to VEGF (a technology I will discuss in another review), Eylea combines the normal receptor for VEGF with a relatively inert protein tail which leads to the inhibition of VEGF.  It is hoped that by flooding the tissue with VEGF receptors (Eylea), the free receptors can bind up all the active VEGF protein before it has a chance to make the blood vessels within the retina “leaky”.

For those who would like an analogy: think of VEGF as a key that normally opens the lock in a door and allows the door to open up.  Now think of Eylea as a bunch of “free” locks or keyholes without doors that the VEGF keys can insert into.  The hope is that by throwing a bunch of non-door locks or keyholes into the tissue, they can quickly catch all the VEGF keys before any of them can reach a real lock and open the doors.  Avastin functions similarly, but would be more akin to a hand reaching out and specifically grabbing the VEGF keys and preventing them from going into the keyholes in the first place.

In both cases, VEGF is prevented from doing what it normally does with the end result being less fluid moving into the retina and hoping this leads to the stabilization of the disease and preventing total vision loss.


Potential Consequences

Knowing more about the role of VEGF in the body, the consequences of blocking its activity are mostly related to the body’s ability to regenerate blood vessels and fight infection within tissues.  Blocking VEGF could prevent blood vessels that actually need to become leaky to allow white blood cells through to combat an infection.  To overcome this worry, doctors have developed a way to deliver Eylea and prevent it from reaching the rest of the body…they inject the drugs directly into the eye!

Have I grossed you out yet?

Based on the product information sheet provided to ophthalmologists and other healthcare providers (found here: http://www.regeneron.com/Eylea/eylea-fpi.pdf) it would appear that Eylea is normally administered about once per month for three months and then once every two months.

You would think that an easier way to prevent being stabbed in the eye for the sake of saving your vision (think of the irony!) would be to prevent Drusen build up in the first place.  And you would not be alone; many scientists would tend to agree with you!  There is just one problem though, scientists still do not know the exact reasons Drusen begins to form in the first place!  Some have speculated it could be diet related since cholesterol and fat make up a large portion of the ingredients of Drusen, but as of this review, I have not been able to find a study where this connection has been absolutely determined yet.  So until medical science can identify the reasons and risk factors that cause Drusen formation, we can only hope that our eyes don’t become garbage dumps for Drusen.


1)      Lan Wang et al.; Abundant Lipid and Protein Components of Drusen; PLoS ONE 5(4); 2010.

2)      Miho Nozaki et al.; Drusen complement components C3a and C5a promote choroidal neovascularization; PNAS; 103(7); 2006.

3)      Joan Miller et al.; Vascular Endothelial Growth Factor A in Intraocular Vascular Disease; Ophthalmology; 120(1); 2013.

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CFI-400945 (New “Sharp-Shooter” drugs for cancer)

By now you may have heard about the fantastic news coming out of Toronto regarding the development of new “sharp-shooting” treatments designed to treat cancer.  But you may be wondering just what this development is, and just how it is different from the numerous other treatments being proposed and developed to treat cancer.

As it is being reported from numerous popular media outlets, including The Province1, the drug is currently named “CFI-400945”.  Very little more is discussed in these news releases, except that they are targeting PLK4.  But most people have no idea what PLK4 is!  Why target this seemingly random sequence of alphanumeric characters?  Just how important is PLK4 to cancer?

To answer these questions I have gone into the often messy world of Scientific Literature and have pulled out what we need to know about today’s developments!  As a disclosure however, I was not able to find one, specific, published academic study regarding today’s developments which include both Dr. Tak Mak and Dr. Dennis Slamon.  But I was able to piece together a scientific story, nonetheless, using other indirect methods.  (Reasons for not publishing the results of today’s announcement could be because the authors are seeking patent protection for their invention.)

From my digging I was able to find an academic abstract published by the journal Cancer Research for the 2011 Annual Meeting of the American Association for Cancer Research.  In it the author, from Dr. Tak Mak’s research group, reports that inhibition of PLK4 is a potential anti-cancer strategy.  The method reported in the abstract cites the use of RNAi.  This means that CFI-400945 most likely utilizes RNAi technology to target PLK42.


Back to the original question, what is PLK4 and why would it be important to target it to treat cancer?

Polo-like Kinase 4 or more commonly referred to as PLK4, has been identified as a prime initiator of centriole duplication3.  Centrioles are very important in the cell splitting process known as mitosis.  A cell needs two of these, one at each end of the cell to pull the chromosomes apart as the cell splits into two.  In the case of most cancers, it has been found that PLK4 can be over-produced and this has the effect of causing more than two centrioles to form which can cause a mess in the cell splitting process.  Just imagine trying to split into two with just enough DNA to make two cells but then a third or even fourth force is trying to pull you into three or four parts!  There isn’t enough DNA to go around and the end results are cells with improper numbers of chromosomes!  Cancer cells often don’t have the proper number of chromosomes that healthy cells have.  In humans we have 46 chromosomes (23 from mom, 23 from dad).  Additionally, having missing or additional chromosomes in a healthy cell can be very detrimental to the cell and can lead to tumour formation.  In short, PLK4 is very important in the process of mitosis!

Scientists, like the team in Toronto, then decided to look at stopping PLK4 and seeing if this can prevent cancer cells from forming centrioles and therefore prevent cell duplication.  The technology they most likely used (remember, there is no published data regarding this announcement) is RNAi.



What is RNAi?  RNAi is quite simply interfering (that’s where the “i” comes in) with RNA to block the formation of a specific protein.  Scientists have used RNAi technology to artificially block gene expression and therefore the production of certain proteins within cells for years!  The move into animals is a relatively new development.  Remember, the regular step taken in cells to form proteins is:

DNA –> RNA –> Protein

RNAi interferes very specifically with the RNA sequence that leads to a specific protein, in this case PLK4 and thereby shutting down the production of that protein.  RNAi only works for a short period of time because cells can continually generate more RNA from the DNA and once the RNAi is used up, more needs to be added to continually silence the gene.

DNA (PLK4 gene) –> RNA (PLK4 RNA) + RNAi (specific for PLK4) –> Protein (PLK4)

Benefits and Consequences

The published abstract and the popular news release suggest that using RNAi to stop the formation of PLK4 enzymes in tumour cells leads to their inability to duplicate and eventually their cell death.  The specific nature of RNAi would be the reason that popular media has dubbed the drugs a “Sharp-shooter” approach to cancer treatment rather than the usual “bomb” approach that most, older therapies take (radiation, chemotherapy).  One obvious consequence with blocking PLK4 formation would be that all cells in the body would lose the ability to divide for the amount of time that the RNAi is present in the system.  As this would be beneficial for preventing tumours from growing and even shrinking them over time, it could potentially have serious side effects on other bodily systems that require constant renewal of cells like the gut or the immune system.  Another limitation of RNAi treatment would be the number of times a patient may need to receive RNAi to ensure adequate exposure of the cancer cells to the compound.

But in the end, since RNAi is temporary and is removed from the body relatively quickly after initial exposure, without the nasty side effects of current chemotherapies (cell mutations), the treatment being proposed to stop the growth of cells, in particular cancer cells, could prove very beneficial in the end.  Since it is reported that many cancers develop PLK4 overproduction, we can hope that this treatment will yield a powerful tool in the oncologist’s toolkit to treat and cure many different kinds of cancer!  Only time will tell, after many clinical trials can establish that this treatment will work in humans.

I will try to keep updated on the progress of CFI-400945 and report the developments here.


1)      Sheryl Ubelacker; Canada-U.S. team develops promising ‘sharp-shooter’ drug aimed at several cancers; The Province; June 18, 2013.

2)      Jacqueline Mason et al; Abstract LB-215: Inhibition of Polo-like kinase 4 as an anti-cancer strategy; Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl).

3)      Andrew Holland et al; Polo-like kinase 4 activity limits centrosome overduplication by autoregulating its own stability; The Journal of Cell Biology; Vol. 188(2); pp 191-198.


****Update: June 21, 2013****

Thanks to one of my readers, Alan Chan, who found this link patent using the Google Patent search app. (https://www.google.com/patents/WO2011123937A1)  It now appears that it could be possible that CFI-400945 could be a small molecule inhibitor of PLK4.  Although this perplexes me since they consistently advertised to the media that CFI-400945 was a new “Sharp-Shooter” class of drugs.  Being a small molecule inhibitor, while specific for PLK4, is not really a new class of drug since small molecules have been engineered by chemists to be used as drugs for a long time.  An example of one of the most popular small molecule drugs that we use is Tylenol or better known as acetaminophen!   Another interesting fact about that patent is that Dr. Tak Mak is listed as an inventor whereas there is no mention of Dr. Dennis Slamon.  While during the media release of CFI-400945, they gave both scientists equal praise.   But the possibility still exists, and perhaps Dr. Slamon only became an active scientific contributor on the drug after it was patented.


Regardless on the make up of CFI-400945, we’ll all wait anxiously as we learn more about this drug as the scientific literature will undoubtedly start to roll in after this announcement and we can find out once and for-all what CFI-400945 really is and whether or not it really works in people!  Keep on hoping!


Filed under Drugs in development