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Cancer Research 101

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Cancer Research 101: 2/12/12 - 2/19/12

Friday, February 17, 2012

Welcome to the World of Genomics... [Part One]

Although chronic myelogenous leukemia (CML) which is the main target of Gleevec, would not be considered one of the "major" cancers, I consider Gleevec to be the "poster child" for rational cancer drug design. I think that its importance goes far beyond CML but really creates a "proof of principle" that this kind of approach really will pay huge dividends in the future.

But as I stressed in the last post, approaches like this can only work when we understand more and more at the gene and molecular levels exactly what are the nature of the mutations that underlie particular cancer diagnoses. Which brings us to the brave new world of genomics…

With the success of drugs like Gleevec, combined with huge advances in technology, the field of cancer genomics is exploding and researchers around the globe are trying to catalogue as many cancer-causing mutations as we possibly can. So, what exactly is the study of genomics, and why should we care?

To understand cancer genomics we need to step back and understand what exactly is meant by the "human genome". Simply put, the human genome is the full collection of genetic material in each one of us.

You will recall that normal human beings have 23 pairs of chromosomes, and these chromosomes are comprised of long strands of DNA. If you remember your high school biology you will remember that DNA is comprised of four different chemical building blocks which we abbreviate as "A", "T","C", and "G". In each of our genomes there are about 3 billion(yes, that's billion with a 'B') of these building blocks arranged along each of the 23 chromosomes, but in a very particular order for each unique individual. It is this unique sequence of your DNA that defines the genes that make you an individual, different from me as an individual, different from your friend, different from your siblings etc. So, genomics is simply the study of the genome, and our attempts to understand how differences in the sequences of DNA contribute to human life and to individual variation.

So why is this important for cancer? Simply put, cancer is a disease of genes and mutations, i.e., mistakes in this “DNA alphabet”. The more and more we understand the genome alphabet and the more we learn about the different mutations that are associated with cancer, the better able we will be to understand, prevent, diagnose, treat and even cure cancers.

Now we have known about some fundamentals of DNA for a long time. The famous paper in the journal Nature by Jim Watson and Francis Crick was, after all, published on April 25, 1953! But knowing about some of the fundamentals of DNA is not nearly enough until we developed some tools to really study this in detail. Fast-forward from the famous publication by Watson and Crick about 25 years and you find me, as a postdoctoral fellow at the University of Calgary, doing some sequencing of DNA genes. In those days, in the late 70’s, I would have been able to routinely analyze a few dozen base pairs of DNA at a time, and that would have typically taken me several days to perhaps a week in order to accomplish. When you're dealing with 3 billion base pairs, this is very slow progress indeed.

Let's put the genome challenge in perspective in a different way. The human genome is comprised of about 3 billion base pairs. If your job was to read aloud your own genome starting from one end of chromosome number 1 and going all the way to the tip of chromosome 23, how long would it take you to read your own DNA sequence? Let's assume that you can read at the rate of about five bases per second, and that you work eight hours a day straight, five days per week (I'll give you your weekends off!), and you do this 50 weeks per year. How long would it take you to read your own DNA sequence?

The answer is something in the order of 84 years!! More than a lifetime for many of us…

So when I tell you that on February 15, 2001, the same prestigious scientific journal Nature (the one that published the original Watson and Crick paper in 1953, published a paper from an international consortium of scientists that reported, for the first time in history, the entire DNA sequence of a human genome, I think it's more than fair to say that this was a truly monumental accomplishment.

In fairness, this was not the full DNA sequence of a particular individual - that would come later - but rather what could be termed to be a “typical" sequence or a "reference" sequence. It was created via a precedent-setting, historic worldwide scientific effort, combining the efforts of many, many researchers and laboratories around the world, and stitching together bits and pieces of human DNA sequence to form this prototypical reference sequence.

While I personally don’t consider this accomplishment to be the absolute holy Grail of molecular biology,  I cannot over stress how pivotal, historic and important this accomplishment was. It lays the very groundwork for an unprecedented understanding of human life, genetic variation, and even human disease. And it will have a profound impact on how we view cancers, and how we deal with cancers.

In a future post, I will show you just how far we've come even since 2001 when this first reference human genome was published, and by doing so, give you a glimpse into a future filled with optimism and excitement, yet one that we may not be quite ready for…

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Thursday, February 16, 2012

The era of rational drug design begins…

In a previous post I talked about barn doors and picking locks: how we need to get far more specific and selective in recognizing how to kill only cancer cells and leaving normal cells intact. Let me continue the lock and key analogy just a little bit further.

Suppose you found an old trunk in the basement or in the attic and it was secured by a huge padlock and you had no idea where to find the key. You could search through every key in your pocket or on your key ring, you could look in that little junk drawer in the kitchen that we all have or you could ask all of your neighbours to bring their keys to see if any of them might fit the lock. But that would be like kissing thousands of frogs in the hope of finding one Prince!

That might be great for children's fairy tales, but it isn't what a logical, thinking person would do. I’ll bet you’d call a locksmith who would be able to design a new key for the lock and get you into your trunk. (Actually, you might be prone to get a pair of large bolt-cutters and destroy the lock, but play along with me for the sake of the mind experiment!)

A few years ago anew drug called Gleevec hit the market and was the embodiment of this lock and key analogy. Gleevec was a drug that was targeted at a particular kind of cancer, a leukemia called chronic myelogenous leukemia or CML.

We had known for a long time that CML was characterized by an abnormal chromosome fusion. A small piece of chromosome 9 gets fused to a piece of chromosome 22 and creates a new DNA sequence at the point of fusion that does not exist in normal cells. It just so happens that this new DNA sequence encodes a new protein that is comprised of two pieces of two proteins that normally never see one another. A small part of a gene called BCR from chromosome 22 gets fused with a gene called ABL on chromosome 9. It is the over-expression of this new hybrid protein, not surprisingly called BCR-ABL, that creates the cancerous condition.

If you think of this new hybrid protein as a lock, then think of Gleevec as a specific key that fits into this lock and actually shuts the activity of the protein off. The abnormal protein is effectively stuck in the “on” position, and Gleevec interacts with a critical part of the protein and basically turns it into more of an “off” position. When the new abnormal proteins is no longer abundantly produced, the cancer effectively goes away…

The diagram below shows a schematic of this process. The green “ribbon” is a 2-dimensional approximation of what the CML abnormal protein looks like and the small molecule in red(Gleevec) is shown in the critical pocket of the protein where it interacts to turn it from “on” to “off”.

From a patient’s perspective, what is even more remarkable is that this new drug, that works so specifically, actually comes in a simple capsule. Take a pill, cure a cancer. How elegant is that?

That all sound good in theory. Does it really work?

Well there are countless patients alive today who will tell you that it does. Take Mr. Jason Blake, for example. Many of you will remember Jason Blake as a star hockey player for the Toronto Maple Leafs. Blake was diagnosed with CML a few years ago and was treated with Gleevec. By most accounts of the day, he barely missed any games and continues to play today, now with the Anaheim Mighty Ducks. In January 2010 when he was traded from Toronto to Anaheim, he was naturally asked about his cancer. According to an article in the L.A. Times on January 31, 2010, he said “"It's basically forgotten about now. I take a pill as someone would a vitamin every day...   At the end of the day, I never think about it. It doesn't affect me.“

Pretty hard to ask for a better outcome than that!

But realize that this kind of success of so called “rational drug design” or designing a key to fit a lock, ONLY can happen if you know what the lock looks like in the first place. No more kissing thousand of frogs, but you HAVE to understand at the molecular level what is the specific mutation or mutations that are the root cause of the cancer, and then isolate or design a specific drug that targets that/those mutation(s).

This is why we are beginning an era of trying to catalogue as many cancer-causing mutations as we can, in as exquisite and fine detail as possible, and why the era of “precision medicine” or more “personalized medicine” is firmly upon us.

More about that to come...

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Wednesday, February 15, 2012

It’s all Relative...

Wow, it's hard to believe that it's been about a month since I last posted to this blog. Despite all of my good intentions, somehow the time just seems to have gotten away from me. More than once I have pondered, now that I am notionally "retired", how in the world did I ever find time to hold down a full-time job!

I guess like all things in life, it's all relative…

Which brings me to the subject of today's post. I was having lunch a couple of weeks ago with a former colleague who I have not seen for quite a number of years (one of the perks of now having some time to catch up with old friends!). We got to talking about how difficult it is to maintain an even keel about the promise of cancer research, when the natural tendency is to want to celebrate, even to the extent of often over-hyping preliminary results that are still a long way away from the clinic.

Researchers, after all, need to be able to support their research by convincing granting agencies to fund them, and granting agencies need to justify their own success by keeping themselves in the public eye, especially for those that are charitable organizations dependent on public trust, enthusiasm and donations. Even government funding agencies need to be accountable to their paymasters and compete for ever diminishing funds.

This is a very difficult tightrope to walk, and I know this from personal experience. More than once, I have been very uncomfortable about granting an interview to the press on a result that, while brimming with excitement and potential, was a long way away from being of proven value in the fight against cancers.

But it is very difficult to get that even-handed message across, even when you want to, because the media are not interested unless there is a bit of a sensationalist angle to the story.

There is also a big problem with the perception of the reader or the listener or the viewer. One of the biggest problems comes in the area of non-scientists trying to understand the concept of risk, especially the difference between absolute risk and relative risk. Let me illustrate the problem.

Suppose you read in a headline that a new discovery shows that factor X leads to a 30% increase in the risk of a particular cancer. On the surface, such a huge increase in risk would likely take the reader aback, and possibly create significant fear or concern, especially if factor X was something you personally identified with. And indeed a 30% increase in relative risk might well be significant. But it also may be almost insignificant in the overall scheme of things.

How so? It all depends on what is the ABSOLUTE risk in the first place. For example, if the absolute risk in the first place was one in a million, then a 30% increase raises the stakes all the way to 1.3 in 1 million. I don't know about you, but I don't think I'd be losing one wink of sleep over such an increase when the probability is so minuscule in the first place. This is why we have to be extremely careful about how we report numbers and percentages and risks. Now if you tell me that my risk of something just went from 1 in 10 up to 3 in 10, then that indeed is a very significant increase and one that would cause be to have great concern. But that jump is far in excess of a 30% higher risk, and in fact is a threefold increase in absolute risk.

I don't want to belabour the point, but really to drive home the message that one must look at every headline, not with a grain of salt, but with the wisdom of having an inquiring mind, and asking what is this really telling me? Often times what you think it is telling you is in fact what the writer or the editor WANTS you to come away with, and may or may not be the accurate message that you OUGHT to be coming away with.

In other cases, it may not be a case of hyperbole or any intent to mislead, but simply that the subject matter is complicated and requires the reader or the listener to really think carefully about the data that is being presented.

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