Personalized Medicine [Part 2] - Time for a Reality Check?

Despite the enormous promise of personalized or precision medicine coming from the  genomics era, I think we need to collectively take a deep breath and also ponder the reality of just how far this new technology can take us.

Without in any way diminishing the huge potential of the "$1000 genome" era, I think there are at least two important areas where we need to do a reality check.

 The first of these I have already written about - the need for debate in society about how we want to view privacy and confidentiality, and how are we going to deal with the influx of personal, genetic information that could overwhelm and confuse us despite good intentions to the contrary.

The second area stems (no pun intended) from the reality that cancer is, at its heart, a set of diseases marked by tremendous  genetic instability. The reason that so many cancers are hard to treat is because every time you think you have it pinned down, it morphs into something a bit different.

For example, when a number of the first Gleevec patients started to relapse, the sound of people jumping OFF the bandwagon was an audible thud. Skeptics said "see, we knew it couldn't really work so easily!" Subsequent studies showed, however, that Gleevec indeed worked exactly as advertised, but in the interim, the cancers had “evolved” – they developed some secondary mutations that essentially allowed the Gleevec roadblock to be bypassed.  If  you put roadblocks up on the main highways, cancer will find a way to take a side road to get out of town. If you block the side roads, cancer often will find some other route.

So, the advent of an international consortium like ICGC  that is  so very powerful, coupled with the fact that gene sequencing costs are spiralling downward, leads us logically to anticipate a new era of personalized and precision medicine. The idea is out there that if every patient’s tumour could be biopsied and his/her cancer genome sequenced so that we can determine and understand the underlying genetic defects, then we will be able to choose a tailored therapeutic regimen to treat that patient and his/her cancer in a more targeted way than ever before possible.

But that kind of future scenario depends not only on “cheap” sequencing technologies and an enormous database of mutations associated with cancers (both of which are now or will soon be in our reach), but it also depends, at least in part, on one other crucial factor. If we do a biopsy on a patient’s cancer, are we confident that what we will learn will be sufficient to give us the depth and detail of understanding that we need so that we can put this therapeutic precision and personalization to the test?

As is so often the case with cancers, the answer is, maybe…..

Why the hedge? Because we haven’t yet fully accounted for the idea that tumours are undoubtedly NOT homogeneous, that is, they do not have a uniform structure or character. There may well  be many different types of cancer cells even in a single patient’s cancer. We call this “tumour heterogeneity” which in simple terms means that the tumour may be a “dog’s breakfast” of different kinds of cells and different kinds of mutations.

As Dr. Dan Longo wrote in an editorial entitled Tumor Heterogeneity and Personalized Medicine in the March 8, 2012 issue of the New England Journal of Medicine:  

“A new world has been anticipated in which patients will undergo a needle biopsy of a tumor in the outpatient clinic, and a little while later, an active treatment will be devised for each patient on the basis of the distinctive genetic characteristics of the tumor,” he wrote.  “But a serious flaw in the imagined future of oncology is its underestimation of tumor heterogeneity.”

This “complication” came to the fore earlier this month with the publication of a very important study, entitled IntratumorHeterogeneity and Branched Evolution Revealed by Multiregion Sequencing published in the same New England Journal of Medicine issue. 

That’s a very technical title, and indeed a very specialized and technical paper, but the bottom line of it is this: a team of researchers led by Drs. Marco Gerlinger and Charles Swanton from London, UK found that there was an astonishing degree of genetic variation in biopsies from the same tumour from the same patient. In fact, multiple biopsies taken from single patients with kidney cancer (renal carcinoma) showed that there were many different mutations in each biopsy, and that not all of them showed up in all of the biopsies. In fact, the majority (over 60% of the mutations) did NOT show up across all of the biopsies.

Even worse, the researchers found that the mutations and gene “signatures” found in one region of the tumour were consistent with what we would currently have said is a good prognosis, whereas gene “signatures” found in a different part of the very same tumour were consistent with what we would have expected to be a poor prognosis!

This study, if typical for other tumours, suggests that a simple, i.e., non-invasive biopsy of a limited region of a tumour might NOT be at all sufficient to proceed with a very targeted therapeutic regimen. What if we targeted treatment to the wrong cells, cells that maybe by chance only represented 10% of the tumour?  What if we chose not to treat aggressively based on an ostensibly great prognosis from the biopsied material, only to find out later to our detriment that we were fooled by a “sampling error” of lamentable proportions?

So, bottom line, looking at both sides of the coin of "personalized medicine" (e.g., this post and the previous post), what does this all mean?

Are genomics, DNA sequencing and the building of mutation databases of enormous proportion tantamount going to lead us single-handedly to the Holy Grail of cancer treatments? Hardly.

Does the Swanton et al. study on genetic variation in kidney cancers mean that we are wasting our time with  the pursuit of genomics and precision cancer therapies? Again, hardly.

Like all things cancer, black and white approaches are simply not the way to go. This may be a bump in the road, as some have alluded, but if it is, it is not the end of the road by any means. We will learn some breathtaking insights from genomics, but it will be only one powerful tool in the arsenal, not the whole answer.

As one blogger eloquently put it in describing the kidney cancer study (Jessica Wapner, March 9, 2012, in a PublicLibrary of Science blog)

“It’s for this reason that the idea of personalized medicine—and here we are talking specifically about drugs targeted against the genetic make-up of an individual cancer, not about a whole-person regimen for life based on your personal DNA quirks—is one that has to be held with a long-view. It took decades for the first useful chemotherapy drug to be discovered. If we absorb the notion that targeted therapy is still in its nascent stage, then this new study isn’t a bump in the road, but rather another description of the scenery.”

Personalized Medicine [Part 1] – The PROMISE...

Whether you call it personalized medicine, or precision medicine, or whatever, the promise of the $1000 (or less) genome has captured the imaginations and aspirations of the public and the research community alike.

This excitement is not ill-considered. One can assume that there are going to be vast improvements in our ability to prevent, diagnose, treat and cure cancers as we learn more and more about the mutations that drive the diseases.

As  Colin Hill contributed to Forbes on Feb 9, 2012 in his post “Beyond the $1000 Genome on the Forbes website.

“Larger availability of complete genomic data will have a profound near-term impact on cancer research. The ability to rapidly and economically sequence individual patient tumours will help us to better understand the biological mechanisms of cancer and will facilitate data-driven patient stratification. This, in turn, will facilitate more effective clinical trials and speed the development of new therapies.

The significant near-term growth of rich genomic data will impact the patient care side too. Companies ... will use this data to perform molecular analysis of tumours that will assist in pinpointing the optimal treatment strategies for individuals with cancer.”

But of course, no matter how cheaply it can be done, sequencing a single patient’s genome is not going to tell us much if we don't know what we are looking for. How will we know a “bad” mutation from a “neutral” mutation? As we saw with Craig Venter’s genome, his natural amount of genetic variability, and presumably yours and mine as well, is very high, and yet Craig Venter is by all accounts a healthy man.

Well, the supposition is that if we look at enough DNA sequences of enough cancer patients then a pattern will start to emerge and we will start to see certain mutations showing up over and over. How many will there be? Will some mutations be more directly linked to actual “causation” of the cancer (so called “driver” mutations) or will some be there as a consequence of the cancer and not actually involved in the origin or progression (so-called “passenger” mutations). Will we be able to tell the difference?

Answers to these crucial kinds of questions require a lot more data than we currently have. And that is where and how the International Cancer Genome Consortium (or ICGC) was formed.

Inaugural Meeting of Genome Scientists in Toronto 2007

Much like the Herculean world-wide effort to collaborate in determining the very first human reference genome sequence, the ICGC is also a massive consortium (website at http://icgc.org/) . The ICGC is a consortium not so much of scientists but of whole countries. The consortium was formed in 2008 after an inaugural meeting (Toronto) and report in 2007, to bring a global effort to bear in sequencing enough genomes for each of perhaps 50 or more types of important cancers so that we could start to answer some of the questions posed above. It is estimated that perhaps several hundred genome sequences derived from patients with any individual type of cancer may needed in order to be able to have statistical confidence of which mutations may indeed be the “drivers” vs. those that may simply be the “passengers”. If you consider the effort, and cost, of sequencing hundreds of genomes for each of perhaps 50 types of cancer, you start to see the enormity of the task, and why a consortium of countries in needed.

The ICGC is therefore funded in the main by governments and government agencies (federal and provincial here in Canada) of countries, along with some notable cancer charities and other funders. Each participating member country of the consortium is expected to invest at least $20 Million overall to that country’s activities. Furthermore, a commitment to fully, openly and quickly share ALL data with other qualified researchers world-wide is an absolute requirement for membership.

The secretariat of the ICGC is in Toronto, at the Ontario Institute for Cancer Research (OICR; http://oicr.on.ca), and Dr. Tom Hudson, an internationally renowned genomics researcher who is President and Scientific Director of the OICR heads the Executive.

OICR also operates the main data coordination centre for the consortium. Tom took me on a tour of the OICR server room about a year ago and I can tell you it is like something out of the movies :) The air conditioning costs alone for  just keeping the server room(s) cool must be enormous!

The goal of all of this of course is to have an international database of “signatures” of dozens of types of cancers, with enough confidence that we can start to use that data to better understand cancers at the gene and molecular levels, and be better able to determine predisposition to cancers (leading to better prevention strategies); to determine better and more pin-point diagnostic and marker mutations (leading to earlier diagnosis and better interventions), and to determine many new therapeutic targets for treating and curing more and more cancers.

In Canada, we have taken a leadership role for three different types of cancer – Pancreatic Cancer (ductal adenocarcinoma of the pancreas; collaborating and funding organizations can be found here; Brain Cancer (pediatric medulloblastoma; collaborating and funding organizations can be found here; and Prostate Cancer (adenocarcinoma of the prostate; collaborating and funding organizations can be found here.

 

Whether the ICGC actually achieves all of its lofty goals is of course yet to be fully seen. What is clear is that a major undertaking like this brings out what I consider to be the very best in science and scientists: the desire and willingness to not compete but instead to openly collaborate, to share data, and to work for the common good in ways that no single researcher or even a single country could manage.

This is so-called “big science” at its best and we should all be pleased that it is being undertaken in the international arena, and in the collegial and cooperative manner that it is.

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

In an earlier post [World of Genomics, Part 1], I began a discussion of the powerful new world of genomics, and how this kind of technology has the potential to turn cancer research on its head. The publication in February, 2001 of a complete sequence of a full human genome was indeed a watershed event. But as I indicated, this was what might be termed a "reference sequence" in that it was not the full sequence of an individual person, but rather a compilation of sequences from around the world that were pieced together to indicate what a "typical" human genome would look like.

In 2007 another major leap forward occurred with the publication of the full genome sequence of an actual living individual human being. The individual who contributed his DNA for this purpose was a familiar name to those who were following the world of genomics: Dr. Craig Venter.  

Craig Venter's Chromosomes

Dr. Venter has been one of the pioneers in this field, and was one of the principal architects behind the sequencing of the first human genome. Since I don't know Dr. Venter personally, I cannot comment on whether the contribution of his DNA to science was an act of supreme selflessness, or one tinged with egotism, or both, but it did help to pave the way for another major chapter in the unfolding world of human genomics.

 

By sequencing Dr. Venter's genome we learned many, many important things. First of all, we learned that he has 23,224 genes to be precise!

Far more importantly for our basic understanding of human genomes was the fact that almost half of his genes had variations or mutations of some sort. The genetic diversity that was shown was several-fold higher than anyone would have imagined prior to seeing the actual sequences.

Indeed, the day after Dr. Venter's sequence was published, Carolyn Abraham wrote in the Globe and Mail newspaper (September 3, 2007) that 

"the full human DNA sequence of one healthy middle-aged man is a boggling array of genetic quirks, burps and hiccups".

She then quipped, perhaps whimsically, that "there are 7 billion more humans to go".

I can't say whether or not her tongue was planted firmly in her cheek when she wrote that last comment, but I can tell you that it may have been more prophetic than she knew at the time. Consider that the original human genome program that culminated in the 2001 publication of the reference sequence was a truly international effort that probably took over 10 years to accomplish at an estimated cost of perhaps as much as 1-3 $Billion.

Contrast that with the fact that the determination of the Venter genome took far less time and far less money, perhaps in the order of $10 million. Of course, that is still a huge amount of money but compared to the original project, a significant improvement.

Where can we expect the future costs to be?

Genome scientists have been 100% correct in their assertion that the costs will continue to go down dramatically. Will they ever get to a point where we can see genome sequencing on a much more widespread basis? One look at the graph below suggests that this indeed will be the case, and probably very soon! 

The graph is courtesy of the National Human Genome Research Institute in the United States, and it shows how the cost per genome has been steadily going down over the last number of years. You will see a line on the graph called "Moore's Law". You may be familiar with Moore's Law from the world of computers, where the principal is that the number of transistors per square inch on integrated circuits had doubled every year since the integrated circuit was invented. In other words, computing power approximately doubles every two years.

On this graph, you see an inverse variation of that general concept, because in this case the cost of determining a genome is going down by approximately half every two years. Notice however, that right around the time of the determination of Craig Venter's genome there is a huge downward shift in the curve and the cost per genome has been plummeting ever since (note the log scale - this is an exponential decline!). This is due in the main to new technologies for automated sequencing that have truly revolutionized the field.

To emphasize the point, a company called Life Technologies based in Carlsbad California announced in January of this year that they will be debuting, later this year, an automated sequencing machine called the Ion Proton that will be capable of determining the entire sequence of a complete human genome in less than one day for a cost of less than $1000!

While $1000 is not exactly pocket change for most of us, it does put this into the realm of many other medical tests that might be done today. In other words, is not out of the question that your own doctor may one day be ordering a test for you that will see the complete determination of your genome as part of your doctor's diagnostic regimen.

So, what is the significance of all of this, aside from it being an astounding technological achievement? What it promises is an unprecedented understanding of human genetic variation, human disease (including cancer) that will also teach us much about predisposition to disease, including cancer.

This is where the idea of personalized cancer diagnosis and treatment comes truly to the fore. Instead of a "one-size-fits-all" approach with a cocktail or treatment "off-the-shelf", imagine instead the opportunity to treat your cancer taking into account your genetics and your specific underlying mutations. This idea of much better tailoring your treatment to your specific cancer mutations is the basis of "personalized" medicine that you have no doubt been hearing more and more about in the popular press lately.

Does this truly mean that every single person will be treated differently than every other person? Although one might actually think so based on some of the hyperbole that has accompanied this technological breakthrough, this is in fact not a reasonable extrapolation, in my opinion. Instead, what will be done is to better group individuals to ensure that the treatment that they are getting will actually benefit them.

We already know that many cancers that might appear to be the same to a classical pathologist under a microscope are not actually the same to a molecular pathologist once the genetics and specific gene mutations are better understood. And we also know that based on those specific sets of mutations, that some patients will benefit from certain therapies while others will not benefit at all. Rather than treat everyone the same we will increasingly be placing patients into subgroups to make sure that the treatments they are getting are actually going to produce positive outcomes. Perhaps this is why there is a growing trend away from the term "personalized" medicine and a growing adoption of the word "precision “medicine instead.

I think that there is also a huge significance in terms of the way it is going to impact society, and that is not necessarily all positive. More on that in the next post...

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…

Picking The Lock…

Most everyone has heard the old adage that the three most important things in real estate are "location, location, location".  If you were to use a similar approach for cancer therapeutics it might be "specificity, specificity, specificity".  To my mind, 'specificity' may be the single most important attribute for any cancer therapeutic to be maximally effective, and therefore the search for absolute specificity is in many ways the Holy Grail of cancer research.

Why do I say this?  To start with, there is a myth in the public's mind that it is difficult to kill cancer cells.  Frankly, this is nonsense.  Generally speaking, it is very easy to kill cancer cells.  What is difficult is killing ONLY cancer cells and leaving normal cells unscathed. This is where, by and large, cancer treatments of the past have failed us. 

But aren’t anti-cancer drugs, by their very name and nature anti-“cancer” drugs? There is where a second misconception enters the fray: that most chemotherapeutic agents have been specific anticancer drugs.  Actually, for the most part, most of the “classical" chemotherapy agents have in fact been drugs that interfere with cell division as opposed to being anticancer drugs per se. In fact, most of these drugs of the last generation target rapidly dividing cells, not necessarily only cancer cells. 

While it is very true that most cancers are comprised of rapidly growing cells, unfortunately they are not the only cells in the body that divide rapidly. For example, for those unlike myself were not follicularly challenged <smile>, your hair cells divide rapidly and replenish quickly. The cells in your digestive system and your gut are being replaced at a very fast pace.  And the cells that populate your blood system are also dividing quickly and on a constant basis to provide a (usually) never-ending supply of blood cells of all sorts.

By now, you can probably see where I'm going with this.  What are the major side effects at we usually associate with chemotherapy?  Your hair falls out, you get sick to your stomach, and more often than not you get anemic.  That's because the normally rapidly-dividing cells in your hair, your gut and your bloodstream are also under attack. The chemotherapeutic agents interfere with their rapid division in much the same ways they interfere with the rapid cell division of cancer cells.

So the trick is to discover and develop treatments that recognize truly unique properties of cancer cells, i.e., properties that are not shared with non-cancer cells. Simply targeting rapidly dividing cells is no longer be adequate (not that it ever was...).  We need to discover better signposts that define and identify cancer cells as opposed to normal cells.  We need to find new ways to make cancer cells stand out from the crowd, ways that make cancer cells scream out at us "I am the cancer cell.  Don't waste your time with those other normal cells. Take me!"
 
Look at the two accompanying pictures: I like to think of this as the old barn door analogy.  No longer is it acceptable to do a scatter-shot at the side of the barn in the hopes of hitting the barn door.  Now we want to go in and pick the lock...

I doubt that very many of my cancer research colleagues would appreciate being called the next generation of lock-pickers, but in one very real sense that's exactly what they are! The more and more specific, the more and more targeted and the more and more selective we can make our future cancer therapeutics, the better will be the treatment, the better will be the outcome for patients and the better will be the quality of life for patients during and after treatment.

This notion of targeting and specificity will be a constant thread throughout many of the posts to follow. You've all heard by now, I am sure, of the notion of "personalized medicine" or a related term "precision medicine".  This is a very important part of the whole notion of attaining maximum specificity in the treatment of cancers of all types.