Director of Targeted Therapies Mass General Hospital Cancer Center
Harvard Medical School
Interview by Heidi Legg
Dr. Keith Flaherty is leading some of the most innovative research in melanoma cancer research in the world today at Boston’s Mass General Hospital and at Harvard Medical School, and his discoveries will be applied to other cancers as well. His group is breaking down the process of the cancer cell like a cloak and dagger video game. Interestingly, when Dr. Flaherty spoke with me there were many points in our conversation where he actually switched into the first person point-of-view as the rogue cancer cell. It illustrated, in my opinion, his determination and obsession with beating what has long been one of our most devastating illnesses in America. He is a true visionary in our eyes and he and his team of researchers are breaking new ground that will grow exponentially in the next decade.
Is this the greatest cancer breakthrough in a hundred years?
We are closer to the definitive level of understanding cancer, at least at the genetic level.
The vocabulary to describe what it is that makes cancer tick began being elucidated in earnest in the 1980s and then in a much more accelerated fashion through the '90s and into the 2000s, culminating in the past year with the most complete genetic characterization of cancer that has ever been accomplished.
Decoding cancer in that way, simply put, has allowed us to turn that understanding into therapies that specifically target the genetic or molecular building blocks of cancer.
What has transpired in the research that my group has done in melanoma is seamlessly tied to what has been and continues to transpire in all of cancer research, and that is basically trying to have as deep a molecular understanding of cancer as a disease entity as possible.
And that is not a different proposition in melanoma versus lung cancer, colon cancer or otherwise, and it shouldn't be because there is a common lexicon that's used across all of cancer; which is to say that for a melanocite to turn into melanoma, it has to accomplish some of the same tricks that a normal lung cell has to become lung cancer - same as a breast mammary epithelial cell must do to turn into breast cancer, and so on and so forth.
Are you saying your discoveries in melanoma analogize across different cancers as well?
Absolutely. You have to step back with cancer and think through 'what are the fundamental tasks that must be accomplished by a cell to become cancerous?' To think about cancer at the single cell level, we see it has the same evolutionary drive that we, as a species, have had throughout the history of life.
Cancer cells have their own intrinsic evolutionary drive or engine seeking to survive. And that's a problem because every cell in our body is a member of a tissue or organ that is a member of a whole entity, and all of those components need to get along and perform their specific functions. In a normal healthy body, when any one of those cells age over time and become dysfunctional in very real ways, it needs to know when it's time to go and there's a process by which cells recognize that internally.
It sounds like the problem with cancer cells is that they do not recognize it’s time to go?
To go from a single cell organism to a multi-cell organism to a multi tissue/organ organism is a very orderly development and then life span. Basically, what ultimately has to happen for cancer to be cancer is it has to start violating some of those rules. We’ve discovered there are many ways in which that occurs, but we think of this problem as being basically one of programs. Programs that are basically broken or rewritten to serve the purposes of a cancer cell which is now no longer - by definition - respecting its boundaries and no longer living by the same orderly rules. In the normal cell aging process, the cell dies. It commits suicide. The process referred to is 'programmed cell death' that is intrinsic to every cell in the body.
You, for example, accumulate genetic alterations or mutations over time and that's true of all cells in all living beings, not just people, but in all organisms - part of cell aging is that genetic damage is done. And all of us have repair mechanisms for that; the repair mechanisms are highly elaborated and a certain amount of damage can be overcome and repaired so the genetic code is kept intact, but there is a tipping point.
When a certain amount of genetic alteration happens or cannot be repaired, particularly if it happens very quickly, [the cell] is beyond the tipping point. It’s when the censors detect essentially an insurmountable amount of damage that then is a way of triggering program cell death.
There are other ways. The so-called free radical formations that become unstable and then start shredding cellular components including DNA, which is what anti-oxidants and certain vitamins are meant to absorb and protect us from, then that sensing system executes a program by which the cell commits suicide and will be presumably replaced by a neighbor.
This is a healthy system. How does the cancer cell discard boundaries and rules?
So an essential early phenomenon in cancer is that those sensors must be broken, or the program or the individual components of the pathways that regulate program cell death have to be broken.
The cancer cell is rogue?
Right. You as a living human being don't want them, but if you are the rogue cell that's trying to jump the tracks, then it is essential you not be caught in programmed cell death.
Imagine trying to break into the bank, the first thing you do is spray paint the surveillance camera outside the bank so that you don't get caught. We have learned that this is an essential early step in the process. Now mind you, I'm using very anthropomorphic terms like describing if the cell wants to do these things for the sake of discussion, but the fact is it's random. Genetic damage happens randomly.
In melanoma formation we think the principle version of genetic alteration or [the] damaging agent is ultraviolet radiation - not the only, but largely. When you think about it that way, ultraviolet radiation doesn't know where to target in terms of the genetic code, in terms of where to introduce mutations in your body, it just occurs. But if mutations are introduced in certain portions of the genetic code, then the cell will recognize that and try to repair them, and if it's insurmountable will just say, 'Okay, that's it. We're folding up shop and this cell is going to die.' But if that genetic damage randomly happens in the genes that encode the sensing functions, then click number one in the combination lock has been dialed for cancer.
So rogues cells in the genes that encode our censors are a big problem?
If you don't knock out the sensors as an early step, then all of the damage that could ever happen will just be recognized and the cell will never be able to become cancer.
Do you notice that you are talking in the first person of the rogue cell? That’s just awesome.
This is how one has to think, because it is ultimately an evolution gone wild. You have to think about how you will try to rein it back in step-wise - at least that's how we approach it now. What’s the next step? What are the other things that need to happen for a cancer to become that rogue cancer cell? Well it has to be able to not only multiply itself in an orderly or gradual fashion, but rapidly; otherwise it would never threaten us.
It grows in a very controlled and organized way, and so growing and multiplying is a tightly regulated process that needs to be deregulated. And how is the cell cycle regulated? Well, it partly interacts with this sensing of damage but there are other components that have nothing to do with that at all.
For example?
Cells receive signals from outside of them that tell them about whether there are adequate nutrients and if the environment is good for growing and multiplying. Cells can rewire themselves through certain genetic alterations to believe that they are in a nutrient rich environment when they're not, and that's a necessary trick for cancer cells. As soon as a little nodule of cancer cells grows just the littlest bit and you've got several thousand cells even - much less the millions or billions that it takes to actually form a tumor - they actually create nutrient-poor environments because they don't have blood vessel formation happening in an orderly way. They don't have oxygen and other nutrients delivered to them the way that normal tissues do, and so to survive they have to fool themselves into thinking that they're in a perfectly nutrient rich environment when in fact they're not.
The way they do this is that mutations accumulate in the proteins, in the signaling molecules as we call them, that transmit the message from outside the cell to inside the cell to say that there is or isn't an adequate oxygen supply or nutrient supply. And the cancer cells turn them on. They flip these transmitters on permanently so that the cell always thinks that it's in a good environment even when it's not.
Amazing. Why do I feel like I’m in a high-powered video game? Why were you drawn to this challenge?
When I chose to focus on melanoma, none of this code had been worked out as it pertained to melanoma. I chose to focus on melanoma because nothing worked from the era of chemotherapy in this tumor type, and I figured a totally new approach was needed, and I reasoned that it would be based on this genetic unraveling of cancer. What was discovered in 2002 was this mutation that turns on a protein inside of cells that tricks it into thinking that it is getting kind of a growth signal at all times, tricking the cell that it is in a nutrient-rich environment - this gene called BRAF. Now this is not the case in all melanomas but in about 50% of melanomas BRAF is applicable.
It turns out about 8% of all cancers of all kinds have this same mutation that flips this switch - 8% in all of cancer, 50% of melanoma - and so when that BRAF mutation was discovered and publicized, that was the light bulb moment.
For the first time in the melanoma field we now had an explanation for some of its bad behavior and it was specifically this signal that was sent inside of cells to tell it to multiply, multiply, multiply - everything's fine - multiply - and that signal never stops because of this genetic alteration in the gene that encodes this enzyme or protein called BRAF.
And the good news is that analogous circumstances are across cancer - meaning there are multiple instances of those discoveries being made today. When you can develop a drug that will target that thing and flip the ON switch to the OFF position again, that’s pretty great. And that's critical because you can't always develop a drug.
What about targeting the gene itself?
This is a key point because we don't know how to target genes. We don't. Some day we will but we don't now, and this is all of medicine. It's not just cancer. Furthermore, we only know how to turn things that are ON to OFF. We don't know how to turn things that are OFF to ON, and that's a major problem because we don’t yet know how to restore the sensors that are broken. In all of cancer research, and melanoma specifically, we are looking to understand the things that are turned ON so that we can turn them OFF, hoping that we can be sufficiently complete in doing so and derail cancer's behavior even though we know, at least based on current technology and foreseeable future technology, we will not be able to turn the things that are OFF back ON again.
Also, we believe, and this is based on scientific evidence and generated in a laboratory, that we don't have to address every abnormality. We don't have to look for every ON switch and every OFF switch and flip them all into the correct position. We just need to get to a certain number so that it creates, in the analogous way, this insurmountable signal or stress to the cell where now all of a sudden you have basically told the emperor that it has no clothes, with the idea that that will basically end the charade right there.
Simply put, what we're doing in cancer is trying to turn off all the ON switches that we can. In melanoma what separates us and what puts us in a little bit of a different realm than many other types of cancer is that we have a more complete genetic decoding at the moment. We've identified more of the ON switches than other cancer types, and thankfully many of them are amenable to drugs.
What do and will the drugs look like?
We are building two-drug and three-drug regimes to turn off two and three switches all at once for the first time in cancer, meaning that we know we need to switch off more than one to reverse the tipping point. That's been known before we ever got to one and so BRAF was that approach. BRAF was the first switch discovered. It took us seven years to finally get to the point of being able to drug it effectively, but we knew all along that that wouldn't be the end of the story. The issue is how quickly we can develop similarly rational drug regimes that add to that by turning OFF the next switch and the next switch.
How many switches are there, and do they all need to be turned off to beat cancer?
No one knows exactly how to answer that question. The number of mutations is enormous - thousands. But the number of meaningful ones - the ones that matter – there are no more than dozens. A functional number that many think is the essential number that cancers absolutely need to become cancer is on the order of eight to ten, but we don't think or we certainly hope that we don't actually have to drug eight to ten. We hope that if we get to even three, that could be enough to shut it down. So the issue is when we get to three - and we'll be at three soon in certain cancers and melanoma as an example - when we get to three, will we have recreated HIV - where we've now turned cancer into a chronic disease?
You can see cancer becoming a chronic disease like HIV?
Yes. Nobody’s cured of HIV, essentially, but like an HIV-like illness, as long as you take your medication, you will live indefinitely. The question is can we recreate that and is that the best we can do? Or can we eradicate the tumors by pushing them back before the tipping point? That little arc that we've covered, literally, is how it's all going down.
Fascinating. What’s next?
Let me add another important point because it's a critical theme to be aware of. What if in trying to find all the switches that are turned ON that we're capable of turning OFF with drugs, we're only able to address some substantial fraction, maybe 50% of all cancers? Well, the hope for the rest of the problem, which is not a future hope but a current hope - like a parallel track, if you will - is that if we can't go after the things that are genetically altered, then maybe we can go after indirect strategies such as outstripping the rogue cell’s blood supply or removing their ability to generate new blood vessels.
What are the other fundamental processes? These cells need to escape the immune system. These tumors hide themselves from the immune system. They cloak themselves. How about if we uncloak them? Fortunately, it turns out the immune system is capable of recognizing cells that harbor mutations, and so how about if we do nothing to target the tumor cell itself but we just uncloak it so the immune system can see it? Those are whole other branches, if you will, of cancer therapies that have exploded in these past ten years.
We know how these processes work more than ever before. We don't know them in a complete way, but magnificent gains are also being made in fully understanding how these other processes work like escaping the immune system, like forming blood vessels. So when you understand those processes and their hierarchy, then you can think about drugging the number one and two most important components of those processes.
What number of scientists and doctors in cancer research are being funded?
Across the world? There are hundreds of us in the laboratory and clinical trials.
Do you all know each other?
Yes. It's a small community.
Is Boston and Mass General Hospital the epicenter?
It's certainly one of them, and probably the epicenter when it comes to taking the genetic decoding to drug therapy.
Who funded your practice and research at MGH?
Multiple sources. The National Institutes of Health (NIH) is our primary supporter. The National Cancer Institute, which is within the NIH, funds us to the largest degree. We also have philanthropic support. By that, I mean foundations that focus on melanoma research. One of them is the Melanoma Research Alliance and we have grants - several grants - from them. There is a Melanoma Research Foundation that is more of grassroots patient advocate organization, but they also fund grants and research as well, and they support a good bit of our work. Then we have local level philanthropy that supports us. It ultimately takes all of that to be able to build an enterprise of this size.
Does big pharma fund you as well?
Yes. We need them for the drugs. It is still not yet possible financially - not technically, but more financially - to develop the drugs that are needed for human application in academic laboratories. We can and do develop them for laboratory testing, but to get them to the point of purity, safety and such for human testing and then use, that still requires the private sector in this world today, and that may always be the case. That is why we collaborate with them first and foremost.
How many players are there in big pharma?
Most would say there are eight oncology-focused big pharma companies in the world right now and they have been the big generators of drugs, but not in the discovery of drugs. I use the word 'generator' because they largely have in-licensed, bought up individual drugs, or whole small biotech companies along the way towards having this portfolio of these targeted drugs that turn OFF the ON switches.
Much of the way oncology drugs’ development has proceeded in the past ten years and is proceeding now as we speak is that academic research institutions discover new targets, then small companies develop the frontier initial drug approaches, and finally pharma swallows them up and takes them the rest of the way - meaning towards FDA approval. Huge clinical trials have been needed historically, although smaller trials have been seen more recently, but then even marketing distribution is a pharma enterprise.
It seems that everywhere I turn, another friend is having a chunk taken out for skin cancer. Why the prevalence?
Recreational sun exposure is a thing of our lifetime. If you go back to the early 1900s, laying out in the sun and being exposed to the sun on purpose is a phenomenon of the 1950s/1960s, and in earnest after that - 70s, 80s and later. Even outdoor sports were not nearly as common before these past few decades. In the same way that there were doctors smoking in the hospital and certainly around it in the '50s and '60s, and then we saw lung cancers. Being the son of two doctors, I was on the beach as a child with no sense that there would be a problem for me. The thought for decades as the sun-seeking phenomenon was unfolding was that, overall, it was a good thing to have sun exposure. However, you don’t need a tan to have adequate Vitamin D. You need a trivial amount of sun exposure to have adequate Vitamin D levels.
So it’s nothing more than human behavior as the cause?
Absolutely. It's the human behavior of pale people. There is severe protection against skin cancers and particularly melanoma with just the littlest bit of darker complexion. It doesn't take much. Asian and Hispanic - but even Asian, which we don't think of as being particularly darkly pigmented, are remarkably protected against melanoma.
Caucasians of all kinds are the ones who are susceptible and even then, within the Caucasian population, there is a spectrum of risk. The blond hair/blue eye, green eye/red hair combinations are the most susceptible, and dark Mediterranean complexions within the Caucasian realm are significantly protected.
If you take those extreme examples of the worst skin types, where the skin is essentially unable to protect itself, and migrate that skin type to those latitudes [of] Israel, Australia, New Zealand, that is when you see the world's most markedly high cases..
Are other countries leading this cancer research?
In the US, there are other major cancer centers that have large melanoma programs that are major contributors as well. Europe and Australia are our two other regions of the world that we have essentially seamless collaborations, in both laboratory and clinical research. The countries in Europe that are most notable are Germany, France and the UK - not to leave out Italy who is also a significant player in this regard. In Australia melanoma is a more common cause of cancer death and as a result, they make major contributions. The nice thing about the size of the melanoma research community is that it is fairly seamless for us as a global research community to collaborate and really have a very similar sense of purpose and approach.
What do you wake up thinking about?
First and foremost, I think about my individual patients who have life threatening or imminently life threatening melanoma because we still don't have approaches that are applicable to every single patient under my care.
We have created haves and have-nots in terms of those patients for whom we understand enough about the genetic makeup of their melanomas where we can target their tumors more effectively, buy them a lot more time, and forestall life threatening manifestations, and those for whom our current understanding is lacking in terms of what makes their melanomas tick in a way that we could turn into drugs. There’s work in progress with drugs that are promising and still in trials, but we have a ways to go.
The second thing is how do we break down the problem into tractable units? How do we build this approach of decoding and matching patients to therapies that are suited to their individual tumor and its individual genetic makeup? How do we 'catch up', if you will, the back of the park? Those are the things that wake me up.
What does society need to crack this?
Modifying risk has to be part of the equation. Part of this is not that the medical field will take care of this with single shots and Star Trek scanners.
We need to look at obesity for a lot of cancer, smoking for a lot of cancer, even though only 20% smoke. There is a lot of individual contribution to be made. Yet since we are not built to last, we need understanding and patience on what it is going to take to understand this process in a complete way. The acceleration of technology has its parallel in bio medicine, and if you look at the past three decades and the rate discoveries are being made, it is hard to not predict we are in an exponential rise and will make great advances in the next 20 years.
Decoding the entire cancer genome per person is possible, and being able to do it rapidly and make certain calls will require bio-informaticians, educated by biologists and statisticians.
What public habit would you change?
In the same way that my colleagues who focus on lung cancer would say, 'I'd give it all up if we could just get people to stop smoking,' I'd say that in melanoma we could solve much of the problem if we could raise awareness to the point that people would understand that sun exposure is a thing to be avoided if you have the wrong skin type.
We wouldn't eliminate the problem but we would make major inroads and reverse this decades-long rise in melanoma incidents and fatality if we could just raise awareness to the notion that the sun is unfortunately not our friend and that we were never meant to live in some of the latitudes where we live now. We were never meant to hop on planes and go towards the equator and even spend a week at a time there and we need to be mindful of that and respect it. Prevention. If it could happen in a day, it would be the greatest revolution we could ever have.
You have two young daughters, how do you treat sun protection?
They know the drill now. At the ages of eight and ten they take it seriously and they understand that it is just a part of life. We don't avoid the sun but we are always careful when we go out in the sun, and that means it's going to take more time. It means we wear more in terms of skin covering material because that's more powerful than any sunscreen.
That routine, even though it does not lend itself to instant gratification in getting outdoors or getting on the beach or whatever instantaneously, is part of life.
They also know that it’s paradise to be at the beach at five o' clock in the afternoon and these other messages that we hope they will carry even through the volatile teenage years and obviously beyond!
The best evidence we have suggests that young skin is the skin that needs to be protected most. Lifelong increased risk is incurred by early sun exposure. All of us who grew up in an era when oil on the skin was the standard, not a sunscreen… well, we’re all too late.
Can we trust sunscreen?
You can but not completely. Harmful rays do still get through. However, sunscreen protects against other forms of skin cancer: non-fatal skin cancers quite remarkably and melanoma, modestly. The best prevention is sun avoidance and coverage - meaning with clothing. This is still far, far more powerful at protecting against melanoma than sunscreen will ever be.
Sunscreen is better than nothing but it is hardly a substitute for avoidance/coverage, and that's probably the most important point that still hasn't penetrated. No sunscreen, no matter how it's engineered in the laboratory, will last an entire day. No matter the SPF rating, it has to be reapplied if one is going to be out for much of the day, because the physical properties break down and it doesn't stay on the skin very well after even just a few hours.
Are the chemicals in sunscreen riskier than sun in causing cancer?
No. It's a great misconception that unfortunately fights against us in terms of people's use of sun protective measures, but there's not a shred of evidence that there could be any toxic effect of any of the products that are on the market.
Do aging skin treatments mask cancer?
No.
Do foods or Vitamin D protect us from the sun?
Vitamin D is an antioxidant and while we think antioxidants would be part of the formula, we don't yet understand well enough how one would actually adjust their diet or supplements to take advantage of this. It may be that to use those methods you would have to pump up intercellular concentrations of vitamins to a level that just can't be achieved.
Are we doomed?
No. As a species we're not. But we won't live forever. We're a frail entity and you could say that preventing death from cardiovascular disease makes cancer a bigger problem, because now you've got people living longer and ultimately something is going to get you. But we don't have to die young and we don't have to die because of our own lack of awareness about things that are preventable.
Melanoma is the second leading cause of years of life lost from cancer - which is to say that it affects younger people much more so than other very common cancers like breast, colon, prostate and lung cancer. Those are the most common but happen in much older populations, in general. Brain tumors, leukemia, and melanoma are the top three in the 'depriving people of longevity' category. And so as a cancer research field, we can, should, and will make a dent in that.
Do you believe in climate change?
I do. It is hard to say if there's any relationship between the two. Ozone does protect us against some ultraviolet radiation that is harmful to us and causes skin cancer, but ozone and global warming are only slightly related.
Do you have a mentor who helped you in this career?
If I were to pick a single mentor, I'd have to say Dr. Peter O’Dwyer who I went to the University of Pennsylvania to train under. He is an Irishman who came to the US to train in oncology after having medical training in Ireland, and stayed and worked at the National Cancer Institutes in Bethesda, Maryland. He had learned the ins and outs of how one does cancer research, particularly touching patients as well as laboratory. I credit him for my ability to be able to take a scientific discovery and as rapidly as possible turn that to therapy for patients and still, to this day, it's the case.
Would you describe a day in the life of Dr. Keith Flaherty for us?
When I am in town, I get up at 5 am and exercise and by six, I am in the shower and then make the kids’ lunches and breakfast. By 7 am, I wake the kids and we are out the door by 7:30. I get to the office at 8 am and three days a week, I work until 8:30 pm. The other two days I make it home for family dinner. I do travel a great deal, mostly in the US, a lot to Europe, and a little bit to Asia, Australia and South America. I travel about 200,000 miles a year.
I respond to 300-400 emails a day and I use voice recognition for as many of those as I can. All the research I do nationally and internationally is managed by emails and teleconferences.
You also teach at Harvard, see patients, and are married to a doctor? How do you balance it all?
The first principal is to be present when you are present. In my professional life I multitask like a crazy person, but when I am with my wife and children the goal is the opposite. Single stream thinking and then I can make a fraction of the time meaningful, but there are not enough hours in the day.
What event are you looking forward to?
[There is] an annual conference that began in 2003 where the society for melanoma research collides thoughts and data. This November is the tenth anniversary and it will be in Philadelphia where the first one began.
What website do you frequent the most each day?
National Institute of Health maintains the reference library for all scientific pursuits.
How do you get your news?
Online. iPhone. Non-scientific news is something I have to squeeze in on the T or walking to work. Podcasts are very useful and something I use.