This article was originally published on 25 March 2011
Special Feature: Cancer Crusade at 40
This week, Science and its sister publications take a look at where cancer research stands 40 years after the signing of the National Cancer Act, which marked the beginning of the so-called War on Cancer. For an abbreviated version of this interview with David Solit, see "Q&A: Finding and Exploiting Cancer's Weaknesses ." Also on Science Careers, read about training programs for clinical trials in "Conducting Cancer Clinical Trials ." And for more on molecularly targeted cancer drugs, see the news story "Combining Targeted Drugs to Stop Resistant Tumors " (free full text with registration) in this week's issue of Science.
See the entire list of cancer-related articles in all the Science publications at www.sciencemag.org/special/cancer2011/ .
And then there are compounds that are generated in-house, either by our own chemists here at Sloan-Kettering or from another academic collaborator [at] another institution. And so we use whatever we're able to find that fits the bill that we're looking for: it's particularly sensitive or particularly potent or selected for a particular target.
And then the ultimate goal, as you mentioned, was to try to ultimately bring this into the clinic. I've run certain clinical trials but mostly at this point partner with some of my clinical colleagues to test the hypotheses generated in the lab in the clinic, in actual patients, and then actually try to analyze tumors from those patients to see whether the patterns that we identified in the laboratory in fact hold true in patients.
A recent example would be BRAF. BRAF was identified as mutated by the
Initially when these mutations were identified, it was unclear whether targeting BRAF alone would be an effective strategy in patients. So we had identified model systems that had mutant BRAF. ... We then identified drugs that seemed to preferentially work in tumors that are BRAF mutant and then worked with companies to have those drugs tested in patients. And just recently it's been announced that an inhibitor of BRAF, called PLX4032, that we worked with in the laboratory -- we didn't develop the compound; it was developed by a company called
But we also, unfortunately, on the way, had a number of disappointments. There were early BRAF inhibitors that just were not very selective for BRAF and our data suggested that these were not going to work very well, and that turned out to be the case. We also looked a lot at inhibitors of MEK and they showed a lot of promise in the lab but were somewhat disappointing so far in the clinic, although there's some newer MEK inhibitors that seemed to have better properties than the older ones. And there has been some recent, exciting, and encouraging data with a new MEK inhibitor from
This is part of what we do. But, even after we see a success like this, it's not perfect. We haven't cured these patients and many patients either don't respond or develop resistance to the drugs. So we then go back into the lab to try to figure out why certain patients are responding and others are not. And again, to do that, we take cell lines or tumors generated from patients and try to figure out what is co-mutated, what's co-altered with BRAF that might be causing resistance despite the fact that a BRAF mutation is present.
So I'm very focused on trying to figure out which of the mutations ... are in the patients whose cancers come back after they get their surgery or initial treatment with radiation, for example, because those are the ones that we are in greatest need for developing new therapies for.
The way you do oncology training is you train in internal medicine, which is a 3-year residency program. And then you become an oncology fellow. And the first year of my oncology fellowship is a purely clinical year. ... You learn how to take care of patients with advanced cancer in the clinic.
And then, at least in the ... fellowship program in oncology that I did, which was at Memorial Sloan-Kettering, after your first year you have a choice to spend the next 2 years doing clinical research, participating in clinical trials or other clinical aspects of research, or you can go into the laboratory. And, at that point, I chose to go into the laboratory.
And that could have just been for 2 years, but when I went into the laboratory I really enjoyed the science. I was very interested in the science and, at least for me, looking at the type of treatments that were available for the tumors that I was interested in. And these are mostly the solid tumors, things like lung and prostate and breast and colon cancer and other solid tumors like bladder. At least in my opinion, the treatments that we had were completely inadequate for patients whose tumors had returned. So we just didn't have effective treatments for those types of cancers.
My interest was not to stay in the clinic and try to use the drugs that we had, which, in my opinion, were not very good. I thought it would be best to stay in the lab and to try to actually develop some better treatments that we could bring into the clinic. So I stayed not just in the lab for those 2 years but essentially did a postdoctoral fellowship beyond that for another several years even though I had finished my clinical training.
There was about 5 years, even after finishing my clinical fellowship, that I was doing an additional postdoctoral fellowship in the laboratory, even though I was a full attending on the clinical side. That's not uncommon for people like myself because, obviously, to get your own laboratory you need to have a certain resumé of papers and grants.
In colon cancer, the response rate to the BRAF inhibitor, if you had a BRAF mutation -- again, we're only looking at the group with a BRAF mutant colon cancer -- the response rate was less than 5%.
So why the difference? Why do BRAF mutant patients, almost all of them, respond to the BRAF inhibitor if they have melanoma whereas they almost never respond to the BRAF inhibitor if they have colon? So there's still a lot of science to figure out here.
Plus, again, the patients eventually do progress on the treatment. And is that because their tumors are no longer dependent upon BRAF or has the tumor made something that inactivates the drug or causes it to be pumped out of the cell? These are things that we need to figure out so that we can design strategies to overcome that resistance or design better drugs that can work in those patients where it's ineffective initially.
So yeah; it's typically not something that within a few months or a year or two that we can usually solve the problem. But science is that type of thing. The discoveries happen at their own pace, I guess. We work as hard as we can to try to speed it up, but you never know when that great advance is going to come along. So you have to have somewhat of a long horizon.
On the laboratory side, my laboratory mentor, as I mentioned, was Neal Rosen, and he was very supportive of my career and he gave me a great environment in which to do laboratory work. But I would say equally as important, I had a great clinical mentor in
As you mentioned, I also had different fellowship awards along the way that were critical if for no other reason [than] to allow me to do the research. At most institutions you need to obtain grants if you're going to have a certain amount of protected time. So in particular for me, I received 4 years of funding, which is a lot in total, from the
I also received a
In terms of the science side, I think it's an exciting time to be in cancer research. ... The projects that are ongoing, like the Human Cancer Genome Project that was completed during my fellowship, [have] really opened up a lot of possibilities to understand the molecular basis of cancer. Right now, we've got the Tumor Cancer Genome Atlas that we're part of here at Sloan-Kettering. We are contributing samples actively to this project. This is really a project to repeat the Human Genome Project thousands of times using tumor samples instead of normal DNA and really identify what is the full complement of mutational changes or epigenetic changes that actually cause the cancers to develop and progress. ...
So, when these projects are being completed, it really leaves us with just a list of mutational changes that are found in the tumors, but it doesn't really inform us as to which of those are most important or how they cooperate together. So there's a huge amount of opportunity to try to sort through those questions in the lab. And what's exciting to me is that you can directly potentially use that information to impact and improve the care of patients with cancer. I think the BRAF story is an early example of that where we were able, again, [to] identify an underlying genetic change in the tumors, a somatic change that causes the cancers to develop, and then use that information to develop a new treatment.
I would expect that that type of paradigm will be repeated many, many times over the next decade or so as we find other mutations that can be drugged. So we really need people who are obviously interested in understanding that science. But I think, as well, we need clinicians who understand the science sufficiently that they can use that information to develop rational clinical strategies to test these drugs appropriately in patients, which is ... easier said than done.
So I think it's just an opportunity where the science is really advancing so fast that it's exciting. But, for me, it always gets back to why did I go into it. Well, again, like many people, you know I have family members who have had cancer and I think it's a place where, you know, a clinical-translational researcher can have a pretty big impact right now.
And there are definitely disappointments that come up in this career path. There's always going to be grants that you don't get and papers that get rejected. Without question, I would say even those who go on to win the Nobel Prize or make huge advances had grants that were rejected and papers that were rejected. But, if you're persistent and you're committed, it's not a guarantee, but there's a good chance that you could achieve what you're interested in or what your goals are.
Kate Travis is the editor of CTSciNet: the Clinical and Translational Science Network.