David Solit: I'm Dr. David Solit. I'm a medical oncologist but also run a translational research lab at Memorial Sloan-Kettering Cancer Center. I do see patients. I see patients with advanced cancer, primarily genitourinary cancers like prostate cancer. And then I focus in the lab on cancer genetics and molecular pharmacology. So, we try to identify the underlying genetic basis of different tumor types and then develop novel therapies that will exploit the specific mutations that drive tumorigenesis or cancer progression.

D.S.: We're very focused on the RAS-BRAF pathway and the AKT pathway. So these are two pathways that are very commonly mutated in human tumors, and we try to understand where those pathways are mutated, which type of tumors, what are the mutations that co-occur with mutations in those pathways; and try to understand, if we try to inhibit those pathways, what can we expect in patients. So, can we expect that, if we inhibit, for example, the BRAF kinase, are we going to see the cells stop growing? Are they going to die or are they going to not care at all, depending upon the underlying genetics of a particular tumor type?

D.S.: We do both. ... There are some tumors where there ... have already been significant genetic analyses done to try to figure out what the mutations present are. But, in many cases, either the particular mutations haven't been looked for in particular tumor types or there's still a lot of tumors where we haven't identified any of the underlying genetic changes. So we do try to take tumors and figure out what the frequency of particular mutations are. And, in the cases where we don't even know what the mutations are, [we try to figure out] what's present in those tumors. And then, also, what are the patterns of mutations? Which mutations co-occur in particular tumor types? That can impact on how addicted a particular tumor is to a particular mutation.

D.S.: Exactly, in part. But we also take it a step further. We're very interested in how to actually drug those targets. You can't presume, for example, simply because somebody told you a particular compound is a BRAF inhibitor, that it really just inhibits BRAF, or that's how it, in fact, works. So we try to have models where we really understand the genetic basis for the cancer, and then we try to take compounds and figure out, are they going to be able to work in that genetic background?

D.S.: It's a mix. Some compounds are compounds that a particular drug company has recently developed and we're trying to understand, is this going to be useful in the clinic or can it tell us something about the biology? That's one group of compounds. Another group of compounds are compounds that might have been around for many years that are known to be selective tool compounds, available from Calbiochem or another ... industry partner.

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.

D.S.: Mostly this is in the lab using an assortment of things. We usually start with cancer cell lines, which we both generate here and obtain from other people. We've got hundreds if not a thousand or so cancer cell lines that have been annotated for different mutations or variations in expression of particular genes. We essentially start with those cell lines, try to identify patterns between the mutational status of the cell line and the response to a particular drug, either in terms of the ability of the drug to inhibit a pathway or to induce cell death or inhibit growth. We then usually move onto xenograft models and then also, if available, try to test some of these compounds in genetically engineered mouse models that have particular mutations driving tumor formation.

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 Sanger group initially in 2002. Prior to 2002, it was unknown that BRAF mutations were common in human cancers. And BRAF is one of the kinases that's most commonly mutated in all cancer. ... Around 6 to 8% of all cancers have a mutation in BRAF.

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 Plexxikon who's now partnered in its development with Roche -- this compound actually has a survival benefit in patients whose tumors have BRAF mutations.

D.S.: The initial trials were done mostly in patients with melanoma. So, they've already done a phase III trial in patients with melanoma. And that phase III trial tested the effects of ... PLX4032 against standard chemotherapy; in this case a drug called [dacarbazine]. And it's already been announced publicly. We haven't seen the data presented formally in terms of the actual results, but they put out a press release that the patients who are on the [PLX4032] arm live longer than patients who are on the chemo arm. And they've halted that trial based upon that data and have crossed over the patients who are on the chemo arm to the BRAF inhibitor. So, that's a real success story for the type of stuff we do. And it shows that, if you have a tumor with BRAF mutation, you could respond to a BRAF inhibitor.

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 GlaxoSmithKline.

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.

D.S.: I see patients as well. I'm a medical oncologist, so we typically see patients whose cancers have recurred and have spread to other parts of their body. We use chemotherapy or targeted therapies or immunotherapies to try to slow down or shrink down the cancer. For most of the solid tumors that we work with, unfortunately, once the cancer has spread to a distant place, we're at this point unable to cure those patients, although we can oftentimes improve their quality of life or make them live longer. So we obviously have a long way to go to develop effective treatments for most of the cancers we work with.

D.S.: There's definitely ... some link. We work ... in the research side on a particular target and pathway. And oftentimes that target and pathway doesn't always match up exactly with every patient we're seeing in the clinic, and you have to sort of focus and stick with a project for a long time in the labs. So we can't always be changing the patients we see from year to year based upon what's most exciting in the lab. So, there is overlap, but it's not a complete overlap.

D.S.: Definitely indirectly -- it puts in perspective an understanding of what type of problems we really should be going after. So, for example, I'm very interested in targeting the pathways that are found in patients whose cancers recur. You can imagine that if there was a particular mutation but everyone with that mutation was cured by surgery and nobody ever recurred, that, to me, wouldn't be something I would want to spend a whole lot of time on.

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.

D.S.: My father was a physician. He was a surgeon. And my grandfather was a family practitioner. ... But currently I'm the only [practicing] physician in my generation.

D.S.: My father was a practicing physician and so I came at my career path from that side. I initially went to medical school and then I did what's called residency. So I was an intern and then a resident in internal medicine. And, at this point, I had yet to do that much research. I had done a little bit of research during medical school; by that I mean laboratory research. But I was very interested in it during the whole time.

D.S.: It's very difficult to do laboratory research during your clinical training because you typically work, like, 60 to 80 or sometimes more hours a week back then. So it would be very difficult to do any sort of laboratory based research while you're actually doing your internship or residency.

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.

D.S.: Exactly. I think I was always interested in doing laboratory research, but there's two ways you can do it. You can do that research before you decide what clinical field you want to go into, or you can do it sort of on the back end, ... beginning during your fellowship and then extending out beyond that until you either get your own lab or choose not to get your own lab.

D.S.: I was in the laboratory with Neal Rosen, who was my mentor. And so I entered his lab as a fellow and then stayed on. And there was a period of time where I was an attending, meaning I was a full doctor, trained, had completed all my clinical training and was an attending physician with my own patients and covering the hospital as the head physician on the service. But I was still, during some of that time, a postdoctoral fellow in the lab because I hadn't yet gotten my own lab.

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.

D.S.: Yeah. So, without question, I think the institution, at least in this case, did a great job of providing me with a lot of protected time. So I would say I was about 30% clinical and I was 70% laboratory. And that's not an uncommon balance for someone in that position. I would see patients one day a week.

D.S.: It's actually not that different. ... I would still say it's about 30% clinical, 70% laboratory.

D.S.: I see patients 1 day a week in the clinic, and I take care of patients in the hospital 2 to 4 weeks a year. What that means is that, when the patients are admitted, I would be the attending physician on the service and while I'm doing that, I would have help from residents and students and nurses [and] nurse practitioners to take care of those patients day to day.

D.S.: Well, I think it's very important. You asked the important question, which is how much protected time do you have. Obviously, if you're working 100% of your time taking care of patients, there wouldn't be any time left over to do the laboratory work. And, as you know, especially when you're a fellow in the lab, you need a certain amount of time to actually perform the experiments, and if that time is insufficient, then it's not possible to do both. So that is a really important question.

D.S.: Well, unfortunately there's still other cancers where we don't know whether the BRAF inhibitors are going to work. And there's already some data on that. So, for example, in melanoma the response rate to the BRAF inhibitor -- so we're just looking at the patients with the BRAF mutation -- was 81%. So it was an 81% response rate to the BRAF inhibitor if you had a BRAF mutation in melanoma.

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.

D.S.: Well, you say the timeline is long. That's actually one of the quickest from target identification to a drug that we've ever seen. Of course we would love to see it much shorter, but that was actually I guess in the timeline of oncology drug development not too bad. But I agree, you have to have in this sort of field, somewhat of a longer horizon because this is a difficult problem. I think that it's going to take many years to solve the underlying basis of cancer and try to come up with effective treatment strategies.

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.

D.S.: I think without my mentors I would not have been successful. I think probably many people would say a similar thing who have gotten their own labs or have been successful in their career. I had both a great laboratory mentor and a clinical mentor. And I think that, for someone who tries to do both, that's really important. I think that's sometimes missed as students and fellows are going through their training.

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 Dr. Howard Scher, who is head of the Genitourinary Oncology Service at Sloan-Kettering. He's an expert in prostate cancer and he did many things. First of all: made sure that I had adequate protected time to do the laboratory research [and] helped me in terms of my career, in terms of trying to get promoted over time. And, in that regard, that was invaluable. Pointing me towards certain fellowship grants that I could apply for in the interim before I got my own space and just giving me overall good career advice as to what projects might be interesting to pursue or how to move forward with my career development. So I think I was very fortunate there to have two mentors, one on each side: the laboratory side and the clinical side, who could give me great career advice.

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 American Society of Clinical Oncology (ASCO). And I received both the Young Investigator Award and a career development award from ASCO, which were very important during those early years where I was still a postdoctoral fellow in the lab but an attending on the clinical service. And that, in part, allowed me to stay in the lab and have that protected time.

I also received a career development award from what's called the Kimmel Foundation, helping me bridge that time before I got my first R01. So eventually I did get that first R01, but, before then, I had these types of fellowship awards, career development awards, that allowed me to continue to do the research.

D.S.: Well, I think it's never easy, I would say, but I think I've been very lucky ... in that I have a very supportive wife ... and I have three daughters, ages 5, 8, and 12. It's obviously a challenge to have three kids without any career. So I guess I'm pretty fortunate that I've been able to do both.

D.S.: I think it's both the science and the clinical side. I got interested in cancer because my aunt had breast cancer and, unfortunately, passed away from breast cancer. So that had always had me interested in pursuing this in medicine in particular. ...

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.

D.S.: Well, I think you want to go into something that you're interested in, that you enjoy. Obviously you work harder or spend more time doing it if you're interested in doing it. But I would be more than happy to have us solve this problem and find something else to do if we can cure cancer. I'm not sure if we'll ever cure all cancers, but I think we can clearly improve treatments for many of the cancers we treat. So ... what's the long-term goal? It's to cure cancer and then move onto something else.

D.S.: I just would say if you're interested in this career path, I would just do it. I think that, like many people, I had many people along the way who probably told me that it's just too hard to pursue this type of career. It's very hard to get your own lab or it's very hard to get this position. But I think persistence is the key in large part. I think you have to be intelligent. You have to be hard working. But I think persistence is really what separates many people who succeed from those who do not.

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.