Q&A: Finding and Exploiting Cancer's Weaknesses

Oncologist David Solit, 41, has some close professional role models: His father was a surgeon and his grandfather a family practitioner. Like many doctors who pursue oncology, he became interested in the disease after a relative died from breast cancer. But it was a laboratory rotation during his oncology fellowship that sealed his interest in cancer research.

"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," Solit says. "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."

Now, Solit holds the Elizabeth and Felix Rohatyn Chair for Junior Faculty and heads his own laboratory in the Human Oncology and Pathogenesis Program at Memorial Sloan-Kettering Cancer Center in New York City. His lab studies a particular signaling pathway, the RAS/RAF/MEK/ERK pathway, which regulates cell growth and survival in several cancers. "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," he says. Solit is the author of an upcoming Perspective in Science Signaling on MEK resistance, which will be published on 29 March.

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. This article is one of two in Science Careers on the topic; see also " 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 list of cancer-related articles in all the Science publications at www.sciencemag.org/special/cancer2011/.

Solit spoke with Science Careers earlier this month about his research and his career path. The following highlights from the interview were edited for brevity and clarity. A full transcript of the conversation is available on CTSciNet.

D.S.: We're very focused on the RAS-BRAF pathway and the AKT pathway. 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.: 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.: 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 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.

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.: 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.: 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. ...

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.

That could have just been for 2 years, but when I went into the laboratory, I really enjoyed the science. 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.: Yeah. Without question, I think the institution, at least in this case, did a great job of providing me with a lot of protected time. 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 think without my mentors I would not have been successful. ... 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. ... My laboratory mentor 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. [He] 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.

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, [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 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.

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.