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From the Basic Lab to the Clinic

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Basic discoveries, which drive much of cancer research, were showcased at a recent dinner held by the National Foundation for Cancer Research. At the dinner, Fox Chase Cancer Center's Beatrice Mintz was honored for her work developing transgenic mouse models with the sixth annual Albert Szent-Györgyi Prize. "This prize should really celebrate the discoveries and celebrate the translation of the discoveries into cancer patients," says Sujuan Ba, the foundation's chief operating officer.

Before the celebration began, Genome Technology's Ciara Curtin sat down with the five previous prize-winners to discuss basic cancer research, funding, and how new technologies are affecting cancer research.

GT: Many of you have made basic science discoveries that have had an impact on the clinic, yet some findings are slower to translate. What are the challenges to moving basic research into the clinic? What are the biggest holdups there?

Web Cavanee: Money. It's always the same answer.

Peter Vogt: If you look at cancer research today — and compared to 10 years ago, 15 years ago — basic research has had a lot of impact on translation and on the clinic. And we're seeing small steps of success in the clinic that are derived directly from basic research, and from the kind of research that the National Foundation [for Cancer Research] supports. I think that it is probably unrealistic to think that cancer will be cured with a single drug, but it's not unrealistic to believe in the stepwise, steady progress that we are making. That's been tremendously encouraging and inspiring in the last few years.

Carlo Croce: If you look at the new drugs that are used in cancer therapy now, they are essentially all targeted drugs and they are active against targets that come from fundamental research.

WC: One of the problems is that cancer is not a single disease, and I think that is what Peter is talking about. There are two to three hundred different kinds of cancers and there is great progress in some areas, but not in others. If you get cancer, you have to choose the right one.

GT: Besides an influx of money, what could help translational research?

WC: I think money really is the major thing. I think that if the NIH budget cannot be stretched, there will be blood on the streets and I think it is going to be a great setback.

Hal Dvorak: I have the same reservations. With the NIH budget as it is, we might really have an emergency situation in cancer research. I could even foresee that there could be institutes that could have whole floors of lab space empty because young scientists cannot be funded.

CC: When the payline is the top 7 percent, you have a lot of very good people — outstanding people — who are going out of business, and if you go out of business, you are going out of business forever. In science, you cannot come back. It is very hard to come back. We are ruining the young generation of scientists, but, in addition, we are hurting even senior investigators.

HD: And the crux of that timeline is that companies are also cutting back on research. Pfizer and other companies are just bleeding.
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WC: I think the problem the public doesn't understand is that to train scientists is about a 20-year proposition. To get a scientist from the point where they were interested enough in science to go to classes or read textbooks to the point where they can be an actual practicing scientist — with a couple of people working for them and being able to get grants and have a possibility of making a discovery — is probably about 20 years. It might even be a little bit more. So, the investment that the country makes in a person like that is very large.

I think from a national investment point of view, if there's not continued investment, we're going to lose this. This is one of the very few things that the US is still at the forefront of. We can give that up, too. We gave up cars — we can give up everything else, I suppose. But it doesn't make a whole lot of sense when the future of the country really depends on the development of technology and scientific discovery. Why do you then cripple it? Because you have to slash a budget for some reason or another?

If you just do it on an economic basis, that for every dollar that is invested into medical research, 7 or 8 or 9 or up to 30 dollars are returned. That's an investment proposition that any Wall Street banker would jump at.

HD: Even before this [financial] crisis, native-born Americans were not interested in going into science because they see it is too risky. It is extremely risky. Even in the best of times, even when there was a 25 percent payline — remember those days? I remember them; I am old enough — it was a very risky proposition because the success rate was only 25 percent and it's not that you go through this once, but every three to five years you go through this. It's really tough. Now with the payline — you were saying 7 percent, I hadn't heard that — I thought it was 10.

CC: It's the NCI payline.

PV: There is no peer review committee in the world that can determine the upper 7 percent. It becomes a lottery.

GT: Switching gears a bit now, there are now many genes associated with different types of cancer and its prognosis, progression, and treatment possibilities. How personalized do you think cancer therapies can become?

WC: It depends if you are a lumper or a splitter. I think personalization is going to be very important. It's very expensive.

PV: But it's becoming cheaper all the time.

GT: Is it viable, though?

WC: I think that the splitters have gone a little too far. The splitters are that "everything is separate for every single person" and the lumpers are "every population is the same." I think what's happened is that the splitters are looking at individual mutations in individual genes, rather than in pathways. I think what's going to happen is that the splitters are going to come back toward the lumpers because it is going to be clear that you have to treat this pathway and that pathway, either of which might have 20 or 30 different possibilities, but the drug development will have to be at the pathway level rather than at the individual mutation level. And then we'll start to see things happen.
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Quite appropriately, the public is demanding that some discovery be pushed into translational research and, ultimately, therapies. But we don't really understand how all these things interact with each other — which ones can substitute for other ones, how cancer cells can rewire things — we don't really understand all that.

GT: There are many cancer genomes that have been sequenced and more to come. How do you think that will be of help?

PV: That will be of help, but as Web pointed out, it will have to be integrated into the concept of the pathway. Only at the level of the pathway will it be really useful.

WC: That is the way that you pinpoint the pathways that you want to look at because if they are mutated in tumors and not in normal tissues in the same person, there is likely to be some sort of activating or inactivating situation. Whether it is that exact protein that matters or something that is just illuminating a pathway for you, that we don't know, but the faster and higher throughput this can be done at, the better.

Ronald DePinho: Basically, one nine-day run on Illumina in a lab is equivalent to all of the sequencing that was done by all of the sequencing centers and its hundreds of sequencing platforms in 2009. This has been a disruptive technology, but I think that what Web was referring to was, that's really just the first step in trying to understand what's going on. You have thousands of mutations and rearrangements and copy number alterations — how do you figure out what's important? The power of this approach that is being used is that a lot of samples are being done, so you get to see recurrent events. That gives you the first clue. Mouse models of cancer provide another triangulation. There's also different ways that the same gene could be altered, so a gene could be translocated and [Carlo Croce] illuminated that mechanism. The same gene could be mutated or over-expressed, and when you see the same gene being targeted by different mechanisms and different cancers, it gives you another level of confidence. But, believe it or not, that just gives you the parts list. It's like having an airplane disassembled in a hangar — you don't really know what they are useful for, but you know that they belong to something. Once you assemble it, once you functionalize that information, and say it is relevant to the biology of cancer or it seems to be correlated with some kind of human biology or prognosis or response to therapy, that's like having the airplane assembled. But what you really have to understand is genes operate against the backdrop of other mutations, against the backdrop of a cell biology in a particular organ system, in a particular person who is in a particular macro-environment. The context of the mutations is important, and that would be like seeing the airplane fly. Then you know how the parts actually work and what they do and how they all hang together. I would say that the genome project is putting us on first base, and the functionalization of that is putting us in scoring position. That's now becoming possible.

Roundtable participants
Sujuan Ba, National Foundation for Cancer Research
Webster Cavanee, University of California, San Diego
Carlo Croce, Ohio State University
Ronald DePinho, Dana-Farber Cancer Center
Harold Dvorak, Harvard Medical School
Peter Vogt, Scripps Research Institute

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