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State of the Science

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Basic research allows for a better understanding of cancer and, eventually, improved patient outcomes. Zhu Chen, China's minister of health, and Shanghai Jiao Tong University's Zhen-Yi Wang received the seventh annual Szent-Györgyi prize from the National Foundation for Cancer Research for their work on a treatment for acute promyelocytic leukemia. Genome Technology's Ciara Curtin spoke to Chen, Wang, and past prize winners about the state of cancer research.

Genome Technology: Doctors Wang and Chen, can you tell me a bit about the work you did that led to you receiving the Szent-Györgyi prize?

Zhen-Yi Wang: I am a physician. I am working in the clinic, so I have to serve the patients. … I know the genes very superficially, not very deeply, but the question raised to me is: There are so many genes, but how are [we] to judge what is the most important?

Zhu Chen: The work that is recognized by this year's Szent-Györgyi Prize concerns ... acute promyelocytic leukemia. Over the past few decades, we have been involved in developing new treatment strategies against this disease.

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You have two [therapies — all-trans retinoic acid and arsenic trioxide] — that target the same protein but with slightly different mechanisms, so we call this synergistic targeting. When the two drugs combine together for the induction therapy, then we see very nice response in terms of the complete remission rate. But more importantly, we see that this synergistic targeting, together with the effect of the chemotherapy, can achieve a very high five-year disease-free survival — as high as 90 percent.

But we were more interested in the functional aspects of the genome, to understand what each gene does and also to particularly understand the network behavior of the genes.

GT: There are a number of consortiums looking at the genome sequences of many cancer types. What do you hope to see from such studies?

Webster Cavenee: This is a way that tumors are being sequenced in a rational kind of way. It would have been done anyway by labs individually, which would have taken a lot more money and taken a lot longer, too. The human genome sequence, everybody said, 'Why are you going to do that?' ... But that now turns out to be a tremendous resource. ... From the point of view of The Cancer Genome Atlas, having the catalog of all of the kinds of mutations which are present in tumors can be very useful because you can see patterns. For example, in the glioblastoma cancer genome project, they found an unexpected association of some mutations and combinations of mutations with drug sensitivity. Nobody would have thought that.
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The problem, of course, is that when you are sequencing all these tumors, it's a very static thing. You get one point in time and you sequence whatever comes out of this big lump of tissue. That big lump is made up of a lot of different kinds of pieces, so when you see a mutation, you can't know where it came from and you don't know whether it actually does anything. That then leads into what's going to be the functionalizing of the genome. Because in the absence of knowing that it has a function, it's not going to be of very much use to develop drugs or anything like that. And that's a much bigger exercise because that involves a lot of experiments, not just stuffing stuff into a sequencer.

Peter Vogt: [The genome] has to be used primarily to determine function. Without function, there's not much you can do with these mutations, because the distinction between a driver mutation and a passenger mutation can't be made just on the basis of sequence.

Carlo Croce: After that, you have to be able to validate all of the genetic operations in model systems where you can reproduce the same changes and see whether there are the same consequences. Otherwise, without validation, to develop therapy doesn't make much sense because maybe those so-called driver mutations will turn out to be something else.

GT: Will sequencing of patient's tumors come to the clinic?

CC: It is inevitable. Naturally, there are a lot of bottlenecks. To do the sequencing is the, quote, trivial part and it is going to cost less and less. But then interpreting the data might be a little bit more cumbersome.

Sujuan Ba: Dr. Chen, there is an e-health card in China right now. Do you think some day gene sequencing will be stored in that card?

ZC: We are developing a digital healthcare in China. We started with electronic health records and now by providing the e-health card to the people, that will facilitate the individualized health management and also the supervision of our healthcare system. In terms of the use of genetic information for clinical purposes, as Professor Croce said, it's going to happen.

GT: What do you think are the major questions in cancer research that still need to be addressed?

PV: There are increasingly two schools of thought on cancer. One is that it is all an engineering problem: We have all the information we need, we just need to engineer the right drugs. The other school says it's still a basic knowledge problem. I think more and more people think it's just an engineering problem — give us the money and we'll do it all. A lot of things can be done, but we still don't have complete knowledge.

Roundtable Participants
Sujuan Ba, National Foundation for Cancer Research
Webster Cavenee, University of California, San Diego
Zhu Chen, Ministry of Health, China
Carlo Croce, Ohio State University
Peter Vogt, Scripps Research Institute
Zhen-Yi Wang, Shanghai Jiao Tong University