WIN 2012, June 28-29, Paris, France

A new direction for development of targeted cancer therapies

Dr Edison Liu – Jackson Laboratory, USA

Dr Liu, we’re here at WIN in Paris and you gave a very nice talk describing, explaining genomic medicine. Can you summarise a little bit of your talk?

Yes, genomic medicine can be many things to many people, however, in our direction we think that genomic medicine is actually a portal to understanding the complexity of human disease and, in this case, the complexity of cancer. Cancer is an unusual disorder in that it is both a genetic disorder, genetic on the basis of somatic mutations, but also an evolutionary disorder in the sense that it is a culmination of many generations of cellular evolution whereby the economy of the cell trumps the viability of the organism and that’s why, unfortunately, our patients die. By looking at the genome, to a certain degree we construct the logic that the cancer cell used to achieve that cellular triumph, as it were. And these would then become the grist, the substrate for discovery in terms of the combinations of drugs or combinations of genes which are the targets for the combination of drugs that will cure cancer ultimately.

So this genome screening, looking for these mutations as a way of potential targeted therapy, it’s going to create a huge amount of data. How do you envisage resolving this problem?

There’s really fundamentally two ways that we’re approaching it now. I’m not certain that these will be the ultimate ways but the first aspect is, of course, just to have the parts list, to understand what is the difference between the cancer genome and your normal genome. The second part of it is really the assembly of this as a system. I think we’re going to have to move beyond trying to address the effect of each individual gene on the phenotype of the cancer, it’s way too complicated for that. We’re going to have to look at it in combinations – what kind of cassettes are actually present and whether those cassettes have a higher order of organisation that can actually explain the heterogeneity that is there. In order to do so, I think it’s very similar to how we look at each other in terms of facial recognition or what have you. You have blue eyes, blond hair, I have dark eyes, dark hair but yet our general facial structure is pretty much human, we understand how that is. The variances are very important but the higher order organisation of who we are makes us actually more distinctive than the slight differences that are actually there.

How is this going to relate to targeted drug development?

There are potentially two ways to address the targeted complexity of the components that make up cancer. One, if you look at each component and attack them separately, which works, that’s one of the focuses of this combinatorics, targeted combinatorics, that we’re talking about. But the second approach is actually to address how the different components, the perturbed components, converge on a hub, a nexus point, of all these effectors, molecular effectors, and attack the hub as opposed to the periphery. You heard some of the talks later on in the afternoon trying to reconstruct the networks, not necessarily the pathways but the networks of the interactors that are constituent in a cancer. By looking at the nexus of those networks, you can attack the most vulnerable part of the cancer.

In fact, because some of the targeted drugs that have come out, one of the big problems is resistance – they work for a while and then whether the pathway is circumvented and so the patients relapse. So do you think by getting at this nexus you may overcome this problem?

Yes. The nexus component of it actually triggers, perhaps, a more systems response which, again, apoptosis is one of them and others. So by triggering the systems as opposed to the peripherals, one can actually address the poor survival of that cancer. But the second component of this, I think, is also obvious, that because cancer is such a multi-faceted genetic machine we shouldn’t expect, except on rare occasions, that attacking one node is going to kill that cancer. Some of the most effective so-called targeted therapeutics are actually oligo targeted therapeutics, in other words they address maybe two or three targets even though they may be marketed for one.

So Dr Liu, you are from the Jackson Labs, which we all associate with mice, but you were telling me that you’re setting up a 280 million new institute in Connecticut?

Yes, as of January of this year we are embarking on a very exciting and ambitious plan of setting a whole new campus in Farmington, Connecticut, with the great support of the state of Connecticut and of the University of Connecticut. It’s a $291 million facility, 175,000 square feet, we plan on having up to 300-350 individuals but it’s completely focused on genomic medicine. We’re doing that, not to move away from our core competency in mammalian genetics, particularly with the mouse model, in fact we’re doing this as an extension of what we think is a natural extension of our science. The mouse model is becoming one of the core research tools in all of medicine and including in cancer and that has to do with the fact that we can actually engineer the mouse in remarkable ways. But in order for us to really understand that universe, that system, which is the mouse genome as it relates to human disease, we need another facility to actually have that interaction with human genetics and human disorders. So the Connecticut campus is going to be called Jackson Genomic Medicine or Jackson Laboratory for Genomic Medicine. Our Jackson Laboratory in Bar Harbor will be the focus on mammalian genetics; we have a third campus in California that really functions to work in collaboration with biotech and with pharmaceutical companies. So now we’re a complete show.

OK, thank you.