ASCO 2010: The Human Genome Project and Cancer Advances
Bruce Johnson, MD, discusses the human genome project and how it has helped advancements in cancer treatment.
Selma R. Schimmel, Founder & CEO, Vital Options International: Dr. Johnson, with all of this, these new compounds that are based on one’s genomic tumor characteristics and biology of their own cancer, what role has The Human Genome Project played in this?
Bruce E. Johnson, MD, Professor of Medicine, Harvard Medical School: Well this is a, well the… it’s played a very important role as far as developing a catalogue—and when I talk about the catalogue, what I mean by that is putting together all the genetic changes that we think are important pathways and giving us clues to understanding what is activated and what is inactivated. And when we talk about the cancer genome atlas, this is a program that’s run by the National Cancer Institute and The National Human Genome Research Institute to go through and characterize thousands of genes and hundreds of different tumors.
And adenocarcinoma of the lung was one of the first, and it’s being followed on by a lot of studies in leukemia and other diseases, but the plan is to go through most of the major cancers some time over the next two to five years. By doing that we found out that the four most common ones are ones we already knew about, but when you get beyond that, we find there are quite a few that were undiscovered. And the other part is they also share abnormalities across different types. So you’ll find some of the same mutations in colon, lung, and for instance, melanoma. So one of the genes happens to be called B-RAF that’s mutated and mutated in, not only is it mutated in all those cancers, but it tends to have similar types of mutations. So that as we go through this and we develop drugs, we hope it will work across there.
Selma R. Schimmel: In order to help a patient understand the modality of these drugs, how can we explain a bit more about the mechanism that allows these drugs to be effective?
Bruce E. Johnson: Now one of the things, and this goes back to what we talked about before about how these particular genes are activated—so in the accelerator analogy, and that is that these genes that we talk about that new drugs are for, they’re all called activated mutations. They also can call them driver mutations, they also call this
oncogene addiction—and what that means is that these particular genes are making the cancer. So if you set up systems where you can turn the gene off, the cancer goes away when we take a look in models outside the human—so they’re very important for it. Then the second step is to have drugs that specifically inhibit that activated target, that’s what I talked about turning on the brakes. Now one of the things that has happened in a couple of these examples is that the drug was actually originally developed for a normal gene. So the two drugs gefitinib and erlotinib, or Iressa® and Tarceva®, were developed against one that wasn’t mutated. It just so happened it works really well or even better against the mutated form than the unmutated form. Two things have happened, one is is that now we know the catalogue of mutations are taking place so that there’s specifically developed drugs that are just for the mutated or the mutated form, which is present only in the tumor, and it’s not in normal tissues.
Selma R. Schimmel: And so let’s clarify that these are genes we all have normally and then what happens is there is a mutation to this gene, thus the disease.
Bruce E. Johnson: And the other thing to emphasize is that these are not genes that we have in our normal tissues, you know, so if you looked at your blood or your skin or other normal tissues, these genes would be—have a normal sequence or something that is referred to as wild type. These genetic changes are only found in your tumor, not in the normal tissue. So what happens is that by developing these drugs against the form that is changed or mutated, you can have the effect on the tumor and getting rid of some of the side effects. And one of the examples of it, it doesn’t happen to be in lung cancer, but one of the first dramatic examples of this is in melanoma (skin cancer, cancer of the pigmented cells in your skin), and there about half of them will have a genetic change in a gene called B-RAF, and there’s this drug plex, called PLX7402, and that works in more than half of the patients with melanoma—a disease where almost nobody responds to the other therapies and in guidelines, there’s no specific ones, and this drug is now in a registration trial. So that’s one example of drugs that have been specifically developed using the information from having characterized large numbers of tumors.
END OF INTERVIEW
