I'm Doug Andres. I'm the chair of the biochemistry department in the College of Medicine. Each
time that we gain fundamental insight into a problem, that is an exhilaration. Sometimes
those things happen in six months of work or a year of work. Or I think this is a great
example, it's taken 15 years between when we made an initial discovery and when it was
actually found that our initial hypothesis was correct, and that the ideas that we’d
had 15 years ago actually came to fruition. So we study a family of proteins called Small
G-proteins, and you can think of them as on-off switches. And so, they control everything
from how cells differentiate to how they grow. In a disease like cancer, what happens many
times is that these switches get broken and they get broken on the “on” position.
And so, the cells that have mutations constantly grow even though they don't have the right
signals coming from the environment. And actually, the first project I worked on as a new assistant
professor, was to define and first identify this RIT1 protein. And with my graduate students,
we were able to show that RIT1 had the ability to control cell growth and we showed that
when the switch was broken, it actually could cause cancer-like growth properties. And so,
I was very excited and set out to try to get funding for the work and it failed, and the
reason it failed was because the reviewers of that grant came back with a very rational
question. They said, “We know that cancer's a genetic disease and we really like the data
you’ve developed, but you have to show us that mutations actually occur in human cancer
within this gene.” And at the time, that was an incredibly difficult thing to do. We
didn't give up. And it just so happened that a little over a year ago, I got a call out
of the blue from a group that's at the Broad Institute at MIT and Harvard, and Dr. Meyerson there
has a very large program in which he's doing genome sequencing of a variety of different
cancers. And so, he informed me that one of his postdocs and he had found mutations within
RIT1 in a project they had been doing for many years looking at lung adenocarcinoma.
And so, we then collaborated to really repeat many of the studies that I had done with my
students back in the late '90s. And so that provided evidence – exciting evidence – that
indeed RIT was mutated and that it’s a driver. So initial mutations in this switch that breaks
it, are one of the first mutations that happens in a cell on its way from being a normal cell
within the lung to a lung cancer. The data that we have suggests that RIT1 mutations
are most closely associated with cigarette smoking. I think that RIT1 mutations are likely
to be more prevalent – unfortunately – in patients in the state
of Kentucky than in many other parts of the country, because of the very high smoking
rates that are still found within the state. So my hope is first that by identifying these
mutations with my collaborators at the Broad Institute, that we'll be able to develop diagnostic
tests so that patients that come in with lung adenocarcinoma may be diagnosed as having a RIT1 dependent
sub-type. And with that understanding, perhaps clinicians can develop better treatment strategies
for those people in the near term. Longer term, I hope that the research that we will
do – that's funded by the Kentucky Lung Cancer Research Grant that I just got – will
help to give us additional insight into what makes RIT dependent lung cancer different
than some of the other driver mutations that develop the similar types of disease, but
they are clearly different because their genetic underpinnings are different.