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2014 BCRP Investigator Vignette

Title: Targeting the Unfolded Protein Response to Circumvent Endocrine Resistance in Breast Cancer

Investigator: Robert Clarke, PhD, DSc; Georgetown University Medical Center

The DoD Breast Cancer Research Program is a fabulous program. You know we all live from hand-to-mouth in many ways-particularly in the current environment-and funding from any source is valuable. But the way in which it's selected in BCRP, it feels so much better [Laughs]. It's like it's a greener dollar in a sense, because you know that not only has it gone through peer review, but you know that people who live with this disease have also felt that what you were trying to achieve had relevance for them.

There's a big question that I would like to help answer, and that's "Why do some breast tumors respond well to endocrine treatments and others don't?" And "Why do some initially seem to respond very well and then later come back?" And the earlier work that we had done led us to think that a certain stress response, called the unfolded protein response, might play a significant role in sensing what endocrine therapy is doing to breast cancer cells, and how those cells choose to respond to it. And we found one component of that which required the splicing of a specific gene that we thought was really important in driving that survival response, which would lead to resistance. And so we identified that as a molecular target, and we were able to find some small molecules that seem to block that splicing event. And we think that might lead to some new treatments and some new ways of understanding the stress response, and how it contributes to both resistance and perhaps also to dormancy.

What we think happens with endocrine therapies is it changes the cell's metabolism. So the cell doesn't have enough energy to fold all of its proteins properly, particularly if the cell is attempting to make copies of itself. So one of the things we've known for a long time about endocrine therapies is cells that are sensitive stop at G0, G1 of the cell cycle-complete wherever they are-and you have this profound cell cycle arrest. The cells just go to sleep. We think that's because when they can't fold their proteins adequately, they use all of their reserves to finish the cell cycle and they stop. Now they've got all the material they needed to make another copy, but they made the decision not to use it. So let's not waste anything; we'll recycle it, which allows the cell then to digest the bits and pieces that it doesn't need. And it's really going to sleep, so it's turning off a lot of its basic needs, and it's simply feeding off itself until it can figure out how to get its metabolism back into balance. And if it can't, it either goes to sleep and dies of old age, or it dies. If it can, it sits there long enough until it can get its metabolism to a point where it can support making, executing the decision to go through the cell cycle, and off it goes and makes a copy of itself, and you've got recurrence.

So this is now focusing in on the little piece of the overall programming that we're interested in looking at. And IRE-1 is a fascinating molecule because it activates that gene XBP1, and it does so by splicing it. This becomes a transcription factor when it's spliced. And so if we could stop it being spliced, it's unstable, its turnover is very rapid, and it can't function as a transcription factor so well. And so you block the cell's survival process, if would could knock this out. So that's the concept behind the DoD grant that we have.

We know it doesn't explain everything, but it seems to explain a significant component of the resistance phenotype because the short-term response to this allows the cells to survive the drug. But we think it also explains the dormant phenotype because it allows the cells to go to sleep for years and years and years. I want to understand how that signaling that makes that differentiation and says we're going to live and if we live we're going to make a copy, because if I can intervene in any of those places in a way that was specific to breasts, I would have a very targeted treatment.

I think the Breast Cancer Research Program has fundamentally changed the research landscape for breast cancer. It has not just funded outstanding science, but it funds young investigators. It's funded different stages of the program-it has funded graduate students and post-docs and clinical fellows. It's funded those people who will take whatever those of us-who are more advanced in their careers-they will take that knowledge forward in the future. So it's not just what have they achieved today, they've changed the landscape for the future.