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Early Discoveries and Initial Research Results of the GCS Project

An interview with Dr. Michael Birrer

Dr. Michael Birrer: Introduction
Hello, I am Dr. Michael Birrer.

I am Professor of Medicine at Harvard Medical School. I direct the Gynecologic Research Program at Massachusetts General Hospital [MGH], and I also lead the Gynecologic Carcinosarcoma [GCS] Project at Dana Farber Harvard Cancer Center.

1. Diane Redington: There is currently no research specifically targeted for Gynecologic Carcinosarcoma, or GCS as we call it, other than what you are doing at MGH. We understand that this is a rare disease, and it lacks numbers significant enough to attract big dollars. We are so appreciative of you taking this on. It is such a huge endeavor.

I want to ask you a little bit about the research. We started talking about this about 7 months ago. Can you tell me if there have been any early discoveries in the research?

Answer, Dr. Michael Birrer: Let me start by saying that we are also honored and very privileged to do this research. And the effort in funding that you have garnered has been extremely helpful. And we have already had some initial results. So, we are doing what I call a molecular “deep dive,” meaning a very sophisticated analysis on a fairly large set of tumors. We have already been able to characterize [describe in detail] some of the mutational events that occur in carcinosarcomas coming from the ovary and coming from the uterus. They are not necessarily the same. Some of those events are going to be what I call “targetable,” meaning that they may be molecular events that we can treat. So, that is exciting. It’s also important to note that we are characterizing the gene expression patterns of these tumors and have early data to suggest that the way the DNA is packaged in these tumors is actually quite important for their development and progression.

2. Diane Redington: Can you expand on that a little bit?

Answer, Dr. Michael Birrer: Yes. So, there are a lot of ways in which normal tissue becomes cancer. The simplest way to understand it is if a gene gets mutated, it then hyper-functions and the normal tissue becomes cancer. And again, in these particular tumors, we are seeing some of those events. But what is unique about it,  the carcinosarcoma, is that there is another event, which is the DNA is stored in chromosomes and it’s wrapped in something called chromatin, which is a series of proteins. And the early data that we have – and there have been a couple of other small groups who have suggested this also – is that packaging is abnormal. And the reason why it is important to identify that is, there’s a whole new set of drugs that are called chromatin remodeling drugs. And they [the drugs] are coming into the clinic, so they may be very relevant in the treatment of this disease.

3. Diane Redington: How far are we from the molecular analysis to actually being able to take those new drugs that are coming and test them on some of this?

Answer, Dr. Michael Birrer: So, of course, it is always difficult in research to predict these things. To be perfectly honest, I think we are as little as a year away of translating some of these findings into the design of clinical trials. And so we are positioned so well for that here at Mass General, and the team is very motivated to do that.

4. Diane Redington: Can you tell me a little bit about the research team and the different components that they are working on?

Answer, Dr. Michael Birrer: Certainly, it involves extensively my laboratory, which we are sitting in right now in the Jackson Building, and that team has 8 Post-Docs – MDs and PhDs – and they are doing a lot of the molecular analysis, and they also assisting with obtaining the tissues from the patients in the clinic, which is not easy. It has to be all ethically and IRB-approved. We need to do it in a way that is safe and comfortable for the patients. And of course, this patient population is highly motivated. And it is a wonderful group of women who are very dedicated to providing the appropriate tissues to answer these questions.

Now in order to be successful in the analysis of tumor lines, we need to reach way beyond one lab. And so we have engaged actually a neuro-oncologist as somebody who deals with tumors of the brain. And you might think that is kind of odd, but Priscilla (Priscilla Kaliopi Brastianos, MD) is a wonderful scientist – physician scientist – who is very interested in these particular tumors and is assisting us in the sequencing of them. She has a collaborative arrangement with the Broad Institute, which is probably one of the top three sequencing institutes in the World. They are across the street in Cambridge. So, they are involved. And then we have several pathologists who are GYN pathologists who have expertise in being able to carefully look at these tumors under the microscope and that has been very, very helpful for us to identify the right cases, dissect them, and obtain the nucleic acids to do the analysis.

And then finally we have some really high-level advisors. Brad Bernstein is a spectacular scientist who is advising us in this effort. He is an expert in methylation and chromatin structure of tumors. So, that is obviously very relevant because of what I said a few minutes ago. This tumor, in many ways, is a tumor of chromatin remodeling.

5. Diane Redington: Is there any other ongoing research related to GCS or MMMT anywhere else in the world?

Answer, Dr. Michael Birrer: Historically, the molecular analysis of these tumors has sort of been left to the more common tumors from the same organ. So carcinosarcoma of the ovary has been treated clinically, as you know, and from a molecular standpoint, assumed to be the same as, what I will call “run of the mill” ovarian cancer. We know that is absolutely not true. So, it has been a neglected area. There are not a lot of centers specifically dedicated to doing the research like this project. I will mention, out of respect, Dr. Santin at Yale has had an interest in carcinosarcomas and has recently published one quite interesting paper showing some initial molecular analysis. So, there is scattering of labs but not a lot, and I think that this project will be far out in front of anything being done anywhere in the world.

6. Diane Redington: Do you anticipate any clinical trials in the pipeline for 2017?

Answer, Dr. Michael Birrer: So, that’s a really great question. The good news is that because of the molecular analysis and because of a general appreciation for the natural history of the disease, it is now well recognized that it is a unique disease. So, that has prompted cooperative groups like Energy and institutions like the National Cancer Institute to start to think about carcinosarcoma-specific trials. It’s been discussed. I have been present at those discussions, and I think you are going to see at least one or not two carcinosarcoma-specific trials in 2017.

7. Diane Redington: What are your goals for this project? What will this do to make a difference?

Answer, Dr. Michael Birrer: I am a concrete thinker. I am a practical kind of person. So, I think what I would see and the timeline I would see it in, would be that in a year – at most a year and a half – we have mapped out the molecular origins of this tumor. When I mean “this tumor,” I mean carcinosarcomas coming from either organ and potentially any differences between these two. We will have a set of biomarkers that would be at least prognostic, meaning which patient is at highest risk for recurring and which is not, because we think there’s a spectrum there. So this would be important for stratifying patients. We’d have the molecular data to potentially design trials. And then I really would like to get into the chromatin remodeling issue, because I think there’s an important element within this tumor from that angle, and those trials – those drugs – are now in Phase 1. They are not in Phase 2. So we would be perfectly positioned in about a year and a half – maybe earlier – to begin to design a couple of trials and run with it.

Diane Redington: That sounds like a breakthrough – like new science, breakthrough science.

Dr. Michael Birrer: That’s right.

8. Diane Redington: So that could really impact other cancers as well?

Answer, Dr. Michael Birrer: Absolutely. So, I will tell you … you could guess what another tumor is that has chromatin abnormalities. It’s soft tissue sarcomas. And that may be why carcinosarcoma shares that. I don’t know. But the exciting part would be where we would we be 1½ to 2 years from now. That women who suffer this disease will not be alone and they will have a portfolio, a smorgasbord of scientifically sound clinical trials to either chase this tumor away or at least hold it at bay. Rather than just pulling off random drugs from the shelf, we’ll have that, and I think that is important.

9. Diane Redington: It seems like there’s broad variation in terms of treatment, knowledge base, innovation. Women who are out there in the hinterlands don’t have access to the knowledge base to be able to even access clinical trials. Are there any clinical trials available for women with carcinosarcoma now, that women who are kind of along that continuum of disease might help them?

Answer, Dr. Michael Birrer: Well, as you know, the answer at least in this country is really nothing that’s specific to carcinosarcoma. You were able to identify one across the pond, so to speak. And that’s, unfortunately, the state of the science right now. I am anticipating that changing. I think the only way you can drive it, though, is with the scientific rationale.

How many times do ladies with this tumor hear, that sort of dreaded comment that, “This is a rare tumor, so we have to extrapolate from [other cancers]”? Those days need to disappear.

Diane Redington: Well, again, I can’t thank you enough. I feel so fortunate that we were able to connect and establish this wonderful research and meet your team. You guys inspire me every day. I just can’t thank you enough.

Dr. Michael Birrer: You inspire us. That’s why we do it. Thank you.

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