Rethinking Breast Cancer MetastasisJan 31, 2014
Patients with the most aggressive forms of breast cancer die because the disease spreads to other organs, or becomes metastatic. Researcher Alana Welm, a professor at Huntsman Cancer Institute has discovered a new way by which breast cancer metastasis works, and how to stop it. She discusses her findings and clinical trials that are already underway. Her breakthrough was published in the January 2 issue of Cell Reports.
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Interviewer: Researcher Alana Welm, a professor at the Huntsman Cancer Institute investigates the worst cases of breast cancer and has discovered a new way of thinking about how tumors in these patients progress and spread. Her work may lead to new type of cancer screening and new treatments. Dr. Welm, this work focuses on the most aggressive forms of breast cancer. Can you explain?
Dr. Welm: Yes, most patients with breast cancer who die from that disease, die because their disease spreads to other organs and that's called metastasis. So, we are trying to understand the most aggressive forms of breast cancer that are not cured by local therapy, like surgery and radiation but actually have the chance of spreading to other organs.
Interviewer: You were able to gain new insights into metastasis by looking at tumors from real patients.
Dr. Welm: Yeah, for example, we have one particular who presented with metastasis breast cancer. So, in this particular patient, it's a really interesting case in which the therapy was changed to a new combination of therapy and she had a very good response to this therapy and had stable disease for almost an entire year. Unfortunately, her disease eventually became resistant to that therapy and progressed. So what were able to do is, take her cells both before and after that therapy, put it in the model system and then test those exact therapies. What we found was, in fact in the model system, we could show that the first batch of tumors cells was sensitive to that therapy but then eventually became resistant and that matches the batch of tumor cells that have progressed after the treatment. So what this just tells us is that our model system is, at least in this case, faithfully recapitulating the progression of the disease and potentially will be able to predict whether or not a therapy would work for a given patient with cancer.
Interviewer: And this is a new way of researching tumors?
Dr. Welm: It's new in the sense that we are able to do this straight from patients instead of using well established cancer cell lines that have been grown in tissue culture, on plastic dishes for decades.
Interviewer: Either way, so you can use your model system to come up with personalized treatment plans?
Dr. Welm: Yes, we are in the process of designing a clinical trial in which we could grow individual breast cancer patients' tumors in our model system, in order to test the variety of therapies that are available to patients with metastasis breast cancer, and then determine which of those is the most effective in the model system, and then use that if necessary, if in the case of a metastasis relapse in that patient.
This would be initially just limited to people who have very aggressive form of the disease because it's pretty labor intensive and would be expensive, but we think it's a more accurate model of how an individual tumor behaves and so, it should also be more accurate model of how that tumor responds to therapy.
Interviewer: You were able to use this model system to discover a new mechanism for metastasis or a different way of thinking about metastasis.
Dr. Welm: Many people think about progression of cancer as a mutational event where more and more mutations are gained or acquired and then, the cancer cells just become out of control and very very aggressive. That is the case in many instances but in aggressive breast cancers, what we found is that in fact the program that is driving metastasis through this Ron protein is actually not doing so through mutation. It's actually so through, what we call epigenetic effects, and epigenetic effects are changes to DNA that are not involving mutations but ultimately, cause regulation of gene expression and in a sense what is happening is that, Ron activation can turn on more than a hundred genes at a time and it's collective nature of these genes acting that is allowing us to drive metastasis.
The reason why that's important is because it's very unlikely, given the complexity of cancer, that targeting a single gene, two genes or three genes or some combination of more genes is ever going to lead to a cure for cancer because it's so very complex, and every time you block a single gene function, the cancer finds a way to compensate by [inaudible 00:04:50] another gene. So the reason why we are so excited about this is because we found a single protein that can, by itself, work to activate more than a hundred genes, and we have an inhibitor to block this and we were able to show complete blockade of metastasis in our model system with cells from two different patients.
Interviewer: That's pretty remarkable.
Dr. Welm: It was very remarkable. There are not many things that can cause complete blockade of metastasis, it's a high hurdle. We know that this pathway isn't the only one that drives metastasis, so there is still a lot of work to be done. But one of the things that we have been able to get from this is, in [inaudible 00:05:31] fingerprint of a tumor that will tell us whether or not the pathway is on, and for those patients with pathway on and their tumor cells, they may be good candidates for this new inhibitor that is currently being developed. Interviewer: Do you have any idea of how common this mechanism works in cancer patients?
Dr. Welm: We found that this pathway is activated in approximately 25 percent of all breast cancers that we examined and we looked at around 2000 patients.
The other important thing to note is that, the signature is on more often in the so called triple negative subset of breast cancers. Those that are negative for the estrogen receptor, progesterone receptor and the [inaudible 00:06:13] gene, and this the subset of breast cancers for which we currently have no targeted therapy. The only current therapy there is chemotherapy and radiation, and so, if we can inhibit Ron, we will have potentially the first targeted therapy for triple negative breast cancer. It's also the most aggressive form of breast cancer.
Interviewer: And might this pathway be involved in other types of cancer?
Dr. Welm: The Ron pathway is actually [inaudible 00:06:38] in most solid tumors of epithelial origin. So pancreatic cancer, lung cancer, colon cancer, etcetera, and it has been shown to [inaudible 00:06:50] with poor prognosis. We haven't done the mechanistic work yet to determine whether this exact pathway is driving metastasis in those cancers. It's certainly worth to look at because it again goes with poor prognosis and bad outcome.
Interviewer: So how do you think you can use this new information to help patients?
Dr. Welm: Well, we hope that we can use this information to identify patients who might be at high risk of metastatic relapse because we can identify that their tumors have this pathway active. For me, the most important next step is getting this into clinical trials. So, the inhibitor that we have decided to work with is currently in phase I trials, which are simply to determine safety and dosing regiments for this drug and that trial is being conducted right now in Australia. So, we are working with the company who developed the drug to get a trial going in the U.S., like a phase II setting, so we could try and determine the ability to either shrink existing metastasis or block the growth of new ones.
Interviewer: Do you think finding this mechanism will prompt other scientists to look for epigenetic pathways being involved in cancer or cancer progression?
Dr. Welm: It's already being looked at in many settings. So, I think that's really the new frontier in cancer biology as we are learning that mutations do drive cancer. There are certain mutations for which you can use a targeted therapy and have some success but resistance is always a problem, so with any single mutation that you are targeting, you also will select four resistance populations. So, combinatorial therapy or therapies given in combination are really what's happening now at the forefront of clinical cancer care, but the problem becomes toxicity. If you can identify a pathway like we have, where hundreds of genes are regulated by a single targetable protein, you might have more impact to that disease than hitting a single mediator within a hundred genes.
Of course, I still think resistance will be a problem with Ron inhibitors, if history holds up. That's why our lab is also working separately on understanding all of the signaling pathways downstream the Ron, so that we can anticipate what might be the resistance pathways and preemptively think about combination therapies.
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