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Monday, July 16, 2012
Since joining MGH in 2010, Dr. Baselga has pursued key innovations in breast cancer treatment
Jose Baselga, MD, PhD, is chief of the Division of Hematology/Oncology at Massachusetts General Hospital and associate director of the MGH Cancer Center. He is also the incumbent Bruce A. Chabner Chair in Hematology/Oncology. Read more at massgeneralmag.org
How is a targeted cancer therapy different from a traditional therapy?
First, you try to identify a particular gene, protein or process that is unique to a given tumor and is driving the growth of that tumor. Then, you seek to develop a therapy that will interfere with that gene, protein or mechanism in a specific manner while not interfering with any function of normal cells.
So by focusing only on the tumor, the therapy is much less toxic?
Correct. Let’s look at chemotherapy. Cancer cells are the cells that are most sensitive to chemotherapy. So in a way it’s targeted, but it is also hitting normal cells. You hit that breast cancer, but also you’re seeing low blood counts, fatigue, anemia, hair loss, brain damage, heart damage. And you may question whether, in some situations, the damage is exceeding the potential benefits.
Can you do as much damage to cancer with targeted therapy?
Yes, if it’s the right target. You need to find something which a tumor is exclusively dependent on. And this sometimes happens and it sometimes does not. People ask if we are going to be using targeted therapies for everybody. We’re not there yet. But conceptually, if you have a tumor that is driven by a specific oncogene, the efficacy that we may achieve with targeted therapy may be far superior than chemotherapy.
In terms of targeted therapy, what are we capable of and where are we headed?
First, we have about 16 genes that we can routinely analyze for mutations for which we have therapies that work. Second, technology is making things much easier. You have the capacity to sequence much better. Also, the cost of sequencing is dropping fast. It’s going to be relatively easy once you have a target identified to develop a therapy against it in most cases. Chemistry has advanced tremendously. So we’re going to have therapies against all these mutations, no question. Point number three, in many cases, we are seeing sometimes dramatic responses but eventually the tumors come back. We need to understand the mechanisms of resistance to these therapies.
You mean we need to know more about what makes the cancer come back?
Yes. It is our feeling that the repertoire of mechanisms of resistance in cancer cells is going to be finite. So I feel that if we could begin to devise smart combinations of therapies to prevent the development of resistance, we would cure many more cancers.
When you talk about the development of resistance, do you mean something that wasn’t there initially?
There are several possibilities. One is that you have different populations of cells within a tumor. Under selective pressure with one agent, you kill all of one type but another survives. Then it becomes the dominant species or clone. Another possibility is that the tumor itself develops a new mutation that renders the tumor resistant to the therapy that you began with and that it was initially sensitive to. The third one, which is where my main effort is at this point, involves the activation of alternative signaling pathways that may rescue a tumor from the lethal effects of the targeted therapy.
So some pathways allow a cancer tumor to grow or its cells to divide?
Yes. We are targeting pathways to which the tumors are addicted because they are oncogenic. These oncogenes, in order to be the only dominant player in regulating critical cellular processes, silence any other pathway that could also regulate these same functions. So the cell becomes addicted to a given oncogene-driven pathway. After you break that pathway, one of the first things that happens is that all the other pathways come to life again and rescue the cells.
So they’re usable again?
Exactly. So if you identify which ones they are and they are limited in number, then you can hit them at the same time. So then you are not only blocking the oncogene but, from the beginning, you’re blocking any potential escape mechanism. Then the cell dies.
That’s work to be done in future research?
We’re beginning to have trials in which we start a patient with a therapy, we do a biopsy a week later and we see which pathways are being turned on. We’re not there yet, but the next step would be then to adapt the therapies depending on how the tumor is responding. It will be like a continuous dialogue in which you intervene, you look at what’s happening and then you go in again. You’re not going to let that tumor develop escape mechanisms. You’re going to hit them because you’re going to be watching them and be able to react to their reaction, so to speak.
You were the lead author of two related studies recently published in the New England Journal of Medicine. Could you talk about their significance, starting with the so-called Cleopatra study, which involved a form of breast cancer that has tested positive for HER2, a type of protein that makes it very aggressive?
HER2 is really, really important. We identified a number of years ago that it can be activated by two separate mechanisms. One mechanism is being targeted by the drug Herceptin, which is very efficacious. But there was another mechanism of HER2 activation that was left untouched. And that’s where pertuzumab comes in. It is an antibody that blocks the other big mechanism of HER2 activation. Then the idea becomes very simple: Let’s put them together. So the concept we are using is that of total HER2 blockade.
Just to put things in perspective, when we began to use Herceptin in patients with metastatic breast cancer, the time to disease progression, or for the tumors to grow out of control despite the best chemotherapy, was in the range of less than four months. Today, the Cleopatra study shows that, in the group that received the combined therapy, the time to progression is 18.5 months. It is a big change. Now this is in patients with metastatic disease. So I think this is a proof of concept that dual HER2 blockade is superior to a single-agent anti-HER2 therapy. And I think this could have effects not just for the field of HER2 but for the field of cancer therapy in general. I think the lesson is that is it’s not enough to hit the target a little bit. You have to silence it.
Let’s talk about the other study, known as Bolero 2.
About 70 percent of tumors are endocrine responsive or, if you wish, hormone-dependent. They have estrogen receptors. For estrogen receptor breast cancer, the main single therapy is hormonal therapy. Yet resistance eventually occurs in everybody with advanced disease.
How to delay or revert resistance to hormone therapy is the Holy Grail of anti-estrogen therapy in breast cancer. MTOR is a protein that regulates cell growth and other functions.There was some evidence in the lab that the mTOR pathway mediates resistance to hormone therapy. So if that’s the case, let’s combine mTOR inhibitors with antiestrogens. And this study shows unequivocally that an mTOR inhibitor delays endocrine resistance. The patients that received mTOR together with an antiestrogen had almost a tripling in the time to progression as compared to those that just received standard antiestrogen therapy.
This is the first time we have been able to address an issue that we thought was not doable. Now we can focus on this and try to identify more precisely which patients benefit. There are second and third generation compounds that may be better than what we studied. We can study patients up front as opposed to studying patients at the end of their lives. I think Bolero 2 basically opens up a whole new field that we much needed. That, to me, is extremely exciting.
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