Science behind phase I clinical trials: targeting tumour cell development pathways
Dr Gary K. Schwartz - Memorial Sloan-Kettering Cancer Center, New York, USA
So this year at ASCO we heard about three exciting new drugs based on three very different targets; the three targets were Notch, Wnt and CDK-4. And you’re probably wondering what does that have to do with oncology. So it turns out that all those pathways are critical for tumour cell growth and development and we’ve learned that by blocking these pathways we may in fact be able to stop cancer growth and cancer development. So with the drug that blocks the Notch pathway, that’s a drug made by Regeneron, there has been a major effort over the last three or four years to see could we block this pathway. Now the classic way to block it has been targeting a protein called gamma-secretase. So Notch is a receptor, it spans the outer membrane of the cell. When that pathway is activated a piece of the receptor gets broken off and goes to the nucleus. That breakdown of that receptor is affected by a protein called gamma-secretase. So most of the effort in targeting Notch has been in developing drugs that block gamma-secretase; they block the ability of the cancer cell to break down that particular protein so that it doesn’t activate the cancer cell and that’s what the gamma-secretase inhibitors do. So a lot of that work, in fact, came out of work in Alzheimer’s disease where the same pathway seems to be important in developing proteins responsible for Alzheimer’s and dementia. So using those same molecules, the cancer industry has focussed now on cancer therapeutics by targeting the gamma secretase pathway.
The way the Regeneron drug differs, it blocks a protein called Delta ligand 4. Delta ligand 4 activates the receptor directly. So rather than being responsible for the breakdown of the receptor, this one binds to the receptor and activates the cancer cell. So what the Regeneron drug does, it binds to the protein that activates the receptor. You can think of this as sort of a lock and key idea. The lock is the growth factor in the blood, the Delta ligand 4; it circulates in the blood until it finds the receptor on the cell surface. The receptor could be thought of as the lock. The key then fits into the lock, turns on the lock and opens the door or the key fitting in the ignition and turning on the car. DLL4 antibody, which is what this drug does, binds to the key and prevents it from going into the ignition. So if you can’t ignite the cancer cell, you can’t turn it on, the cancer cell will die. That’s the concept behind this very complex pathway for activation.
What success have we had so far?
So in the clinical trials what they showed is actually rather remarkable activity in several tumour types, especially ovarian cancer. In ovarian cancer they were able to report partial responses in patients who had failed prior chemotherapy and they had a number of responses in the ovarian cancer population. Now the complex part of ovarian cancer is that there are many drugs that actually target similar pathways we call angiogenesis, because that’s what this drug really does. DLL4, when it activates Notch, actually is unique among all the Notch pathways because what it does it turns on blood vessel growth. So what this antibody does, by blocking the key fitting into the ignition it blocks angiogenesis, it blocks the ability of the cancer cells to form actin and blood vessels in the tumour cell. So it’s another type of anti-angiogenic therapy. And in certain ways there are several drugs already undergoing evaluation in ovarian cancer, such as bevacizumab; we heard about at this meeting a drug called pazopanib, which is an anti-VEGF therapy, it blocks angiogenesis, being given to women after completing chemotherapy and was shown at ASCO this year to prolong median progression free survival significantly for patients maintained on an anti-VEGF therapy. So the DLL4 antibody, which targets the Notch pathway specifically, represents another class of drugs that by targeting Notch in fact also blocks angiogenesis and blood vessel formation in cancer cells.
So ultimately the question will be how this will be positioned for patients and whether this represents another way of approaching a complex process of blocking cancer growth by blocking blood vessel formation in tumour cells. And that’s how the drug works; it looks promising in a disease we already have some drugs active in blocking angiogenesis. It represents another new class of drugs and does represent a new avenue of hope for patients with ovarian cancer. It’s different than the other drugs already being tested in this particular disease.
How long before we find out if the drug will work?
Well I think they’re going quickly, I know there is some discussion already with the ovarian cancer community to quickly move this into clinical trials specifically for ovarian cancer. So I think we’ll see some new, more advanced trials. Remember, this is a phase I study where the goal was to find a safe dose; it wasn’t necessarily to find activity of the drug. The luck is that they found signs of clinical activity, that’s unusual in a phase I. We’re lucky if we see an activity of any drug in a phase I, we’re really just looking to see can we come up with a safe dose. So there was an extra bonus for Regeneron – not only did they find a safe dose for the drug but they found a dose that’s effective in a cancer for which there are very few effective therapies once patients fail chemotherapy. So the Ovarian Cancer Committee is aware of the data; they’ve met, I believe, at ASCO, before ASCO, and they were going to move quickly, quickly to into advanced trials with this drug in this particular disease.
Other drugs that were discussed was an inhibitor of Wnt. Now Wnt is a very complex process, I don’t have a cartoon to show you or draw a pathway, but it blocks the pathway of something called beta-catenin which is responsible for cancer growth. Now this drug does effectively block the pathway, they were able to establish a dose for phase II study. Scientifically it looks like it works the way it should work, however they did not see any clinical activity with the drug and their plan is to combine it with chemotherapy. They did present data in laboratory models showing it does enhance the effect of a drug called oxaliplatinum which is used for colon cancer and that’s how they plan to develop the drug, not as a single agent but in combination with chemotherapy as a way of making chemotherapy more effective. And clinical trials are planned or will happen, be initiated very shortly, developing that drug for patients in combination with chemotherapy for colon cancer.
Lastly we have a drug from Lilly that blocks a protein called CDK4 or cyclin-dependent kinase 4 and cyclin-dependent kinase 6, another complex pathway. This pathway is responsible for cell growth. There is a pathway called the cell cycle and when cells grow they go through various phases of the cell cycle. One phase is from G1/S phase which is regulated by this protein, a kinase. Now there are a number of drugs in development already in this pathway. One is by Pfizer called PD-0332991 and it lasts 4-6 months. There has been great excitement about this drug in breast cancer. In the breast cancer community when this drug was combined with letrozole and compared to letrozole alone it greatly increased the median progression free survival and exceeded the expectations of anybody in the oncology field. In addition, the Pfizer CDK4/6 inhibitor, which is further along, shows activity in a disease called liposarcoma, a rare sarcoma subtype for which there are no effective therapies. And the reason for this, in liposarcoma, this protein, CDK4, is highly expressed and represents 90% of all the patients with this very rare cancer. And in this meeting also Dr Mark Dickson showed that the Pfizer CDK4 inhibitor had exceptional activity in this particular cancer and plans are now underway to do a registration trial in liposarcoma as a global study between America and Europe for a CDK4 inhibitor. That study is forthcoming, people should keep an eye on it, it may be an amazing new development for a rare cancer for which there are no effective therapies.
Meanwhile the Lilly drug looks very promising. It may show some exciting activity in breast cancer. They showed a case of a woman with advanced metastatic breast cancer, ER , again indicating that this class of drugs may be active in metastatic breast cancer, and that data was very exciting. In fact they showed a number of responses across tumour types with the drug. We’ve yet to see how this drug will work in phase II studies, it’s a phase I trial, they have to define fully the safest dose in future clinical trials and we’ll have to wait to see how effective it is in phase II studies. But the preliminary data with the drug does look very promising and studies, I think, will be initiated. Obviously breast cancer is a hot topic, patients want new drugs for breast cancer. The Pfizer drug which is ahead of it by at least a year or two has already promising activity and I’m sure the Lilly company will pursue breast cancer quite aggressively based on their clinical data presented at the meeting.