Dr. Azra Raza, Professor of Medicine and Director of the MDS Center at Columbia University, discusses Why Curing Cancer is So Hard at TEDxNewYork event. Here is the full transcript of the TEDx Talk.
Listen to the MP3 Audio here: Why curing cancer is so hard by Azra Raza at TEDxNewYork
Cancer is going to strike one in two men and one in three women. So we’re not exactly winning the war on this disease.
Tremendous advances have been made in understanding the biology of cancer but treatment options have not kept pace with the biologic understanding. One of the reasons is that our system for developing drugs for cancer is essentially broke. We can and should do better.
I’m here on this stage today, really, because of a mouse. Earlier this year, I pointed out that one of the reasons we’re not developing novel therapies for cancers fast enough is that we’ve been relying way too much on animal models. I’ve been getting hate mail since then, but the fact of the matter is that we cured acute myeloid leukemia in mice back in 1977. And in humans, today, we are using the same drugs with absolutely dreadful results.
We have to stop studying mice because it’s essentially pointless, and we have to start studying freshly-obtained human cells. In the next few minutes, I’d like to just explain to you the complexity of doing that.
We decided to study a disease called myelodysplastic syndrome, or MDS, because it is a pre-leukemic condition. It is a cancer by itself, it can kill by itself, but it can kill faster if it develops into acute myeloid leukemia, which one-third of the patients develop. We felt that if we could catalog the genetic and molecular lesions that occur as the cell traverses the distance from pre-leukemia to leukemia, it could serve as a model system to understand how malignancy develops also.
So, in other words, studying MDS would allow us to understand the malignant process that happens in pancreatic cancer, or lymphomas or leukemias. This is what happens: it starts in the bone marrow, which contains certain stem cells. These stem cells divide and make colonies of themselves. And then they can also, in addition to dividing, mature and become red cells, white cells, platelets, and these then enter the blood.
So, every single day, your bone marrow makes a trillion cells that enter the blood. Now what happens in MDS is that there are the stem cells. One of these becomes abnormal, this red cell, for whatever reason, and the first abnormality it has is that, by the time a normal stem cell divides into 2, this one will divide into 50, and so very soon, its daughters fill up the whole bone marrow, and now, it’s still able to undergo maturation; so they divide, they mature.
The only problem is that just around the last step of maturation, they can die prematurely before they enter the blood. So what happens is that blood counts begin to fall, and fewer and fewer cells are entering the blood, so the patients develop anemia, they develop low white counts or low platelets.
Another thing that can happen now, in this process, is that one of these cells also does not mature; it remains immature or as a blast. So what happens with that is these blasts, if they accumulate in the bone marrow and reach up to 20%, that becomes acute myeloid leukemia. And this is, of course, a disease that is universally fatal and kills very rapidly.
So now let’s say that we develop a drug, which is a perfect cure for this acute myeloid leukemia in the patient. With few exceptions, what we are finding is that even when we have the most effective targeted therapies and they produce a complete response, the response only lasts a certain amount of time. And I’d like to explain now why that happens also.
So here’s the bone marrow again. Here are the stem cells. One of them becomes an MDS stem cell and expands its clone. It also gives birth to a few daughter cells which are sub-clones that have slightly different passenger mutations than the original parent clone. So now we come in with treatment, and let’s say that our treatment was very effective and all of these cells that were malignant disappeared from the bone marrow. The problem is that this response, which the patient now enters as a result of this effective treatment, will only last as long as it takes the next clone of cells to rear its ugly head and expand and dominate the marrow.
So this way there is a sequential activation of clones, one after the other, and you have to keep up with each. This is why it is so complex to treat cancer. So you could then ask me: “Well, if it’s so complex, how many drugs are you going to have to develop even for the same patient going longitudinally?” Our contention is that a lot of the drugs are already there. We just need to know what pathway we have to block. So for example, in this particular patient, there were four mutations we identified in the genes, and using a very complex computational analysis and systems biology approach, we were able to identify two pathways, one of which could be blocked by Metformin, a drug used in diabetes, and another, Celebrex, which is an anti-inflammatory drug. So once we knew which pathway to block, even commonly existing drugs could be effective.
Another daunting problem that we face is that it’s not just the cancer cell, it doesn’t exist in isolation. It exists in the soil, in a microenvironment, which is feeding it. Again, I’d like to show you what that is.
Multiple mutations can come one after another and then the bone marrow microenvironment is playing a role here. So once again, you have the cancer cell, it expands itself and becomes this clone and gives birth to certain sub-clones, daughter cells. Now, each of these are producing growth factors and cytokines, which are affecting the microenvironment, which keeps changing with time as well.
So how are we going to study this bone marrow microenvironment, which changes with each subsequent new clone of cells? The next slide may not be ideal for those who are faint of heart, but this is how we do a bone marrow. And when we actually put in our syringe and pull out the bone marrow, the liquid that you’re getting only has the seed in it. The soil, or the microenvironment cells, are contained in this bottom picture, which is the bone marrow biopsy. So in other words, what I’m saying is we have to study everything. We have to study the cancer cells, as well as their microenvironment.