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.
Three decades ago, when I decided to dedicate my life to the study of this illness, I also decided to start saving cells on my patients. I started when I was 28 years old, which was 100 years ago and now, we have a tissue repository, which has over 50,000 samples, which were collected over three decades. It’s not just one of the richest, but it’s definitely the oldest in the country. And why is that important? Because it gives us the luxury of having that perspective.
Why did one patient take 14 years to go from pre-leukemia to acute leukemia, whereas another one took three months to do so? What molecular genetic events characterized their unique diseases? So, we really have to give up studying mouse models. We really have to start studying humans. We have to take advantage of what we have, especially historically available. Art is I. Van Gogh would stand and paint the starry nights by himself, but science is we. We all have to work together: patients, oncologists, basic researchers, computational scientists, institutions, academia, funding agencies, philanthropies. We all must band together to work.
And where is the will? Everyone thinks that so much money is being spent on cancer research. That is not exactly true. So, just take a look at this. This is how we spend money. $4 billion are spent on cancer research. $358 billion are spent on shoes alone. That’s got to change. We really need to invest money in research. There is probably no one in this room whose life has not been touched in one way or another by a cancer.
So to end, I would just like to read a short paragraph written by this little girl whose picture you see here.
“My father died of leukemia. Now it is 10 years since death parted us. I recall that last morning, as he laid dying. At 7 a.m., Mom came into my room and said that dad wanted to see me. I ran into his room with the sinking, instinctive certainty of an 8-year-old that all was not well, only to find him sitting up in bed, smiling and stretching his wasted arms out to hug me. We spent the next several hours with me alternately reading to him, jumping on his bed, running away with his walker, having a serious discussion with him about Madagascar frogs, and every few minutes, taking his temperature with the thermometer that I loved to play with. Each time, he would oblige me by smiling sweetly. Finally, a family friend came and took me out to the park. This was the last time I would see my father. He died less than two hours later. It was only after several years that Mom told me how Dad had woken up at five that morning, bleeding from multiple sites, and being the oncologist that he was, and director of the Cancer Center, calmly informed my mother that he was going to die that day. After she cleaned him up and changed his dressings around the port, all he wanted to do in those last hours was to spend time with the family. Even as he got more and more short of breath and his lungs filled up with blood, Dad calmed himself in those last hours by watching me play, listening to me chatter on, reading and discussing biologic facts about my pet frogs. The perfect example of “amor fati”, love of fate. Dad truly lived up to this concept of amor fati, defined by Nietzsche as ‘the meaning of life is to do well what must be done.’ And the one thing he definitely did well was to die with dignity.”
Ladies and gentlemen, that young girl is my daughter and that is my husband.