The Professor of Cell Biology and of Medicine (Oncology) at Albert Einstein College of Medicine, and associate chair for translational research in oncology at Montefiore Health System (New York) spoke to MDS News at the International Society of Experimental Hematology (ISEH) conference in Brisbane in 2019. His presentation was on Understanding and Targeting the Stem Cell Origins of Myeloid Malignancies.

What does an experimental haematologist do exactly?

The treatments applied to patients in the clinic involve a decade-long process of research and development. An experimental haematologist does all the work that happens pre-clinically; the experimental work that ultimately leads to something that helps develop therapies. This is everything that goes on before and including clinical Phase I, II or III trials – the clinical testing. It also includes the study of normal blood and bone marrow and normal blood cell formation and generation, and how blood cells function, which is a very important part of that research. This basic biology is an extremely important starting point for the study and understanding of diseases.

“If you don’t know what’s normal, you can’t understand what is going wrong.”

Tell us about your background

I trained as a physician scientist. At medical school I quickly realised just medical school was not what I wanted to do. I wanted science training and education, so simultaneously pursued a PhD in a leukaemia lab. For my clinical training, I picked medical haemato-oncology, but found the clinical care of patients, especially with leukaemia, incredibly frustrating because the cure rates of many of the diseases I am now researching in the lab are very low, especially MDS and AML. You see the patients; you want to do the best. You do the therapy, you develop personal relationships with the patients, but ultimately you see 90% of your patients die. You realise you are just delaying the inevitable in most cases. After a few years, I decided I wanted to make a more fundamental difference and I knew where the real improvements were coming from. I had to focus on research and that is what I am doing now – laboratory research and translational research on devastating diseases like MDS and AML.

What is your overall objective?

Ultimately, to improve patient outcomes, that is still the goal. But there are many steps and I see a high value also in generating and contributing to the fundamental knowledge, biological knowledge, and understanding of diseases that enables others (colleagues and the field in general) to do better research, to think about things differently and to help other researchers to succeed. Research is a matrix-type endeavour. You do your own thing, but you are in this network and meetings like this (ISEH, Brisbane, August 2019) are a great example. You hear what everybody else is doing, you read [scientific] papers, the data, and this constantly changes how you think about a problem. It is a huge team effort. I contribute my little piece to this mosaic. Maybe other people make the big discoveries or have a great idea that ultimately leads to a breakthrough. Of course, we all want to be the one that makes the next big step, but we all are moving together as a field and everybody makes little additions here and there. Then hopefully, for one of us, this all will lead to a big leap at some point.

“This is a team sport. There is no doubt about it.”

What’s new in your research?

We have been very interested in the stem cell origin of diseases like MDS and AML for a long time. If you go back 15 years, the field had a rather simplistic view of cancer, and it was not fully recognised what the contribution of different subpopulations in a tumour are. Around 2005, people started to realise there are differences between the cells, and that in a complex process like cancer one of the biological requirements is that multiple events can accumulate and lead to tumour formation. It basically requires cell types to have a sufficient lifespan to actually accumulate multiple steps of transformation. In simplistic terms, if you take a skin cell that is shed off every day, essentially, if something bad happens to that cell, a day later that is irrelevant because that cell has fallen off and cannot acquire another event. But if bad things happen in stem cells, which have a very long lifespan and are around for decades in the human body, these cells have the biological ability to accumulate multiple aberrations. That is a concept that we, and others, started to pursue many years ago.

In the last few years, we have made significant advances in our understanding of the stem cells in MDS and AML. Technological advances allow us to isolate these stem cells better and to analyse them better through molecular biological methods. We’ve made a lot of progress pinpointing the problems at the stem cell level that cause the production of bulk tumour cells that are ultimately diagnosed in the clinic, and that cause all the symptoms. We are now much closer to a causative treatment approach, where we get to the root of the problem rather than dealing with the symptoms and with late-stage consequences of the disease-driving events.

Some of these discoveries have led to new therapeutic approaches that we hope will lead to a more lasting disease control. A good analogy is… if you have a weed and you can use a lawnmower to cut it back, that works for a few days, but it grows back. Unless you get to the root of the problem, you will never truly get rid of the weed. Using that metaphor, we are now much closer to the root of the problem, which I think is at the stem cell level. We are now better able to understand what is wrong and we’ve reached the point where we can begin to interfere with that in a targeted manner and to develop targeted therapies for some of the abnormal pathways that we and others have discovered in these abnormal stem cells. Some of those have reached early-phase clinical trial status, so we will see in the next five to 10 years how and whether some of these approaches will pan out.

How do targeted approaches work?

These targeted therapy approaches won’t necessarily fully replace chemotherapy and that is something that is very important to understand. Bulk tumour cells cause a lot of the clinical symptoms patients deal with and is why they initially show up in the clinic or doctor’s office and are diagnosed. You must get rid of those cells just to alleviate acute symptoms, then stem cell targeting hopefully will lead to lasting control of the disease. Chemotherapy is actually very good at eradicating or eliminating the bulk tumour, but the problem in MDS and AML is that it is a very transient success. Most patients will respond very well to chemotherapy, but only for a few weeks or months, then the disease grows back. Ultimately, a combination approach would mean initial chemotherapy supplemented with a targeted therapy, to keep the stem cell compartment in check. In an ideal world, we would love to just give targeted therapy and not do all the chemotherapy with all the bad side-effects. Chemotherapy is good in the short-term but has lots of dangerous and problematic long-term consequences because it is genotoxic. This means it induces additional mutations in other cells, including these long-lived stem cells, on top of the mutations that are already there because of the cancer. We would love to reduce chemotherapy as much as humanly possible, to the bare minimum required, even get rid of it entirely, but that really may be a long-term goal for AML and MDS in particular.

What is your lab working on?

We are an academic lab with about 15 researchers – a 50/50 mix of post docs and graduate students and a few research technicians. We have been very active in target identification and we collaborate with other academic groups or companies that have drugs that are active against the targets we identify. One is a cell-surface target our lab discovered in MDS and AML stem cells, called IL1RAP, and which other groups have validated. We publish our results, so everybody has access, and there is significant interest. Several companies and academic groups are developing immunotherapy approaches now against IL1RAP. These range from antibodies, and T-cell engagers, to CAR-T cells, and we will see some in the clinic soon. We discovered another target in MDS and AML stem cells; an endogenous inhibitor of p53, which is one of the key tumour suppressor genes in human cancer. That molecule, called MDMX, is frequently overabundant in MDS and AML stem cells. After making this finding, we collaborated with a company that developed a new therapeutic, called a stapled peptide, which is now being tested in a clinical trial. This modified biologic is an MDMX inhibitor, so it acts against the target we discovered.

What happens in your lab day-to-day?

Molecularly, we are very interested in transcription, which is still an understudied area in disease-focused, translational cancer research. There are genes that encode the information that cells, and the body, need to produce proteins, and the genes are the same in every cell. Transcription factors are the molecules that regulate gene activity – decide which gene is switched on and off, and which genes are used to make RNA (and then ultimately translated into a protein). Transcription factors are very hard to target therapeutically but we know they are very important biologically as activators and suppressors of genes. And they are key biological components of the transformation process in cancer. Our lab focuses on abnormal transcription, to understand it better, and we have made considerable progress in the therapeutic targeting of transcription factors, which five to 10 years ago were considered ‘un-drug-able’. Now, more and more people believe many of them are actually ‘drug-able’. The targeting of aberrant transcription, as opposed to targeting more general epigenetic regulators or kinases, is something we have a huge focus on. We want to add something that not everybody else is already doing.

We spend a lot of time doing experiments to test an idea and a lot of thinking and planning is involved to come up with a waterproof plan to either prove or disprove a so-called hypothesis. We have an idea that this or that could be relevant for the function of leukaemia cells. Then we come up with an actual experiment to test that idea, based on what we must do to either prove our idea is right, or wrong. What model do we need? Do we need a cell line, and do we need cells from a patient, or do we need cells from a mouse model system, or a combination of all? Experiments are hands-on work that is very labour intensive and once you have done the experiment you get the data and interpret it. The reality is that what you get out of experiments is almost always more complicated than you thought. We sit down, scratch our heads and try to make sense of what came out of an experiment. Then the next experiment we do is to further clarify or refine it or make the next step.

There are other things beyond the research to do, as a lab head. You make sure the results are disseminated; publish papers, go through a peer review process and get funding. And when we have success stories, we go out there and say, “look, we have done things that are helpful for the patients and the scientific community”. Then we have a new idea and a new plan, so we also spend a lot of time writing and proposing these ideas and convincing other people they are worth being funded, so we can actually do them. That is particularly time-consuming, and I spent a lot of time on that rather than in the wet-lab.

What is the overall aim of your research and why focus on MDS and AML?

It is to improve our understanding of the development of MDS and AML and to ultimately use those insights to develop more effective targeted therapeutics. Blood cancer was attractive to me for a variety of reasons. From my clinical experience, MDS and AML are really devastating diseases with cure rates below 15% in the majority of patients. There is a real need and that has always motivated me from the get-go. The other reason is the accessibility of specimens and samples, so it is relatively easy to study because you need blood or you need bone marrow, but you don’t need complicated surgery to remove a tumour. And because of that, blood cancer and/or experimental haematology in general, has always been one step ahead of other tumour entities in science. Blood is a very well-defined organ in terms of where the stem cells are, where they come from and how do they differentiate [become different]. So, you have a very good baseline, which is not necessarily as good in other organs, to then compare to what is going wrong in leukaemia. I felt, therefore, the study of blood is a more exact, precise science, and has better possibilities to make fundamentally important advances then starting to study tumours of other organs. There are many examples of discoveries, initially made in blood and in leukaemias, that are then looked at in other organ systems and then they find similar things.

“Experimental haematology has always had a spear-heading kind of function in all cancer research.” 

Have you any advice for people undergoing or recovering from treatment?

It is very important not to believe every piece of information you have access to on the internet or from other sources. For a variety of reasons, some information is just plain wrong, and it is very difficult sometimes to see what’s a solid source and what’s not. And, some of information you find in the literature is outdated because it’s based on research done five or 10 years ago. It is important to connect with the experts; people who know what is going on right now and who can give the best advice of what possibilities there are to move forward, and what the newest clinical trials are, especially for MDS and leukaemia. You need to see specialists who really know what is going on. There is a lot of research progress so even something that wasn’t available last year may be in a new trial this year, and a new experimental drug may be worth trying. That is just very important, and you only know about this if you work with the actual specialists and the best doctors that are available. There are logistical challenges, because even if you have the trials, they are often available in the big centres, and in a country like Australia, and in parts of the U.S. as well, the distances are very big. It is sometimes challenging to get state-of-the-art care if you have a very complicated and rare disease like MDS and AML.

What is your holy grail – the one thing you would like to achieve in your career?

I would love to see some of the things I have described [above] come to fruition. I would be the happiest man in the world even if there was just one subset of patients or subset of leukaemia that we could cure, and where my lab contributed a piece of knowledge that helped make that possible. That would be extremely great to see. Of course, we want to cure cancer in general, but it is not realistic in the short term. That’s a big vision. The problem right now is, MDS and AML are fairly rare diseases. You can’t screen the entire population to look for abnormal stem cells, just to fish out four or five from 100,000 that may be at a particular risk. But we are getting to a point where, with markers like clonal haematopoiesis, if we understand a little bit more about what makes them progress, we could do targeted screenings in subpopulations that we think are at risk. We may get to that point, with our increased understanding, in the next five or 10 years. I also would really love to prevent MDS and AML altogether. It is possible in principle, to detect the stem cells from which the blood cancer is coming from early, and when that is happening, to intervene pre-emptively. There are other cancers where breakthroughs have come from prevention – e.g. cervical carcinoma and certain types of colon cancer, and a few others. We must get to a point of early detection and then ideally, prevention. There is good data to support that concept and approach in MDS and AML now, so I am really hopeful.