Research Overview – Recent Past Progress and Projections for the Near-Term | Aplastic Anemia and MDS International Foundation

Research Overview – Recent Past Progress and Projections for the Near-Term

An Interview with Dr. Alan List

Dr. Alan List is the president and CEO of Moffitt Cancer Center in Tampa, Florida.  He is a senior member in the Department of Malignant Hematology and the Experimental Therapeutics Program.  Dr. List’s research interests include novel therapeutic agents to treat acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).  Prior to joining Moffitt in 2003, Dr. List was a professor of medicine and director of the Leukemia and Bone Marrow Transplant Program at the University of Arizona Tucson, as well as director of the Division of Translational/Clinical Research. Dr. List shares his thoughts about the developments in the recent past and possibilities for the immediate future in bone marrow failure research – and the importance of patient participation in clinical trials to keep research moving forward for all bone marrow failure diseases.

Patients want to keep up to date with research, but there are distinct phases - basic, translational, and clinical research. Can you explain what part of the process each area of research represents -- and can activity in one phase of research affect another?

For basic research, there are other terms we also use – preclinical, meaning before it gets to the clinic, or bench research – research conducted in the laboratory. But basic research means that you’re studying the features of the biology of the disease. This is generally done in a laboratory setting and may involve mouse models. But one of the challenges we have in MDS basic research is that unlike solid tumors in leukemia where there will be cell lines that are taken from the disease and propagated or reproduced. With MDS, the bone marrow cells are destined to die, which is the reason for peripheral blood cytopenias. So we have to use fresh patient specimens for that part of the research. Basic research can involve looking at molecular features of a disease. This would be looking at things that drive the phenotype, meaning the DNA, the expression of genes, and the proteins that are made from those genes. Or we look at biologic processes that may be disregulated to see if there is a way to understand the disease pathogenesis or development. This means understanding how the disease came to be, or also understanding what the weak point – the Achilles heel-- may be, so you can factor that into a possible treatment.

Translational research is what bridges the basic and clinical research. It means acting on the lab findings before going to the clinic.  In other words, testing them further for clinical development. Before going to the clinical phase, you have to have some assurance that you have a relevant target, that there’s sufficient evidence that it will be relevant to the clinical setting, and may have therapeutic value.  For instance, translational research may involve looking at gene mutations across the DNA.  If we found specific gene mutations in the basic side, what does that mean for the patient? We can look at outcomes for patients who have had those gene mutations to see their prognostic or predictive relevance. Or, the translational part may involve the mutation of an enzyme that turns it on. With that, we want to know if we can inhibit this enzyme, and would this have any therapeutic effect in the laboratory with an animal model that is therapeutically appropriate, and with minimal toxicity. Then, if all looks good, it goes to the next stage which is clinical research.  Clinical research is simply where we do our testing of a potential new therapeutic compound in individuals who have the disease.

There’s a bi-directional influence at work between the different phases of research. Of course if something is discovered in the laboratory that has relevance to the disese biology, including the propagation and maintenance of it, after proper translational studies, it can then go to the clinical phase of research.

But the opposite also can occur. In the clinic you can have a discovery that takes you back to basic research.  Lenalidomide is a good example of this –in the laboratory we saw it affected angiogenesis—the formation  and development of blood vessels, which is important in MDS. But in the clinical phase, we found in our first MDS trial that there was a subset of MDS – patients with chromosome 5q deletion, where it worked exceptionally well to suppress the clone and that this was a different mechanism altogether. We went back to the lab because of that observation to find out what targets in deletion 5q  allowed lenalimide to suppress the clone. Then when patients failed lenalidomide, we went back and studied the mechanism for resistance to the drug that was acquired over time. This is a good example why it is important to have the clinical investigators working with the basic researchers.

Have there been particular recent trends or directions in bone marrow failure disease research that have helped bring it to its present status?

When you look back over the last six to eight years, what happened in MDS research gives a good example of our better understanding of the biology, and especially the molecular biology, of the disease. Some of this was made possible by the sequencing of the human genome in 2000. Having the technology that let us survey the genome at a reasonable price has allowed us in more recent years, to understand that many patients have specific gene mutations and learn more about which mutations may be driving the disease. We hope this will translate into new therapeutics that will be specific to that person’s genetic makeup.

Another trend that got us to this point is that we’ve learned a lot more about the role of innate immunity being chronically activated in MDS. That has led to a lot of new work in the laboratory to identity potentially new targets that can be exploited therapeutically.  So it’s two things – the advances in understanding the molecular biology of MDS and the role of the activation of innate immunity.

Were there particular presentations at ASH 2013 you found be of particular interest?

At ASH, there were interesting things, including a study of oral rigersotib given in lower risk MDS patients, where they found that a good number anemic patients who were transfusion dependent, became free of needing transfusions. That will go through further clinical development to test and validate the activity of the process. I also was interested in a drug – an inhibitor of energy metabolism targeting pyruvate dehydrogenase. This wasn’t just in MDS, but in all advanced hematologic malignancies. In this study they had three MDS patients in the trial who all had major responses, even one complete response.  This is CPI-613 by Cornerstone Pharmaceuticals, and it will be interesting to see how this one develops further. There will be more about this at future meetings.

Because of the time it takes for research to have a direct impact on treatment, what is most important for patients who follow bone marrow failure disease research keep in mind?  

We all would all to see the process accelerated – so we  can test new ideas faster and get the right drugs in to the hands of the treating physicians as fast as we can. It as a process that often moves slowly, taking many years. Patients read about encouraging progress, but may not realize a new therapy could be many years away. But one thing patients can do to help accelerate the process is to consider participating in clinical trials when it’s right for them. That’s what’s going to move the field faster!  None of the drugs we are using now would be there unless patients had participated in trials, and helped us to prove their activity and effectiveness.