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. Prior to joining Moffi tt in 2003, Dr. List was a professor of medicine and director of the Leukemia and
Patients want to keep up to date with MDS 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 – such as preclinical, meaning research that precedes clinical testing, or bench research – research conducted in the laboratory. But basic research means that one is studying the features involved in the biology of the disease. This is generally done in a laboratory setting and may involve animal models.
One of the challenges we have in MDS basic research is that unlike solid tumors and leukemia, where there are cell lines that are propagated from the disease, we do not have reliable cells lines from MDS. With MDS, the bone marrow cells are often destined to die, which is the reason for peripheral blood cytopenias. So we rely upon studying fresh patient bone marrow specimens for that part of research. Basic research can involve evaluating molecular features of the disease. This would involve examining those nuclear components that drive the disease phenotype, such as the DNA, the expression of genes, and the proteins that are made from those genes. Or, we focus on biologic processes that are deregulated to see if there is a way to understand the disease biology and pathogenesis. This means understanding how the disease came to be, or also understanding what the weak point – the Achilles heel-- may be, so you can exploit that for a possible treatment.
Translational research is what bridges the basic discoveries to clinical research. It means determining the potential clinical application of the laboratory findings, in other words, testing them further for clinical development. Before proceeding to the clinical phase, you have to have assurance that you have a relevant target, that there is sufficient evidence that it will be relevant in the clinical setting, and that these may have therapeutic value. Translational research may involve looking at gene mutations across the DNA. If specific gene mutations are discovered 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 relevance. Or, the translational science may involve studying the mutation that turns on the activity of an enzyme in a critical regulatory pathway. With that, we want to know if we can inhibit this enzyme, and can we further discern its potential therapeutic benefit by testing such an inhibitor in an animal model with minimal toxicity. Then, if all looks good, it proceeds to further animal studies to identify possible side eff ects before the next stage which is clinical research. Clinical research involves the testing of a potential new therapeutic compound in individuals who have the disease.
There is a bi-directional influence at work between the different phases of research. Of course something that’s discovered in the laboratory may enter into clinical testing in the scenario just described. But the opposite also can occur. In the clinic, you can have a discovery that takes you back to further science basic research. Lenalidomide is a good example of this. In the laboratory, we saw it affected angiogenesis, which is important in MDS. But after the translational studies and the clinical phase, we found in our first MDS trial that there was a subset of MDS, i.e., those cases with chromosome 5q deletion, where it worked exceptionally well to suppress the clone. It was not until after its FDA approval, that we went back to the lab to find out what are the targets in deletion 5q that allowed lenalidomide to suppress the clone. Later, as patients failed lenalidomide, we went back and studied the mechanism underlying the development of resistance to the drug that was acquired over time. This is a good example why it is important to have the clinical investigators working closely with the basic scientists.
Have there been particular recent trends or directions in MDS research that have helped bring it to its present status?
When you look back over the last six to eight years, research gave rise to a much a better understanding of the biology underlying MDS and especially the molecular biology of the disease. Some of this was made possible by the sequencing of the human genome in 2000 and then innovation in technology that allows us now to survey the reading frames of the human genome quickly and at a reasonable price. This has in more recent years provided new insight to previously unrecognized gene mutations and learn more about which mutations may be driving the disease. We hope that this over time will translate into new therapeutics that will be specific to the genetic makeup of a given individual’s disease.
Another new area of focus is the role of innate immunity and its chronic activation in MDS. Innate immunity, or the so- called non-specifi c immune system, is normally the fi rst line of defense against host infection. However, in some diseases it is chronically activated, such as autoimmune disorders like rheumatoid arthritis. Recognition of its role in MDS led to a lot of new work in the laboratory to identity potentially new targets that can be exploited therapeutically. So it is two particular trends – the advances in understanding the molecular biology of MDS and the role of the activation of innate immunity.
What are some current themes that you fi nd intriguing and feel have promise to shape future directions for MDS research?
In the last few years, we have been able to fi nd out more about some of the signaling pathways that are aberrantly activated in the MDS bone marrow cells that contribute to their early death, or impaired survival. One of those examples is a signaling pathway involving the TGF–beta family members that acts to suppress normal blood development. So discovering that this pathway is overactive in MDS is leading to new drugs that are in clinical development that interfere with the signaling of these aberrant pathways. One of agents is sotatercept, which neutralizes that activity of the TGF–beta family member called activin-A. Another one is an inhibitor of the TGF-beta Type 2 receptor made by Lilly. One trial has already started, and the second agent will begin clinical testing in MDS patients later this year.
What we’ve also learned is that activation of these signaling pathways occurs as a consequence of chronic activation of innate immunity. That has allowed the identifi cation of a number of new targets that lie upstream of TGF-beta that that can be exploited therapeutically. Certain innate immune effector cells get activated, called myeloid derived suppressor cells (MDSC) that is driven by high levels of a soluble infl ammatory protein and stimulant of MDSC, called S100A9. We have been able to dissect the components of this signaling axis to get to the more proximal part and bring along new therapeutics that might be eff ective. That’s a good example of where things are currently moving in MDS research.
Were there particular presentations at ASH 2013 you found be of particular interest?
At ASH, there were interesting things presented, including a study of oral rigosertib given to patients with lower-risk MDS, where they found that a good number of anemic patients who were dependent on transfusions became free of needing transfusions. That will go through further clinical development to test and validate the activity of the drug in this setting. I also was interested in a new drug – an inhibitor of energy metabolism targeting an enzyme called 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 that all had major responses, even one complete response. This agent, CPI-613 by Cornerstone Pharmaceuticals, will be interesting to follow to see how it develops further. There will be more about this at future meetings.
Moffitt recently announced results of a study (Wei) on control mechanisms for the development of MDS. What are ‘control mechanisms’ and what potential does this new study have for affecting the course of future investigation?
This relates to what I mentioned earlier about innate immunity activation. Dr. Wei is an immunologist that works closely with me in MDS. He had been studying one of the major eff ectors of suppression of immune response–the myeloid derived suppressor cells, known as MDSCs. It turns out that these are markedly expanded and activated in the bone marrow of MDS patients. They can account for as much as 30% of the cells in the bone marrow. What he showed is that they are directly suppressing blood production and causing the death of the bone marrow precursors, and they also are the source of all the inflammatory cytokines that we see in the bone marrow and blood of MDS patients.
What’s important is that if we remove those cells from the bone marrow, there is a restoration of the blood forming capacity in the laboratory. Of greater importance is the discovery of a soluble infl ammatory protein that triggers these cells to expand and grow in patients with MDS. It is S100A9, levels of which are more than fi vefold elevated in the plasma of MDS patients. It directly activates the MDSCs through a receptor called TLR-4 and also directly binds to white blood cell precursors in the bone marrow to activate their cell death. Knowing that, we next want to know if this is a potential cause or mediator driving development of MDS.
What was done next was the creation a mouse model that over expressed S100A9, making excess levels of the protein that approximated what was seen in MDS patients. These mice developed MDS within six months, with pancytopenia and bone marrow cells that were profoundly dysplastic, the hallmark of MDS. Now we know that that protein alone can drive the entire phenotype. So with this data, we have a new target that we can potentially exploit therapeutically by trying to neutralize it. Or, we can work on it from a diff erent perspective, that is, by blocking the signaling that it triggers This gets us closer to a driving factor of what causes MDS.
Because of the time it takes for research to have a direct impact on treatment, what is most important for patients who follow MDS research keep in mind?
We all would like 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 and patients as fast as we can. It is a process that often moves slowly, taking many years. Patients may read about encouraging progress, but not realize the potential benefi t of a new therapy for many years. Patients can help accelerate the process is to consider participating in clinical trials when it’s right for them. That is precisely what moves the fi eld 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.