Moon Shot update: Gaining ground on hard-to-treat blood cancers

Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) encompass a spectrum of diseases characterized by an overproduction of immature blood cells, resulting in a lack of healthy, mature blood cells in patients.

Unfortunately, the majority of patients with these diseases are not cured with currently available therapies, so MD Anderson’s MDS and AML Moon Shot™ team has committed to developing new treatment options. The effort is part of MD Anderson’s Moon Shots Program™, a collaborative effort to accelerate the development of scientific discoveries into clinical advances that save patients’ lives.

Simona Colla, Ph.D., associate professor of Leukemia, is leading research efforts on the Moon Shot to better understand and overcome the resistance of MDS to current treatments. She spoke with Cancer Frontline about her research.

Q: Can you summarize the impact of MDS/AML and why there is a need for a Moon Shot focused on these diseases?

A: The incidence of MDS in the U.S. is between 10,000 – 15,000 cases every year, with the majority of cases occurring in older individuals — those over 65 — because MDS is a disease of aging. Thus, we expect the incidence to increase dramatically in the coming years because our population is living longer and we’ll have many more people in this age group.

The situation is a bit different for AML. It stills occurs more in older people, but is diagnosed in very young people as well. In the U.S., about 20,000 cases are diagnosed every year, and there are about 10,000 deaths from AML annually.

This is the reason our Moon Shot team is working on MDS/AML — this remains a very aggressive disease and there are too many lives lost. We’re committed to finding new treatment options for these diseases to save patients’ lives.

Q: Your work is focused on MDS. Can you explain the current state of treatment for this disease and how effective it is?

The standard of care for MDS is therapy with hypomethylating agents (HMAs). While these agents have been improved over time, they have remained almost the only option for many years. Unfortunately, although this therapy results in some clinical improvement in over 60 percent of patients, the majority of patients will eventually fail treatment with HMAs.

The major issue for patients with MDS is that they become cytopenic, meaning their bone marrow cannot produce mature blood cells, so these patients have a very low number of neutrophils, platelets and red blood cells. These patients are often dependent on blood transfusions to survive, particularly in the beginning of treatment. If they respond to HMAs and their body begins producing blood cells again, they don’t need continued transfusions, but almost everyone eventually stops responding.

When that happens, patients may die from the cytopenia or may go on to progress to AML. For those that progress from MDS to AML, we don’t have any approved therapies. It’s just terrible. So it’s a disease for which there is an urgent need for novel therapies.

Q: Your Moon Shot project has focused on understanding why patients inevitably fail when treated with hypomethylating agents. Can you share what you’ve learned thus far?

We’ve discovered that treatment with HMAs doesn’t eliminate the stem cells in the bone marrow that give rise to the disease, or the cells of origin. So, the therapy works downstream, on the more differentiated cell populations in the bone marrow.

Of course, if you still have the originating cancer cells that give rise to disease inside the bone marrow, these cells will very soon become resistant to treatment, acquire new genetic alterations and expand, leading to failure of the therapy and, ultimately, relapse.

Once we discovered this, we wanted to better understand which mechanisms in these cells drive HMA treatment failure and are responsible for disease progression. To this end, we performed in-depth molecular profiling of these cells, often working with just 500 cells from a patient’s bone marrow.

Through genomic and genetic analyses, we worked to understand the characteristics of these cells that make the disease resistant to HMAs. Through our analysis, we discovered that there are two subgroups of MDS, each with a distinct stem cell population harboring specific alterations.

Q: What are your next steps or goals for your work going forward?

We are at the point where we have characterized these disease cells of origin responsible for therapy failure both before treatment and after the patients stopped responding to therapy. We identified potential vulnerabilities for each subgroup of MDS, and now we are trying to target these vulnerabilities with specific drugs.

We’re trying to perform targeted treatments based on the molecular characteristics we identified through our genetic profiling efforts. We want to target the cell of origin, because if you don't, the disease will eventually progress.

Once we are able to validate that we can target these stem cells, we hope to work with our colleagues to initiate clinical trials and rapidly bring forward new options for treating patients with MDS.

Q: How has the Moon Shots Program enabled you to conduct this work in a way you weren’t able to previously?

First of all, the Moon Shots Program gave us the opportunity to perform the in-depth analysis of more than 250 patient samples, which is very expensive. However, because MDS is a very heterogeneous disease, it’s fundamental when studying MDS to be able to analyze a large number of samples. This would not have been possible without the support of the Moon Shots Program.

Also, through the Moon Shots Program, we’ve been afforded the opportunity to collaborate with platforms, such as the Cancer Genomics Laboratory. These groups enabled us to do the work of analyzing mutations in our very small cell populations, and we are grateful for the opportunities to work with them.

The Moon Shots Program has also stimulated meaningful collaborations, both within and outside of MD Anderson. I had the opportunity to discuss the project in my lab, with other groups in the Moon Shot and also with experts in other disciplines at MD Anderson.

I’ve also collaborated with outside groups based on the work we’ve been able to do in the Moon Shot. For example, I did not have a mouse model to validate some of our findings, but have been able to work with a group at Yale University to study what we’ve learned in a new mouse model of MDS.

Thanks to the Moon Shot’s support, I could collaborate with Yale and bring new techniques here to MD Anderson.