Research

Introduction to pediatric blood cancer research

A history of pediatric leukemia/lymphoma research captures some of the greatest success stories in modern medicine. For example, pediatric B-ALL was largely incurable just a few decades ago. Now, over 90% of children diagnosed with B-ALL are cured, and much of our focus is on optimizing the amount of treatment required for each patient. Treatments for T-ALL, Hodgkin’s lymphoma and B-cell lymphoma have made similarly great strides over the past several decades, and they have high cure rates.

Despite these successes, some leukemias and lymphomas remain difficult to treat. Most of the research in the program focuses on these cancers because there is so much room for improvement. For example, treatments for AML have not changed much in decades. We have made progress in supportive care and identifying patients who would benefit from bone marrow transplants, and we have made progress in the transplants themselves, but we need new tools to treat AML that resist chemotherapy. This situation differs from that of B-ALL, where several new immune-based therapies have become available in the past few years. There are no equivalent game-changing therapies for drug-resistant AML. This raises the question, “How do we develop new tools”?

Tool discovery takes several forms. Some of our faculty oversee clinical trials aimed at introducing new therapies to treatment protocols for difficult-to-treat leukemias. These trials are critically important, but they still require candidate drugs and drug targets. When the targets remain vague, we need to dig deeper into the biology of the leukemia or lymphoma cells to identify new vulnerabilities. Ongoing basic research within our program aims to understand the mutations that cause leukemia/lymphoma, as well as properties of normal childhood blood cells that get corrupted when blood cancers form.

Clinical and basic science take fundamentally different approaches to cancer treatment, and they unfold over different timelines. Both are critically important.

Clinical research

Clinical trials are often designed to add new agents to existing regimens, or to tailor regimens more precisely to balance toxicity and efficacy. The process is iterative. For example, new drugs or drug combinations will be tested in small numbers of patients in phase 1 and phase 2 trials. If an approach appears safe (phase 1) and effective (phase 2), the trial can expand to encompass large numbers of patients (phase 3).

We conduct all three types of clinical trials at Washington University. We have an active experimental therapeutics program that conducts phase 1 and 2 trials. We have open phase 3 protocols for newly diagnosed ALL, AML and several lymphomas. Finally, we have investigator-initiated trials aimed at developing new approaches for hard-to-treat leukemias, particularly for treating relapsed AML with immune cells.

Basic research

Our leukemia/lymphoma program integrates basic research from several exceptional, well-funded, highly-productive labs. The leukemia program alone currently holds nine R-level grants from the National Institutes of Health, along with several large foundation grants. We routinely publish in high-impact journals, and we have trained exceptional students, postdocs and fellows to conduct independent research of their own.

Work from individual faculty is summarized in the next section, but there are some core themes to our research, including an emphasis on hard-to-treat leukemias, a focus on stem cell biology, and heavy utilization of cutting-edge techniques (genomics, single cell sequencing, mouse modeling and metabolomics). Our program benefits from access to one of the largest genome sequencing facilities in the world, collaborations with a diverse group of scientists across the university, and strong institutional support.

Very few programs, nationally or internationally, can bring such expertise and resources to bear on the fundamental questions that surround childhood leukemia biology.

Sample of motivating questions

Why do children get blood cancers, and how are they different from adult blood cancers?

Several factors that promote leukemias in adults – such as environmental exposures, chronic inflammation and old age – do not cause childhood cancers, yet cancer is the most common cause of death due to illness in children in developed countries. Why does it happen? Furthermore, childhood leukemias have different mutations than adult leukemias. Again, it is not clear why. Work at our institution has shown that genes that regulate normal blood development can also determine whether a mutation will cause leukemia. The genes can sometimes aid leukemia formation and in other cases prevent it. We can manipulate the developmental switches to stop leukemias from growing. This will provide a powerful new tool for treatments if we can harness it.

How do blood-forming stem cells contribute to leukemia formation?

Stem cells have the unique ability to divide extensively without stopping, and leukemias frequently hijack this ability. Work in several labs focuses on understanding this process. For example, the Schuettpelz lab studies how stem cells decide to divide, and then stop dividing, when they are stressed. The Bednarski and Magee labs both study genes that control stemness at the epigenetic level. The Sykes lab studies stem cell metabolism. In each case, the projects seek to understand how leukemia cells misappropriate normal stem cell programs.

How do childhood leukemias alter their metabolism to support growth?

Leukemia cells often have higher metabolic demands and use nutrients differently than normal blood cells. These differences may create therapeutic opportunities. For example, Dr. Sykes conducts research aimed at identifying metabolic programs that are hijacked by specific pediatric AML mutations. Dr. Ferris conducts research aimed at understanding how retinoid metabolism might be targeted to treat infant AML and ALL. In both cases, small molecules exist to target the abnormal programs. These molecules can potentially be repurposed to treat these AML or ALL. 

Our Labs