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 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.
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.
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.
These are just a few of our research interests. Please feel free to explore specific lab web pages and reach out to individual investigators if you are interested in training opportunities.
Jeffrey J. Bednarski, MD, PhD
My research has centered on understanding the signals that direct early B cell development. Specifically, over the last several years, we have focused on understanding how signals induced by DNA damage impact developmental signals in B cells. B cell development occurs through a carefully regulated process that centers on the generation of a mature, non-autoreactive antigen receptor. To produce a mature antigen receptor, B cells must intentionally generate and repair DNA breaks in the antigen receptor genes. The creation of these DNA breaks is highly regulated by cooperative signaling from two surface proteins, the pre-B cell receptor (pre-BCR) and the interleukin-7 receptor. Together these two signals control cell cycle proliferation and arrest, induction of genes required for antigen receptor gene rearrangement, and cell viability.
Jeffrey Magee, MD, PhD
The Magee lab is working to answer several important questions that surround the causes of childhood leukemia. How do childhood leukemias arise from normal blood forming stem cells? How do leukemia cells hijack normal stem cell programs? Why do childhood and adult leukemias have different mutations? Can we identify and target programs that maintain leukemia cells that are unique to childhood leukemia?
Laura G. Schuettpelz, MD, PhD
The Schuettpelz lab studies how inflammation regulates hematopoietic stem cells (HSCs) and contributes to the development of hematopoietic malignancies. Inflammatory signals are important for the normal development of the immune system and the response to acute infection or injury, however sustained inflammatory signaling can impair HSC function. Furthermore, inflammatory signals can promote the clonal expansion of mutant HSCs and the development of hematopoietic malignancies. Understanding how both normal and mutant HSCs respond to inflammation is important for identifying strategies to optimize HSCs function and prevent blood cancers.
Shalini Shenoy, MD, MBBS
My academic focus is on the development of safer less toxic methods of hematopoietic stem cell transplantation in children. Toward this, I am investigating reduced intensity transplantation for children with hemoglobinopathy (sickle cell disease and thalassemia) using the best available related or alternate donors.
Stephen Sykes, PhD
The principal objective of my laboratory is to identify and define those molecular features that drive leukemogenesis and then use that information to develop rational therapeutic strategies for improving outcomes in acute leukemia.
The lab is most interested in molecular pathways that: 1) are differentially regulated between malignant cells and their healthy counterparts; 2) promote resistance to conventional chemotherapies; and 3) support leukemia stem cell biology.