Transcription factors are proteins that help to regulate genes. Our goal is to develop an entirely new treatment for neuroblastoma that is directed towards novel transcription factor targets and that uses an innovative strategy to do so. Our studies show that the transcription factors ATF5, CEBPB and CEBPD are required by neuroblastoma cells for their survival. Conventional thought is that targeting such factors clinically is not feasible.

Acute lymphoblastic leukemia (ALL) is the leading cause of cancer-related death in young people, and commonly has a poor outcome in adults. The high-risk ALL is a subtype of ALL that fare a high rate of relapse and mortality. Intriguingly, high-risk ALLs show increased signaling response to growth factors that results in uncontrolled cell proliferation. This study focuses on a critical regulator of growth factor signaling pathway and also a novel tumor suppressor, to improve our understanding of the pathogenesis of childhood leukemias.

Novel therapeutic strategies are still needed for hematopoietic malignancies (HM), which are the most common cancers in children. Harnessing the potency of the immune system has great promise for some of these patients, but limitations in available approaches remain. Our long-term goal is to develop novel therapeutic strategies for HM based on a greater understanding of the mechanisms of immune evasion. The objective of this project is to investigate a novel therapeutic target for HM, Siglec15 (Sig15).

Project Goal: 

Diffuse intrinsic pontine glioma (DIPG) is the deadliest brainstem cancer in children, and significant therapeutic progress has not been made in decades. DIPG is resistant to pro-apoptotic chemotherapeutics, exhibits a profile of oxidative stress, and has disrupted cellular metabolism. Ferroptosis is an iron-dependent form of cell death mediated by the accumulation of toxic lipid peroxides. The Lyssiotis lab recently found that the disrupted oxidative/metabolic state in DIPG sensitizes these cells to ferroptotic cell death.

Project Goal

This grant supported research to understand how the bone marrow microenvironment influence the response of acute lymphoblastic leukemia cells to drug treatment. We used multiple laboratory approaches and identified multiple new proteins and cellular pathways that mediate drug resistance. We also identified a population of leukemia cells that acquire stromal-like properties on engagement with bone marrow stroma. We used this information ro identify and validate a new therapeutic approach to overcome resistance, which is potentially translatable to the clinic.