In this project I aim to develop a new prognostic platform for an aggressive pediatric cancer, T-cell acute lymphoblastic leukemia (T-ALL), based on patterns of gene splicing that may predict which children are most likely to develop drug resistance to standard chemotherapies. I will then examine novel targeted therapies by testing splicing inhibitors in vitro and in vivo to evaluate mechanisms of action and effectiveness[SJF1] . In this Hartwell Individual Biomedical Research project, I aim to address the unmet need of treating children with drug-resistant T-ALL. Acute lymphoblastic leukemia (ALL) is the most prevalent childhood cancer and represents approximately 25% of cancer diagnoses among children younger than 15 years1-6 . Approximately 3,100 children and adolescents are diagnosed each year in the United States, and the incidence of ALL is increasing7. Frontline chemotherapy for children with ALL can last up to three years and includes three main phases: induction, consolidation and maintenance. Unfortunately, these chemotherapeutic regimens often cause cognitive problems and lead to secondary cancers later in life. One-fourth of pediatric patients with ALL do not achieve a complete remission or relapse after consolidated chemotherapy, making resistance to therapy the most substantial challenge in disease treatment5,8,9. Allogenic stem cell transplantation (ASCT) is the primary current treatment for patients that relapse, but this method is often accompanied by strong side effects, including graft-versus-host disease, which can be lethal(Review 1) . Immunotherapy using engineered T cells appears promising for some patients, but these experimental therapies are unproven and exhibit some toxicity. Unlike other hematological malignancies, such as B-ALL1 (REF), in T-ALL current therapeutic options and drugs in clinical trials are rather restricted. Mechanisms of resistance in ALL remain poorly characterized due to the absence of appropriate mouse or other in vivo leukemia models and needed technologies. Since establishing my independent laboratory two years ago, I have worked to identify oncogenic mechanisms that lead to resistance to therapy and disease relapse and that might be addressed by targeted therapies. I have recently discovered that protein levels of splicing factors are significantly upregulated in T-ALL compared to physiological tissues. This leads to aberrant splicing events affecting tumor suppressors and enzymes that metabolize chemotherapy drugs. I have observed that high-risk T-ALL cases exhibit higher levels of aberrant splicing compared to diagnosis and hypothesis that these splicing errors are responsible for drug resistance. Others have documented similar mutations in diseases such as myelodysplastic syndromes (MDS). Previous work has overlooked a significant portion of cases without any mutations, however, and has therefore failed to associate disease progression with splicing alterations. My proposed innovation of applying a splicing inhibitor promises to provide a targeted therapy in aggressive T-ALL, ameliorating the effects of systemic therapies.
|Effective start/end date||4/1/18 → 3/31/21|
- Hartwell Foundation (Agmt 4/4/18)
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