Research Project
10304780
PROJECT SUMMARY / ABSTRACT Pediatric T-cell acute lymphoblastic leukemia (pT-ALL), with limited treatment options, has been historically associated with inferior treatment outcomes with chemotherapy, compared to B-cell ALL. Despite the advances made in our understanding of the etiology of pT-ALL, the overall survival of this disease has not significantly improved. Children with recurrent T-ALL have a dismal survival rate of < 25%, and long-term survivors have an increased burden of disease associated with the curative chemotherapies they received. Therefore, novel targeted therapeutics in combinations are much needed. Population-based genomic and transcriptomic studies have revealed the inter-leukemia diversity of pT-ALL. However, very little is known about intra-leukemia clonal heterogeneity in pT-ALL that were known to contribute to drug resistance and disease recurrence. For example, it remains mysterious what molecular and cellular features of the rare clones have to allow them to survive treatment as other major clones are eliminated. T-ALL arises during the dynamic developmental processes and retains hallmarks of their cellular origins. However, it remains unclear how T-cell development contributes to clonal heterogeneity of pT-ALL. Moreover, whether cell?cell communications between cancer cells and normal cells in the tumor microenvironment contribute to disease recurrence is unclear. Using bulk systems pharmacology and single-cell systems biology approaches, we discovered the leukemia heterogeneity associated with T-cell maturation and drug sensitivity in single cells. Therefore, we hypothesize that clonal therapy by targeting signaling networks in clonal subpopulations arising from T-cell differentiation will minimize relapsed/refractory diseases and improve outcomes for pT-ALL. Our team at St. Jude is uniquely positioned to tackle these challenges, capitalizing on vast expertise in systems biology, ALL pharmacogenomics, and T-cell development. Specifically, in this proposal, we will determine how T-cell development contributes to the intra-leukemia heterogeneity in pT-ALL (Aim 1). We will map clones in pT-ALL to T-cell maturation stages by single-cell analyses of primary samples and normal developmental T cells. We will identify clone-specific hidden drivers that drive clonal heterogeneity and drug sensitivity. Next, we will identify drug combinations that target signaling drivers in multiple clones (Aim 2). We will integrate bulk systems pharmacology with single-cell hidden-driver analyses to unbiasedly predict synergistic drug combinations and validate them by drug screening. We will use patient-derived xenografts that retain clonal complexity for in vivo validation. We will also investigate how TME reprograming modulates clone selection with treatment in pT-ALL (Aim 3). We will reconstruct the tumor and TME communication network from scRNA-seq data and elucidate the molecular mechanisms of clonal selection with treatment in pT-ALL. Taken together, this project will address fundamental unanswered questions in intra- leukemia clonality and provide a new clonal therapy approach that eliminates multiple clones, including those that contribute to disease recurrence, thereby, improves the outcomes for children with T-ALL.
