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http://hdl.handle.net/11375/22031
Title: | DOPAMINE RECEPTOR TARGETING IN HUMAN ACUTE MYELOID LEUKEMIA |
Authors: | Aslostovar, Lili |
Advisor: | Bhatia, Mickie |
Department: | Biochemistry |
Publication Date: | Nov-2017 |
Abstract: | Standard of care chemotherapy for acute myeloid leukemia (AML) has remained unchanged for decades and is associated with therapy failure and unsatisfactory survival rates. While several theories have been put forth to explain the issue of therapy failure in AML, their clinical relevance remains ambiguous and they have yet to advance therapy decisions. To date, the underlying basis of therapy failure remains unresolved, partly due to a lack of reliable surrogate models that authentically reflect the biology of human AML. To dissect the unique biological basis of therapy failure in a clinically-relevant system, we developed a unique patient-derived xenograft model that simulated chemotherapy regimens in vivo. Using this model, we characterized residual leukemia populations immediately after chemotherapy exposure, and monitored their longitudinal growth kinetics towards relapse. Despite the prevailing hypothesis of therapy resistance that involves leukemia stem cells (LSCs), we found that LSC pools were profoundly depleted shortly after chemotherapy, as determined by a lack of LSC-related functional and transcriptional properties. Instead, the residual leukemia cells displayed a unique transcriptional profile that emerged prior to the unrestrained regeneration phase that led to overt relapse. With the goal of identifying novel therapeutic targets, we searched for druggable gene products within the unique transcriptional signature of these leukemia regenerating cells (LRCs), which revealed a member of the dopamine receptor (DRD) family. Functionally, AML recurrence was prevented in mice treated with DRD antagonist thioridazine (TDZ) in combination with chemotherapy. Mechanistically, DRD modulation by small molecules and immunotargeting resulted in suppression of neoplastic self-renewal towards cellular maturation, exclusively in leukemia progenitor cells with no adverse impact on healthy hematopoietic cell function. These findings provided proof-of-concept for our targeting approach and defined a novel role for the DRD pathway in human AML biology. These pre-clinical observations motivated a phase I clinical trial to evaluate the safety and efficacy of DRD antagonist TDZ in AML patients. In a cohort of older patients with relapsed/refractory AML, treatment with TDZ resulted in a reduction of leukemic blasts, predominantly in the peripheral blood. The suppressive effect of TDZ was selective to leukemia cells and was associated with patient-specific DRD expression levels. Collectively, the data presented in this thesis offer a novel perspective on human AML biology with a focus on targetable vulnerabilities of leukemia, derived from sophisticated xenograft systems and validated with clinical level data. Our findings describe a novel role for DRDs in regulating leukemic hematopoiesis and propose DRDs as a cancer-selective therapy target for AML. |
URI: | http://hdl.handle.net/11375/22031 |
Appears in Collections: | Open Access Dissertations and Theses |
Files in This Item:
File | Description | Size | Format | |
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Aslostovar_Lili_201709_PhD.pdf | 14.63 MB | Adobe PDF | View/Open |
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