The discovery and characterization of lenaldekar: a selective compound for the treatment of T-Cell acute lymphoblastic leukemia

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Title The discovery and characterization of lenaldekar: a selective compound for the treatment of T-Cell acute lymphoblastic leukemia
Publication Type dissertation
School or College School of Medicine
Department Oncological Sciences
Author Ridges, Suzanne
Date 2013-05
Description Acute lymphoblastic leukemia (ALL) is the most common cancer of childhood, with approximately 2000 cases diagnosed annually in the US. Although cure rates for childhood ALL are currently ~80%, T-cell ALL (T-ALL) is still more difficult to treat than B-cell ALL, requiring harsher treatments with concomitant harsher side effects. The goal of this study was to identify more targeted therapies for treating T-ALL with the intent of reducing harsh treatment side effects, thus preserving both lives and long-term quality of life. To meet this goal, 26,400 compounds from the ChemBridge library were screened utilizing zebrafish larvae since they have the combined attributes of vertebrate physiology and small size. The transgenic lck:eGFP zebrafish line with T-cell specific GFP was chosen since compounds which eliminate immature T-cells in the thymus might also eliminate developmentally arrested leukemic blasts. The screen identified five "hit" compounds that cause reduction in GFP without sickening the larvae or causing general cell cycle effects. Of these five compounds, one compound, "Lenaldekar" (LDK), was effective in killing human Jurkat T-ALL without harming healthy lymphocytes. In vivo, LDK shows efficacy in treating leukemia in both zebrafish and mouse xenograft models of T-ALL without observable toxicity or endorgan damage. Furthermore, expanded leukemia testing showed that T-ALL, B-ALL, and CML are all largely LDK-sensitive, including most treatment-refractory relapsed Ph+ leukemias and primary patient samples. Moreover, some AML and multiple myeloma cell lines also show LDK sensitivity. Molecular characterization shows that LDK down-regulates the PI3K/AKT/mTOR (P/A/mT) pathway, which pathway is up-regulated in ~50% of T-ALL cases. Recent results suggest that LDK may achieve this effect via inactivation of the insulin-like growth factor 1 receptor (IGF1-R), which activates the P/A/mT pathway. In addition, LDK treatment elicits a second activity of G2/M arrest in most sensitive cell lines, which arrest appears to be independent of P/A/mT pathway inhibition. Future directions include identifying and modeling LDK's direct biochemical target(s) with the intent of utilizing structure-activity relationships to optimize LDK's chemical structure and efficacy. This study's ultimate goal is to bring LDK into clinical trials for the treatment of T-ALL in both monotherapy and combination therapy applications.
Type Text
Publisher University of Utah
Subject MESH Precursor Cell Lymphoblastic Leukemia-Lymphoma; Quinolines; Sirolimus; Zebrafish; Drug Therapy; Protein Kinase Inhibitors; Oncogene Proteins; Receptor, Notch1
Dissertation Institution University of Utah
Dissertation Name Doctor of Philosophy
Language eng
Relation is Version of Digital reproduction of The Discovery and Characterization of Lenaldekar: A Selective Compound for the Treatment of T-Cell Acute Lymphoblastic Leukemia. Spencer S. Eccles Health Sciences Library. Print version available at J. Willard Marriott Library Special Collections.
Rights Management Copyright © Suzanne Ridges 2013
Format application/pdf
Format Medium application/pdf
Format Extent 6,339,307 byters
Source Original in Marriott Library Special Collections. RM31.5 2013.R53
ARK ark:/87278/s64j3p9q
Setname ir_etd
ID 196374
Reference URL https://collections.lib.utah.edu/ark:/87278/s64j3p9q
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