Development of Novel Targeted Anti-Leukemia Therapies Público

Abstract

Constitutively activated tyrosine kinases are frequently implicated in the pathogenesis of human leukemia, making them attractive therapeutic targets. Though tyrosine kinase inhibitors have proven remarkably effective for leukemia treatment, they are disease-remitting rather than curative, and many patients develop overt resistance during therapy. This underscores the importance of designing alternate and/or complementary anti-leukemia therapeutic strategies. Our phospho-proteomics studies revealed that serine/threonine kinase p90RSK2 (RSK2) is a common substrate of distinct leukemogenic tyrosine kinases including BCR-ABL and FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD). We found that RSK2 is dispensable for BCR-ABL-induced myeloproliferative neoplasm, but required for FLT3-ITD-induced myeloid transformation in a murine bone marrow transplant assay. Moreover, inhibition of RSK2 by selective RSK inhibitor fmk induces significant apoptosis in FLT3-ITD-positive, but not BCR-ABL expressing leukemia cell lines and primary leukemia cells from human patients. These results suggest that RSK2 may represent an alternative therapeutic target in the treatment of FLT3-ITD-positive leukemia. Our phospho-proteomics studies also revealed a group of metabolic enzymes as tyrosine phosphorylated in leukemia cells transformed by different leukemogenic tyrosine kinases. Among those identified, we found that glycolytic enzyme phosphoglycerate mutase 1 (PGAM1) is important for the coordination of bioenergetic and anabolic biosynthetic pathways in leukemia cells, which is essential for cell proliferation and disease development. We developed a selective PGAM1 inhibitor, PGMI-004A, that effectively inhibits viability of diverse leukemia cell lines and primary leukemia cells from patients with no off-target activity and minimal toxicity. Additionally, we found that 6-phosphogluconate dehydrogenase (6PGD) in the pentose phosphate pathway (PPP) is commonly upregulated by lysine acetylation in cancer/leukemia cells. 6PGD provides an additional link between the oxidative PPP and lipogenesis through 6PGD product-dependent inhibition of LKB1-AMPK signaling, and represents a novel anti-leukemia target. We developed selective small molecule 6PGD inhibitors, Physcion and S3, and found that treatment with 6PGD inhibitors alone or in combination with anti-malarial drug dihydroartemisinin effectively inhibits cell viability in leukemia cell lines and patient samples, and attenuates leukemia cell-derived tumor growth in mice with minimal off-target toxicity. Collectively, these studies provide "proof of principle" for the development of RSK2, PGAM1 and 6PGD inhibitors as novel anti-leukemia agents.

Table of Contents

Chapter 1: Introduction

1.1 Leukemia p.1
1.2 Leukemia therapy in the pre-Gleevec® era: conventional treatment approaches p. 2
1.3 The advent of targeted leukemia therapy p. 3
1.4 Leukemia therapy: the Gleevec® era p. 5
1.5 Clinical challenges in the Gleevec® era p. 7
1.6 Leukemia therapy in the post-Gleevec® era p. 8
1.7 Identifying pan-leukemia therapeutic targets p. 14

Chapter 2: Targeting p90 ribosomal S6 kinase 2 in myeloid leukemia
2.1 Introduction p. 18
2.2 Materials and Methods p. 21
2.3 Results p. 25
2.4 Discussion p. 44

Chapter 3: Targeting leukemia metabolism as a novel therapeutic strategy
3.1 Signaling and targeting of phosphoglycerate mutase 1 in human cancer
3.1.1 Introduction p. 49
3.1.2 Materials and Methods p. 52
3.1.3 Results p. 55
3.1.4 Discussion p. 73

3.2 Signaling and targeting of 6-phosphogluconate dehydrogenase in human leukemia
3.2.1 Introduction p. 79
3.2.2 Materials and methods p. 81
3.2.3 Results p. 87
3.2.4 Discussion p. 103

3.3 Development of novel combinatorial anti-leukemia therapies: a lesson from
dehydrogenase deficient hemolytic anemia
3.3.1 Introduction p. 107
3.3.2 Materials and methods p. 110
3.3.3 Results p. 115
3.3.4 Discussion p. 135

Chapter 4: Discussion
4.1 Summary p. 138
4.2 Future Directions p. 142

References p. 150

About this Dissertation

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Subfield / Discipline	Molecular & Systems Pharmacology
Degree	PhD
Submission	Dissertation
Language	English
Research Field	Health Sciences, Oncology
Palabra Clave	Warburg Effect Leukemia Metabolism Leukemogenic Tyrosine Kinases
Committee Chair / Thesis Advisor	Chen, Jing, Emory University
Committee Members	Kang, Sumin, Emory University Boise, Lawrence, Emory University Nahta, Rita, Emory University Fu, Haian, Emory University

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