The last decade has seen an unparalleled pace of cancer-focused discovery enabled by disruptive technologies. However, for many malignancies, such as acute myeloid leukemia (AML), survival of the disease remains unchanged despite a more granular description of its genomic landscape. My research program seeks to apply new approaches in functional genomics and chemical biology to validate and translate emerging cancer dependencies in AML and other malignancies defined by simple genomes, particularly pediatric cancers. In this proposal, I build upon our past success in 1) inventing new approaches to small-molecule discovery 2) applying state-of-the-art chemical and functional genomic screens to identify new therapeutic targets in leukemia, Ewing sarcoma, and neuroblastoma, and in 3) translating our discoveries to clinical trials for patients suffering from these diseases. Primarily focusing on AML, my future research program seeks to 1) deploy genetic approaches to validate candidate cancer dependencies, 2) discover and test new small- molecule inhibitors of cancer dependencies, and 3) dissect the mechanisms of each target and its role in AML. I will begin with the study of targets that have emerged in our research as relevant in high-risk AML subtypes: the cytoplasmic kinase spleen tyrosine kinase (SYK); a serine-threonine kinase glycogen synthase kinase 3 alpha (GSK-3?), a mitochondrial enzyme involved in folate metabolism, methylenetetrahydrofolate dehydrogenase 2 (MTHFD2); and a member of the cohesin complex: stromal antigen 2 (STAG2). In some cases, such as Ewing sarcoma and STAG2, I will extend testing to other disease contexts where the target is relevant and my laboratory has expertise. With deep expertise in the molecular pathogenesis and care of patients with AML; experience leading highly multi-disciplinary teams focused on high-throughput screening for this disease and a rich network of chemistry, biology, and clinical collaborators, I am uniquely positioned to succeed in the 7 year research plan delineated in this proposal.
New technologies have accelerated progress in understanding the molecular origins of acute myeloid leukemia (AML), but cure rates remain largely unchanged over the last two decades. In order to address this problem, we will apply innovative genetic and chemical approaches to validate new therapeutic targets in AML. We will develop a mechanistic understanding of the role of these targets in AML and ultimately seek to translate our findings to clinical trials for patients suffering from this disease.
|Stolte, Björn; Iniguez, Amanda Balboni; Dharia, Neekesh V et al. (2018) Genome-scale CRISPR-Cas9 screen identifies druggable dependencies in TP53 wild-type Ewing sarcoma. J Exp Med 215:2137-2155|
|Pikman, Yana; Stegmaier, Kimberly (2018) Targeted therapy for fusion-driven high-risk acute leukemia. Blood 132:1241-1247|
|Liu, Suhu; Marneth, Anna E; Alexe, Gabriela et al. (2018) The kinases IKBKE and TBK1 regulate MYC-dependent survival pathways through YB-1 in AML and are targets for therapy. Blood Adv 2:3428-3442|
|Guerra, Rachel M; Bird, Gregory H; Harvey, Edward P et al. (2018) Precision Targeting of BFL-1/A1 and an ATM Co-dependency in Human Cancer. Cell Rep 24:3393-3403.e5|
|Iniguez, Amanda Balboni; Stolte, Björn; Wang, Emily Jue et al. (2018) EWS/FLI Confers Tumor Cell Synthetic Lethality to CDK12 Inhibition in Ewing Sarcoma. Cancer Cell 33:202-216.e6|
|Roti, Giovanni; Qi, Jun; Kitara, Samuel et al. (2018) Leukemia-specific delivery of mutant NOTCH1 targeted therapy. J Exp Med 215:197-216|
|Wagner, Florence F; Benajiba, Lina; Campbell, Arthur J et al. (2018) Exploiting an Asp-Glu ""switch"" in glycogen synthase kinase 3 to design paralog-selective inhibitors for use in acute myeloid leukemia. Sci Transl Med 10:|
|Mohr, Sebastian; Doebele, Carmen; Comoglio, Federico et al. (2017) Hoxa9 and Meis1 Cooperatively Induce Addiction to Syk Signaling by Suppressing miR-146a in Acute Myeloid Leukemia. Cancer Cell 31:549-562.e11|
|Malone, Clare F; Stegmaier, Kimberly (2017) Scratching the Surface of Immunotherapeutic Targets in Neuroblastoma. Cancer Cell 32:271-273|
|Fenouille, Nina; Bassil, Christopher F; Ben-Sahra, Issam et al. (2017) The creatine kinase pathway is a metabolic vulnerability in EVI1-positive acute myeloid leukemia. Nat Med 23:301-313|
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