The development and maintenance of multi-cellular organisms require tight control over the proliferation, differentiation, movement, organization, and death of their constituent cells. We have focused on how intricate molecular communication networks evolve to control these processes in human cells, and how disruption of these processes leads to oncogenesis. In particular, I am interested in understanding the role of protein kinase signaling as well as metabolic activities of cancer that promote tumor initiation, tumor progression, and tumor metastasis. Our ultimate goal is to translate the insights that we obtain in basic research to clinical treatment by developing molecularly-targeted therapeutic strategies that will improve the clinical outcome for patients with cancers.

(1) Identification and characterization of protein kinases that are important in cancer progression There are approximately 500 protein kinases encoded by the human genome that play a major role in controlling many key cellular activities. Uncontrolled kinase activity is a frequent cause of cancers, therefore oncogenic protein kinases and their critical signaling effectors are attractive therapeutic targets in cancer treatment. We combined phosphor-proteomics, oncogenomics, and genome-wide screening strategies to identify and characterize downstream signaling effectors of oncogenic tyrosine kinases. We identified p90 ribosomal S6 kinase 2 (RSK2) as a critical signaling effector of oncogenic tyrosine kinases including FGFR3 and FLT3/ITD in multiple myeloma or acute myeloid leukemia. We have applied the concepts developed in our hematopoietic malignancy research to the study of solid tumors. Distinct from hematopoietic cancers, RSK2 was dispensable for tumor growth but commonly important for multiple steps that comprise tumor metastasis in human cancers including breast, lung, and head and neck cancers. We are currently further exploring the role of RSK2 as a signal integrator in metastatic cancer cells to provide anti-anoikis, pro-invasive, and pro-metastatic signals in cancer cells by phosphorylating and regulating multiple protein factors.

(2) Targeting cancer metabolism as a novel and timely therapeutic strategy Elevated glycolysis and glutaminolysis are one of the well-known hallmarks of cancer. However, detailed mechanisms by which tumor cells control cellular metabolism and how crucial this is for tumorigenesis, tumor growth, and tumor metastasis remain unknown. We recently reported that glutamate dehydrogenase 1 (GDH1) is important for redox homeostasis in cancer cells by controlling the intracellular levels of its product alpha-ketoglutarate (a-KG) and subsequent metabolite fumarate. We also screened and developed small molecule GDH1 inhibitors, purpurin and its derivative R162, which effectively inhibit GDH1 activity and attenuate proliferation of diverse human cancer cells. We are currently performing metabolome-wide RNAi screening to identify novel metabolic enzymes that contribute during diverse steps during tumor progression. These studies will enable us to identify novel metabolic enzymes which could be potential targets to treat human cancers.

(3) Identification and characterization of protein factors required for chemo-resistance in human cancers The treatment of solid tumors with chemo-agents, in particular cisplatin or paclitaxel, often results in the development of chemo-resistance leading to therapeutic failure, but the mechanisms causing drug resistance in cancers remain unclear. Through RNAi screening using a small hairpin RNA library, we are currently focused on identification and characterization of synthetic lethal partners that contributes to cancer chemoresistance.