Our research broadly applies stem cell biology to human cancers. We take advantage of a diverse range of experimental systems to initially formulate general concepts regarding cancer biology then transition to more focused studies in order to develop novel therapeutics.
Cancer stem cell biology
A major focus of the laboratory is examining the biology of cancer stem cells. Cancer stem cells are thought to be the cells containing most if not all, of the growth potential within an individual tumor. Our laboratory initially identified cancer stem cells in the plasma cell malignancy multiple myeloma (1) then later demonstrated that these cells were relatively resistant to most agents used to treat patients with the disease (2). Subsequently, we have used many of the same laboratory methods in our myeloma studies to identify and study cancer stem cells in classical Hodgkins lymphoma (3). mantle cell lymphoma (4), pre B-cell acute lymphoblastic leukemia (5), and pancreatic cancer (6,7).
In order to develop strategies to target cancer stem cells, we have focused our studies on cellular pathways involved in regulating normal stem cells. We have examined signaling pathways involved in embryonic development, most extensively the Hedgehog pathway, and have found that it regulates the fate decisions, including self-renewal, of multiple myeloma cancer stem cells (8). In collaboration with other labs, we have also studied the role of Hedgehog signaling in acute leukemias (5), brain tumors (9), and pancreatic cancer (10). We have also examined the role of telomerase that is normally required for maintaining the ends of linear chromosomes during cellular replication in myeloma stem cells (11), as well as agents inducing the differentiation of cancer stem cells that leads to the loss of self-renewal (12,13).
We are also interested in how cellular pathways active in human cancers regulate normal self-renewing cells, such as hematopoietic stem cells (14) or memory immune cells, using transgenic mouse models and normal human tissues.
A major goal of all our projects is to rapidly translate our laboratory findings to patients. Several of the therapeutic strategies developed in the lab are being tested in clinical trials in multiple myeloma (15, 16), myeloid leukemia (17, 18), Hodgkins lymphoma (19, 20) and pancreatic cancer (21) in close collaboration with clinical investigators at Johns Hopkins. Within the context of these trials, we carry out extensive correlative laboratory studies in order to test our hypotheses in the clinic. Morevoer, we have also begun to develop novel biomarkers to track cancer stem cells in patients undergoing treatment.