Our group focuses on the intracellular signaling events that control the growth and differentiation of normal and malignant cells. Extracellular stimuli lead to a cascade of events that culminates in the regulation of gene expression. It is the activation or repression of specific genes that then determines cellular function. We study how these signaling events occur normally by examining the activation of kinase cascades, transcriptional networks, and key target genes. Among the mediators we have focused on are STAT transcription factors, which can be modulated by both tyrosine and serine phosphorylation, and thus may serve as a convergence point for multiple signaling pathways. Thus, one of the areas of focus in our group is how STATs, alone and in conjunction with other transcription factors, modulate gene expression throughout the genome.
One of the hallmarks of malignancy is the ability of cells to grow independent of external signals. Given this, we have extended our work to analyze the activation of intracellular signaling pathways in primary tumor cells and in models of human malignancies. We have found that STATs and other signaling pathways are activated inappropriately in many forms of cancer. Furthermore, we are identifying the specific target genes that mediate the ability of STATs to lead to malignant transformation of cells. This work has shed light both on the pathogenesis of these diseases and on critical regulators of the biology of normal cells.
Finally, we are developing targeted molecular inhibitors of STATs and other transcription factors using both rational design and chemical-biology approaches. These reagents are useful tools for dissecting the roles of signaling pathways in the growth and differentiation of normal cells. Furthermore, given the inappropriate activation of signaling pathways in malignant cells, these approaches may be useful in developing novel therapeutic strategies for the treatment of cancer. We have initiated a clinical trial of a STAT3 inhibitor identified in our lab for patients with cancer, and we are analyzing the effects of this approach on the gene expression and biology of cancer cells obtained from patients on study. We are in the process of initiating clinical trials with additional transcriptional modulators identified by our group.
In summary, our laboratory pursues the study of signal transduction in normal and neoplastic cells, from molecular systems to human cancer patients.