BBS Faculty Member - David Frank

David Frank

Department of Medicine

Dana Farber Cancer Institute
Medical Oncology, Mayer Bldg., Rm. 522B
450 Brookline Ave.
Boston, MA 02215
Tel: 617-632-4714
Fax: 617-394-2782
Email: david_frank@dfci.harvard.edu



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 which 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, transcription factors, 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. Reflecting the translational nature of this work, we are pursuing the introduction of targeted modulators of STATs and other transcription factors into clinical trials for patients with cancer. This approach also requires the acquisition of cells from these patients to analyze the ability of these drugs to specifically modulate signaling pathways in vivo.

In summary, our laboratory pursues the study of signal transduction in normal and neoplastic cells, from molecular systems to human cancer patients.



Last Update: 6/12/2014



Publications

Walker SR, Nelson EA, Yeh JE, Pinello L, Yuan G-C, Frank DA. STAT5 outcompetes STAT3 to regulate the expression of the oncogenic transcriptional modulator BCL6. Molecular and Cellular Biology 2013; 33:2879-90. PMID: 23716595

Walker SR, Liu S, Xiang M, Nicolais M, Hatzi K, Giannopoulou E, Elemento O, Cerchietti L, Melnick A, Frank DA. Targeting BCL6 for breast cancer therapy. Oncogene 2014; in press.

Lee REC, Walker SR, Savery K, Frank DA, Gaudet S. Fold-change of nuclear NF-κB determines TNF-induced transcription in single cells. Molecular Cell 2014; 53:1-13. NIHMS 567925

Xiang M, Birkbak NJ, Vafaizadeh V, Walker SR, Yeh JE, Liu S, Kroll Y, Boldin M, Taganov K, Groner B, Richardson AL, Frank DA. STAT3 Induction of MiR-146b Forms a Feedback Loop to Inhibit the NF-κB to IL-6 Signaling Axis and STAT3-Driven Cancer Phenotypes. Science Signaling 2014; 7:ra11.



© 2014 by the President and Fellows of Harvard College