BBS Faculty Member - David Frank

David Frank

Department of Medicine

Dana Farber Cancer Institute
Adult 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: 8/22/2013



Publications

Nelson EA, Walker SR, Weisberg E, Bar-Natan M, Barrett R, Gashin LB, Terrell S, Klitgaard JL, Santo L, Addorio MR, Ebert BL, Griffin JD, Frank DA. The STAT5 inhibitor pimozide decreases survival of chronic myelogenous leukemia cells resistant to kinase inhibitors. Blood. 2011; 117:3421-3429.

Nelson EA, Sharma SV, Settleman J, Frank DA. A chemical biology approach to developing STAT inhibitors: Molecular strategies for accelerating clinical translation. Oncotargets. 2011; 2:518-524.

Bar-Natan M , Nelson EA, Walker SR, Kuang Y, Distel RJ, Frank DA. Dual inhibition of Jak2 and STAT5 enhances killing of myeloproliferative neoplasia cells. Leukemia 2011; doi:10.1038/leu.2011.338.

Nelson EA, Walker SR, Xiang M, Weisberg E, Bar-Natan M, Barrett R, Liu S, Kharbanda S, Christie AL, Griffin JD, Stone RM, Kung AL, Frank DA. The STAT5 inhibitor pimozide displays efficacy in models of AML driven by FLT3 mutations. Genes and Cancer 2012; in press.



© 2013 by the President and Fellows of Harvard College