DF/HCC Program Affiliation

Kidney Cancer
Gastrointestinal Malignancies
Lymphoma and Myeloma

Research Abstract

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 in response to cytokines, hormones, and cell-cell interactions 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.

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. Utilizing bioinformatics techniques, we have been able to identify a genetic signature in primary human tumor cells reflecting STAT activation. This work has shed light both on the pathogenesis of these diseases and on critical regulators of the growth of normal cells. An additional control point in the development of malignancies is angiogenesis, the growth of new blood vessels to support the tumor. We have found that STAT transcription factors play an important role in endothelial cell function, and thus understanding this signaling pathway can reveal insights into many aspects of cancer biology.

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.

Publications

• Nelson EA,Walker SR,Kepich A,Gashin LB,Hideshima T,Ikeda H,Chauhan D,Anderson KC,Frank DA.Nifuroxazide inhibits survival of multiple myeloma cells by directly inhibiting STAT3.Blood 2008 Dec 15;112(13):5095-102.
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• Lynch RA, Etchin J, Battle TE, Frank DA.A small-molecule enhancer of signal transducer and activator of transcription 1 transcriptional activity accentuates the antiproliferative effects of IFN-gamma in human cancer cells.Cancer Res 2007 Feb 1;67(3):1254-
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• Battle TE, Lynch RA, Frank DA.Signal transducer and activator of transcription 1 activation in endothelial cells is a negative regulator of angiogenesis.Cancer Res 2006 Apr 1;66(7):3649-57.
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• Alvarez JV, Febbo PG, Ramaswamy S, Loda M, Richardson A, Frank DA.Identification of a genetic signature of activated signal transducer and activator of transcription 3 in human tumors.Cancer Res 2005 Jun 15;65(12):5054-62.
  15958548
• Battle TE, Arbiser J, Frank DA.The natural product Honokiol induces caspase-dependent apoptosis in B-cell chronic lymphocytic leukemia (B-CLL) cells.Blood 2005 Mar 31.
  15802533
• Nelson EA, Walker SR, Alvarez JV, Frank DA.Isolation of unique STAT5 targets by chromatin immunoprecipitation-based gene identification.J Biol Chem 2004 Dec 24;279(52):54724-30.
  15498775
• Yuan H, Liddle FJ, Mahajan S, Frank DA.IL-6-induced survival of colorectal carcinoma cells is inhibited by butyrate through down-regulation of the IL-6 receptor.Carcinogenesis 2004 Nov;25(11):2247-55.
  15284182
• Friedberg JW, Dong DA, Li S, Kim H, Stephans K, Noonan K, Neuberg D, Gribben JG, Fisher DC, Freedman AS, Takvorian T, Jurgens R, Battle TE, Frank DA.Oral fludarabine has significant activity in patients with previously untreated chronic lymphocytic leukem
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• Battle TE, Frank DA.STAT1 mediates differentiation of chronic lymphocytic leukemia cells in response to Bryostatin 1.Blood 2003 Oct 15;102(8):3016-24.
  12855573
• Battle TE, Frank DA.The role of STATs in apoptosis.Curr Mol Med 2002 Jun;2(4):381-92.
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• Barber DL, Beattie BK, Mason JM, Nguyen MH, Yoakim M, Neel BG, D'Andrea AD, Frank DA.A common epitope is shared by activated signal transducer and activator of transcription-5 (STAT5) and the phosphorylated erythropoietin receptor: implications for the do
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• Lin TS, Mahajan S, Frank DA.STAT signaling in the pathogenesis and treatment of leukemias.Oncogene 2000 May 15;19(21):2496-504.
  10851048
• Frank DA.STAT signaling in the pathogenesis and treatment of cancer.Mol Med 1999 Jul;5(7):432-56.
  10449805
• Frank DA, Mahajan S, Ritz J.Fludarabine-induced immunosuppression is associated with inhibition of STAT1 signaling.Nat Med 1999 Apr;5(4):444-7.
  10202937
• Frank DA, Mahajan S, Ritz J.B lymphocytes from patients with chronic lymphocytic leukemia contain signal transducer and activator of transcription (STAT) 1 and STAT3 constitutively phosphorylated on serine residues.J Clin Invest 1997 Dec 15;100(12):3140-8
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