Photo of David A. Frank,  MD, PhD

David A. Frank, MD, PhD

Dana-Farber Cancer Institute

Dana-Farber Cancer Institute
Phone: (617) 632-4714
Fax: (617) 394-2782

David A. Frank, MD, PhD

Dana-Farber Cancer Institute


  • Associate Professor, Medicine, Harvard Medical School
  • Associate Physician, Medicine, Oncology, Brigham And Women's Hospital
  • Associate Professor of Medicine, Medical Oncology, Dana-Farber Cancer Institute


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 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.


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  • Hu T, Yeh JE, Pinello L, Jacob J, Chakravarthy S, Yuan GC, Chopra R, Frank DA. Impact of the N-terminal domain of STAT3 in STAT3-dependent transcriptional activity. Mol Cell Biol 2015. PubMed
  • Kreimer S, Belov AM, Ghiran I, Murthy SK, Frank DA, Ivanov AR. Mass-spectrometry-based molecular characterization of extracellular vesicles: lipidomics and proteomics. J Proteome Res 2015; 14:2367-84. PubMed
  • Toniolo PA, Liu S, Yeh JE, Moraes-Vieira PM, Walker SR, Vafaizadeh V, Barbuto JA, Frank DA. Inhibiting STAT5 by the BET Bromodomain Inhibitor JQ1 Disrupts Human Dendritic Cell Maturation. J Immunol 2015; 194:3180-90. PubMed
  • Yeh JE, Kreimer S, Walker SR, Emori MM, Krystal H, Richardson A, Ivanov AR, Frank DA. Granulin, a novel STAT3-interacting protein, enhances STAT3 transcriptional function and correlates with poorer prognosis in breast cancer. Genes Cancer 2015; 6:153-68. PubMed
  • Liu S, Walker SR, Nelson EA, Cerulli R, Xiang M, Toniolo PA, Qi J, Stone RM, Wadleigh M, Bradner JE, Frank DA. Targeting STAT5 in hematologic malignancies through inhibition of the bromodomain and extra-terminal (BET) bromodomain protein BRD2. Mol Cancer Ther 2014. PubMed
  • Lee RE, Walker SR, Savery K, Frank DA, Gaudet S. Fold Change of Nuclear NF-虜B Determines TNF-Induced Transcription in Single Cells. Mol Cell 2014; 53:867-79. PubMed
  • Ajay AK, Kim TM, Ramirez-Gonzalez V, Park PJ, Frank DA, Vaidya VS. A bioinformatics approach identifies signal transducer and activator of transcription-3 and checkpoint kinase 1 as upstream regulators of kidney injury molecule-1 after kidney injury. J Am Soc Nephrol 2014; 25:105-18. PubMed
  • 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-虜B to IL-6 signaling axis and STAT3-driven cancer phenotypes. Sci Signal 2014; 7:ra11. PubMed
  • Walker SR, Xiang M, Frank DA. STAT3 Activity and Function in Cancer: Modulation by STAT5 and miR-146b. Cancers (Basel) 2014; 6:958-68. PubMed
  • Frank DA. Transcription factor STAT3 as a prognostic marker and therapeutic target in cancer. J Clin Oncol 2013; 31:4560-1. PubMed
  • Lathan C, Frank DA. ACP Journal Club. Review: low-dose CT screening reduces lung cancer and mortality in current or former smokers. Ann Intern Med 2013; 159:JC3. PubMed
  • Yeh JE, Toniolo PA, Frank DA. Targeting transcription factors: promising new strategies for cancer therapy. Curr Opin Oncol 2013; 25:652-8. PubMed
  • Yeh JE, Toniolo PA, Frank DA. JAK2-STAT5 signaling: A novel mechanism of resistance to targeted PI3K/mTOR inhibition. JAKSTAT 2014; 2:e24635. PubMed
  • Klitgaard JL, Koefoed K, Geisler C, Gadeberg OV, Frank DA, Petersen J, Jurlander J, Pedersen MW. Combination of two anti-CD5 monoclonal antibodies synergistically induces complement-dependent cytotoxicity of chronic lymphocytic leukaemia cells. British Journal of Haematology 2013; 163:182-93. PubMed
  • Walker SR, Nelson EA, Yeh JE, Pinello L, Yuan GC, Frank DA. STAT5 outcompetes STAT3 to regulate the expression of the oncogenic transcriptional modulator BCL6. Mol Cell Biol 2013; 33:2879-90. PubMed
  • Walker SR, Xiang M, Frank DA. Distinct roles of STAT3 and STAT5 in the pathogenesis and targeted therapy of breast cancer. Mol Cell Endocrinol 2013. PubMed
  • Chmielecki J, Crago AM, Rosenberg M, O'Connor R, Walker SR, Ambrogio L, Auclair D, McKenna A, Heinrich MC, Frank DA, Meyerson M. Whole-exome sequencing identifies a recurrent NAB2-STAT6 fusion in solitary fibrous tumors. Nat Genet 2013; 45:131-2. PubMed
  • Walker SR, Frank DA. Screening approaches to generating STAT inhibitors: Allowing the hits to identify the targets. JAKSTAT 2013; 1:292-299. PubMed
  • Frank DA. Targeting STATs for cancer therapy: "Undruggable" no more. JAKSTAT 2013; 1:261-2. PubMed
  • Greulich H, Kaplan B, Mertins P, Chen TH, Tanaka KE, Yun CH, Zhang X, Lee SH, Cho J, Ambrogio L, Liao R, Imielinski M, Banerji S, Berger AH, Lawrence MS, Zhang J, Pho NH, Walker SR, Winckler W, Getz G, Frank D, Hahn WC, Eck MJ, Mani DR, Jaffe JD, Carr SA, Wong KK, Meyerson M. Functional analysis of receptor tyrosine kinase mutations in lung cancer identifies oncogenic extracellular domain mutations of ERBB2. Proc Natl Acad Sci U S A 2012; 109:14476-81. PubMed
  • Nelson EA, Walker SR, Xiang M, Weisberg E, Bar-Natan M, Barrett R, Liu S, Kharbanda S, Christie AL, Nicolais M, Griffin JD, Stone RM, Kung AL, Frank DA. The STAT5 Inhibitor Pimozide Displays Efficacy in Models of Acute Myelogenous Leukemia Driven by FLT3 Mutations. Genes Cancer 2012; 3:503-11. PubMed
  • Bar-Natan M, Nelson EA, Xiang M, Frank DA. STAT signaling in the pathogenesis and treatment of myeloid malignancies. JAKSTAT 2013; 1:55-64. PubMed
  • Takakura A, Nelson EA, Haque N, Humphreys BD, Zandi-Nejad K, Frank DA, Zhou J. Pyrimethamine inhibits adult polycystic kidney disease by modulating STAT signaling pathways. Hum Mol Genet 2011; 20:4143-54. PubMed
  • Catenacci DV, Cervantes G, Yala S, Nelson EA, El-Hashani E, Kanteti R, El Dinali M, Hasina R, Brägelmann J, Seiwert T, Sanicola M, Henderson L, Grushko TA, Olopade O, Karrison T, Bang YJ, Kim WH, Tretiakova M, Vokes E, Frank DA, Kindler HL, Huet H, Salgia R. RON (MST1R) is a novel prognostic marker and therapeutic target for gastroesophageal adenocarcinoma. Cancer Biol Ther 2011; 12:9-46. PubMed
  • Marotta LL, Almendro V, Marusyk A, Shipitsin M, Schemme J, Walker SR, Bloushtain-Qimron N, Kim JJ, Choudhury SA, Maruyama R, Wu Z, Gönen M, Mulvey LA, Bessarabova MO, Huh SJ, Silver SJ, Kim SY, Park SY, Lee HE, Anderson KS, Richardson AL, Nikolskaya T, Nikolsky Y, Liu XS, Root DE, Hahn WC, Frank DA, Polyak K. The JAK2/STAT3 signaling pathway is required for growth of CD44竅コCD24竅サ stem cell-like breast cancer cells in human tumors. J Clin Invest 2011; 121:2723-35. PubMed
  • Nelson EA, Sharma SV, Settleman J, Frank DA. A chemical biology approach to developing STAT inhibitors: molecular strategies for accelerating clinical translation. 2011; 2:518-24. PubMed
  • 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; 117:3421-9. PubMed
  • Morikawa T, Baba Y, Yamauchi M, Kuchiba A, Nosho K, Shima K, Tanaka N, Huttenhower C, Frank DA, Fuchs CS, Ogino S. STAT3 Expression, Molecular Features, Inflammation Patterns, and Prognosis in a Database of 724 Colorectal Cancers. Clin Cancer Res 2011; 17:1452-62. PubMed
  • Walker SR, Chaudhury M, Frank DA. STAT3 Inhibition by Microtubule-Targeted Drugs: Dual Molecular Effects of Chemotherapeutic Agents. Mol Cell Pharmacol 2011; 3:13-19. PubMed
  • Walker SR, Chaudhury M, Nelson EA, Frank DA. Microtubule-targeted chemotherapeutic agents inhibit signal transducer and activator of transcription 3 (STAT3) signaling. Mol Pharmacol 2010; 78:903-8. PubMed
  • Yoda A, Yoda Y, Chiaretti S, Bar-Natan M, Mani K, Rodig SJ, West N, Xiao Y, Brown JR, Mitsiades C, Sattler M, Kutok JL, DeAngelo DJ, Wadleigh M, Piciocchi A, Dal Cin P, Bradner JE, Griffin JD, Anderson KC, Stone RM, Ritz J, Foà R, Aster JC, Frank DA, Weinstock DM. Functional screening identifies CRLF2 in precursor B-cell acute lymphoblastic leukemia. Proc Natl Acad Sci U S A 2010; 107:252-7. PubMed
  • Frank DA. STAT6 in PMBL: pathogenic or passenger? Blood 2009; 114:1133-4. PubMed
  • Walker SR, Nelson EA, Zou L, Chaudhury M, Signoretti S, Richardson A, Frank DA. Reciprocal effects of STAT5 and STAT3 in breast cancer. Mol Cancer Res 2009; 7:966-76. PubMed
  • Sakamoto KM,Frank DA. CREB in the pathophysiology of cancer: implications for targeting transcription factors for cancer therapy. Clin Cancer Res 2009; 15:2583-7. PubMed
  • Ikeuchi Y,Stegmuller J,Netherton S,Huynh MA,Masu M,Frank D,Bonni S,Bonni A. A SnoN-Ccd1 pathway promotes axonal morphogenesis in the mammalian brain. J Neurosci 2009; 29:4312-21. PubMed
  • Frank DA. Targeting transcription factors for cancer therapy. IDrugs 2009; 12:29-33. PubMed
  • 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; 112:5095-102. PubMed
  • de la Iglesia N,Konopka G,Lim KL,Nutt CL,Bromberg JF,Frank DA,Mischel PS,Louis DN,Bonni A. Deregulation of a STAT3-interleukin 8 signaling pathway promotes human glioblastoma cell proliferation and invasiveness. J Neurosci 2008; 28:5870-8. PubMed
  • Liddle FJ, Frank DA. STAT1 expression is not required for polyp formation in Min mice. Mol Carcinog 2007; 47:75-9. PubMed
  • Frank DA. Review: Prophylactic use of granulocyte colony-stimulating factor reduces febrile neutropenia and short-term mortality in cancer. ACP J Club 2008; 148:7. PubMed
  • Germain D, Frank DA. Targeting the cytoplasmic and nuclear functions of signal transducers and activators of transcription 3 for cancer therapy. Clin Cancer Res 2007; 13:5665-9. PubMed
  • Frank DA. STAT3 as a central mediator of neoplastic cellular transformation. Cancer Lett 2006; 251:199-210. PubMed
  • 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; 67:1254-61. PubMed
  • Walker SR, Nelson EA, Frank DA. STAT5 represses BCL6 expression by binding to a regulatory region frequently mutated in lymphomas. Oncogene 2007; 26:224-33. PubMed
  • Bhattacharjee A, Xu B, Frank DA, Feldman GM, Cathcart MK. Monocyte 15-lipoxygenase expression is regulated by a novel cytosolic signaling complex with protein kinase C delta and tyrosine-phosphorylated Stat3. J Immunol 2006; 177:3771-81. PubMed
  • Ishii Y, Pirkmaier A, Alvarez JV, Frank DA, Keselman I, Logothetis D, Mandeli J, O'Connell MJ, Waxman S, Germain D. Cyclin D1 overexpression and response to bortezomib treatment in a breast cancer model. J Natl Cancer Inst 2006; 98:1238-47. PubMed
  • Zorn E, Nelson EA, Mohseni M, Porcheray F, Kim H, Litsa D, Bellucci R, Raderschall E, Canning C, Soiffer RJ, Frank DA, Ritz J. IL-2 regulates FOXP3 expression in human CD4+CD25+ regulatory T cells through a STAT dependent mechanism and induces the expansion of these cells in vivo. Blood 2006; 108:1571-9. PubMed
  • Arbiser JL, Govindarajan B, Battle TE, Lynch R, Frank DA, Ushio-Fukai M, Perry BN, Stern DF, Bowden GT, Liu A, Klein E, Kolodziejski PJ, Eissa NT, Hossain CF, Nagle DG. Carbazole is a naturally occurring inhibitor of angiogenesis and inflammation isolated from antipsoriatic coal tar. J Invest Dermatol 2006; 126:1396-402. PubMed
  • Liddle FJ, Alvarez JV, Poli V, Frank DA. Tyrosine phosphorylation is required for functional activation of disulfide-containing constitutively active STAT mutants. Biochemistry 2006; 45:5599-605. PubMed
  • 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; 66:3649-57. PubMed
  • Alvarez JV, Greulich H, Sellers WR, Meyerson M, Frank DA. Signal transducer and activator of transcription 3 is required for the oncogenic effects of non-small-cell lung cancer-associated mutations of the epidermal growth factor receptor. Cancer Res 2006; 66:3162-8. PubMed
  • Greulich H, Chen TH, Feng W, J. Oncogenic Transformation by Inhibitor-Sensitive and -Resistant EGFR Mutants. PLoS Med 2005; 2:e313. PubMed