Photo of Donald W. Kufe,  MD

Donald W. Kufe, MD

Dana-Farber Cancer Institute

Dana-Farber Cancer Institute
Phone: (617) 632-3141
Fax: (617) 632-2934


donald_kufe@dfci.harvard.edu

Donald W. Kufe, MD

Dana-Farber Cancer Institute

EDUCATIONAL TITLES

  • Professor, Medicine, Harvard Medical School
  • Leader, Translational Pharmacology and Early Therapeutic Trials Program, Dana-Farber/Harvard Cancer Center

DF/HCC PROGRAM AFFILIATION

DF/HCC ASSOCIATIONS

  • Member, Center Scientific Council

Research Abstract

The Kufe laboratory identified the human DF3/MUC1 carcinoma-associated protein in the early 1980s. Initial studies demonstrated that MUC1 is aberrantly overexpressed in >90% of human breast cancers. Subsequent work by multiple laboratories showed that MUC1 is expressed at elevated levels by diverse carcinomas and certain hematologic malignancies, including multiple myeloma. Estimates indicate that MUC1 is overexpressed in about 900,000 of the 1.4 million tumors diagnosed each year in the United States.

MUC1 is translated as a single polypeptide that undergoes autocleavage into two subunits (MUC1-N and MUC1-C) that in turn form a stable heterodimer at the apical membrane of normal epithelial cells. Early research on MUC1 focused on the shed MUC1-N mucin component and led to development of the CA15-3 assay to monitor circulating levels of this subunit as a tumor biomarker. Subsequent work then turned to the MUC1-C transmembrane subunit as the potential link between its overexpression and carcinogenesis. Indeed, the MUC1-C cytoplasmic domain was shown to be sufficient to induce transformation.

With transformation and loss of polarity, MUC1-C associates with EGFR, ErbB2 and other receptor tyrosine kinases at the cell membrane. MUC1-C also localizes to the cytoplasm of transformed cells and is targeted to the nucleus and mitochondria. The MUC1-C cytoplasmic domain directly contributes to the regulation of effectors, such as p53, 硫-catenin, NF-虜B and STATs, that have been linked to transformation. The MUC1-C cytoplasmic domain also functions as a substrate for EGFR, MET, Src family members, c-Abl and GSK3硫, supporting a role in diverse signaling pathways.

These findings have provided support for a model in which human tumors overexpress MUC1-C to exploit its role in promoting growth and survival. In addition, the overexpression of MUC1-C in a substantial number of human malignancies has established it as a highly attractive target for the development of targeted agents.

Translational research in the Kufe laboratory has been focused on the development of approaches that target MUC1 with vaccines and with antibodies against the MUC1-C extracellular domain. The demonstration that MUC1-C transforming function is dependent on the formation of oligomers has also provided the experimental framework for designing agents, such as cell-penetrating peptides and small molecules, that block its oligomerization. Based on this work, the first-in-man MUC1-C inhibitor, designated GO-203, has completed Phase I evaluation in patients with refractory solid tumors and a dose has been defined for Phase II trials in hematologic malignancies.

 

Publications

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  • Raina D, Uchida Y, Kharbanda A, Rajabi H, Panchamoorthy G, Jin C, Kharbanda S, Scaltriti M, Baselga J, Kufe D. Targeting the MUC1-C oncoprotein downregulates HER2 activation and abrogates trastuzumab resistance in breast cancer cells. Oncogene 2014. PubMed
  • Yin L, Kufe T, Avigan D, Kufe D. Targeting MUC1-C is synergistic with bortezomib in downregulating TIGAR and inducing ROS-mediated myeloma cell death. Blood 2014. PubMed
  • Kumar M, Gupta D, Singh G, Sharma S, Bhatt M, Prashant CK, Dinda AK, Kharbanda S, Kufe D, Singh H. Novel polymeric nanoparticles for intracellular delivery of peptide cargos: antitumor efficacy of the Bcl-2 conversion peptide NuBCP-9. Cancer Res 2014. PubMed
  • Rajabi H, Alam M, Takahashi H, Kharbanda A, Guha M, Ahmad R, Kufe D. MUC1-C oncoprotein activates the ZEB1/miR-200c regulatory loop and epithelial-mesenchymal transition. Oncogene 2014; 33:1680-9. PubMed
  • Alam M, Rajabi H, Ahmad R, Jin C, Kufe D. Targeting the MUC1-C oncoprotein inhibits self-renewal capacity of breast cancer cells. 2014. PubMed
  • Liu S, Yin L, Stroopinsky D, Rajabi H, Puissant A, Stegmaier K, Avigan D, Kharbanda S, Kufe D, Stone R. MUC1-C oncoprotein promotes FLT3 receptor activation in acute myeloid leukemia cells. Blood 2014; 123:734-42. PubMed
  • Alam M, Ahmad R, Rajabi H, Kharbanda A, Kufe D. MUC1-C oncoprotein activates ERK→C/EBPβ signaling and induction of aldehyde dehydrogenase 1A1 in breast cancer cells. J Biol Chem 2013; 288:30892-903. PubMed
  • Stroopinsky D, Rosenblatt J, Ito K, Mills H, Yin L, Rajabi H, Vasir B, Kufe T, Luptakova K, Arnason J, Nardella C, Levine JD, Joyce RM, Galinsky I, Reiter Y, Stone RM, Pandolfi PP, Kufe D, Avigan D. MUC1 is a potential target for the treatment of acute myeloid leukemia stem cells. Cancer Res 2013; 73:5569-79. PubMed
  • Rosenblatt J, Avivi I, Vasir B, Uhl L, Munshi NC, Katz T, Dey BR, Somaiya P, Mills H, Campigotto F, Weller E, Joyce R, Levine JD, Tzachanis D, Richardson P, Laubach J, Raje N, Boussiotis V, Yuan YE, Bisharat L, Held V, Rowe J, Anderson K, Kufe D, Avigan D. Vaccination with dendritic cell/tumor fusions following autologous stem cell transplant induces immunologic and clinical responses in multiple myeloma patients. Clin Cancer Res 2013; 19:3640-8. PubMed
  • Kharbanda A, Rajabi H, Jin C, Raina D, Kufe D. MUC1-C oncoprotein induces tamoxifen resistance in human breast cancer cells. Mol Cancer Res 2013. PubMed
  • Uchida Y, Raina D, Kharbanda S, Kufe D. Inhibition of the MUC1-C oncoprotein is synergistic with cytotoxic agents in the treatment of breast cancer cells. Cancer Biol Ther 2012. PubMed
  • Vasir B, Zarwan C, Ahmad R, Crawford KD, Rajabi H, Matsuoka K, Rosenblatt J, Wu Z, Mills H, Kufe D, Avigan D. Induction of antitumor immunity ex vivo using dendritic cells transduced with fowl pox vector expressing MUC1, CEA, and a triad of costimulatory molecules (rF-PANVAC). J Immunother 2012; 35:555-69. PubMed
  • Luptakova K, Rosenblatt J, Glotzbecker B, Mills H, Stroopinsky D, Kufe T, Vasir B, Arnason J, Tzachanis D, Zwicker JI, Joyce RM, Levine JD, Anderson KC, Kufe D, Avigan D. Lenalidomide enhances anti-myeloma cellular immunity. Cancer Immunol Immunother 2012. PubMed
  • Hong DS, Kurzrock R, Supko JG, He X, Naing A, Wheler J, Lawrence D, Eder JP, Meyer CJ, Ferguson DA, Mier J, Konopleva M, Konoplev S, Andreeff M, Kufe D, Lazarus H, Shapiro GI, Dezube BJ. A phase i first-in-human trial of bardoxolone methyl in patients with advanced solid tumors and lymphomas. Clin Cancer Res 2012; 18:3396-406. PubMed
  • Ahmad R, Alam M, Rajabi H, Kufe D. The MUC1-C oncoprotein binds to the BH3 domain of the pro-apoptotic BAX protein and blocks BAX function. J Biol Chem 2012; 287:20866-75. PubMed
  • Jin C, Rajabi H, Rodrigo CM, Porco JA, Kufe D. Targeting the eIF4A RNA helicase blocks translation of the MUC1-C oncoprotein. Oncogene 2012. PubMed
  • Avigan D, Rosenblatt J, Kufe D. Dendritic/tumor fusion cells as cancer vaccines. Semin Oncol 2012; 39:287-95. PubMed
  • Kufe DW. MUC1-C oncoprotein as a target in breast cancer: activation of signaling pathways and therapeutic approaches. Oncogene 2012. PubMed
  • Raina D, Ahmad R, Rajabi H, Panchamoorthy G, Kharbanda S, Kufe D. Targeting cysteine-mediated dimerization of the MUC1-C oncoprotein in human cancer cells. Int J Oncol 2012; 40:1643-9. PubMed
  • Rajabi H, Ahmad R, Jin C, Joshi MD, Guha M, Alam M, Kharbanda S, Kufe D. MUC1-C oncoprotein confers androgen-independent growth of human prostate cancer cells. Prostate 2012. PubMed
  • Rajabi H, Ahmad R, Jin C, Kosugi M, Alam M, Joshi MD, Kufe D. MUC1-C oncoprotein induces TCF7L2 transcription factor activation and promotes cyclin D1 expression in human breast cancer cells. J Biol Chem 2012; 287:10703-13. PubMed
  • Yin L, Kosugi M, Kufe D. Inhibition of the MUC1-C oncoprotein induces multiple myeloma cell death by down-regulating TIGAR expression and depleting NADPH. Blood 2012; 119:810-6. PubMed
  • Jin C, Rajabi H, Pitroda S, Li A, Kharbanda A, Weichselbaum R, Kufe D. Cooperative Interaction between the MUC1-C Oncoprotein and the Rab31 GTPase in Estrogen Receptor-Positive Breast Cancer Cells. PLoS ONE 2012; 7:e39432. PubMed
  • Panchamoorthy G, Rehan H, Kharbanda A, Ahmad R, Kufe D. A monoclonal antibody against the oncogenic mucin 1 cytoplasmic domain. Hybridoma (Larchmt) 2011; 30:531-5. PubMed
  • Sakakibara K, Saito N, Sato T, Suzuki A, Hasegawa Y, Friedman JM, Kufe DW, Vonhoff DD, Iwami T, Kawabe T. CBS9106 is a novel reversible oral CRM1 inhibitor with CRM1 degrading activity. Blood 2011; 118:3922-31. PubMed
  • Mine N, Yamamoto S, Saito N, Yamazaki S, Suda C, Ishigaki M, Kufe DW, Von Hoff DD, Kawabe T. CBP501-Calmodulin Binding Contributes to Sensitizing Tumor Cells to Cisplatin and Bleomycin. Mol Cancer Ther 2011; 10:1929-38. PubMed
  • Rajabi H, Joshi MD, Jin C, Ahmad R, Kufe D. Androgen receptor regulates expression of the MUC1-C oncoprotein in human prostate cancer cells. Prostate 2011; 71:1299-308. PubMed
  • Rosenblatt J, Glotzbecker B, Mills H, Vasir B, Tzachanis D, Levine JD, Joyce RM, Wellenstein K, Keefe W, Schickler M, Rotem-Yehudar R, Kufe D, Avigan D. PD-1 blockade by CT-011, anti-PD-1 antibody, enhances ex vivo T-cell responses to autologous dendritic cell/myeloma fusion vaccine. J Immunother 2011; 34:409-18. PubMed
  • Zhou Y, Rajabi H, Kufe D. Mucin 1 C-terminal subunit oncoprotein is a target for small-molecule inhibitors. Mol Pharmacol 2011; 79:886-93. PubMed
  • Yin L, Wu Z, Avigan D, Rosenblatt J, Stone R, Kharbanda S, Kufe D. MUC1-C oncoprotein suppresses reactive oxygen species-induced terminal differentiation of acute myelogenous leukemia cells. Blood 2011. PubMed
  • Raina D, Kosugi M, Ahmad R, Panchamoorthy G, Rajabi H, Alam M, Shimamura T, Shapiro GI, Supko JG, Kharbanda S, Kufe DW. DEPENDENCE ON THE MUC1-C ONCOPROTEIN IN NON-SMALL CELL LUNG CANCER CELLS WITH EGFR AND K-RAS MUTATIONS. Mol Cancer Ther 2011. PubMed
  • Shapiro GI, Tibes R, Gordon MS, Wong BY, Eder JP, Borad MJ, Mendelson DS, Vogelzang NJ, Bastos BR, Weiss GJ, Fernandez C, Sutherland W, Sato H, Pierceall WE, Weaver D, Slough S, Wasserman E, Kufe DW, Von Hoff DD, Kawabe T, Sharma S. Phase I Studies of CBP501,a G2 Checkpoint Abrogator, as Monotherapy and in Combination with Cisplatin in Patients with Advanced Solid Tumors. Clin Cancer Res 2011. PubMed
  • Kosugi M, Ahmad R, Alam M, Uchida Y, Kufe D. MUC1-C oncoprotein regulates glycolysis and pyruvate kinase M2 activity in cancer cells. PLoS ONE 2011; 6:e28234. PubMed
  • Ahmad R, Rajabi H, Kosugi M, Joshi MD, Alam M, Vasir B, Kawano T, Kharbanda S, Kufe D. MUC1-C Oncoprotein Promotes STAT3 Activation in an Autoinductive Regulatory Loop. Sci Signal 2011; 4:ra9. PubMed
  • Yin L, Kufe D. MUC1-C Oncoprotein Blocks Terminal Differentiation of Chronic Myelogenous Leukemia Cells by a ROS-Mediated Mechanism. Genes Cancer 2011; 2:56-64. PubMed
  • Yin L, Ahmad R, Kosugi M, Kufe T, Vasir B, Avigan D, Kharbanda S, Kufe D. Survival of human multiple myeloma cells is dependent on MUC1 C-terminal transmembrane subunit oncoprotein function. Mol Pharmacol 2010; 78:166-74. PubMed
  • Kufe DW. Mucins in cancer: function, prognosis and therapy. Nat Rev Cancer 2009; 9:874-85. PubMed
  • Joshi MD, Ahmad R, Yin L, Raina D, Rajabi H, Bubley G, Kharbanda S, Kufe D. MUC1 oncoprotein is a druggable target in human prostate cancer cells. Mol Cancer Ther 2009; 8:3056-65. PubMed
  • Ahmad R, Raina D, Joshi MD, Kawano T, Ren J, Kharbanda S, Kufe D. MUC1-C oncoprotein functions as a direct activator of the nuclear factor-kappaB p65 transcription factor. Cancer Res 2009; 69:7013-21. PubMed
  • Kufe DW. Functional targeting of the MUC1 oncogene in human cancers. Cancer Biol Ther 2009; 8:1197-203. PubMed
  • Raina D, Ahmad R, Joshi MD, Yin L, Wu Z, Kawano T, Vasir B, Avigan D, Kharbanda S, Kufe D. Direct targeting of the mucin 1 oncoprotein blocks survival and tumorigenicity of human breast carcinoma cells. Cancer Res 2009; 69:5133-41. PubMed
  • Jin C, Rajabi H, Rodrigo CM, Porco JA, Kufe D. Targeting the eIF4A RNA helicase blocks translation of the MUC1-C oncoprotein Oncogene 2012; 32:2179-2188.
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