Donald William Kufe, M.D.
Title Professor of Medicine Institution Dana-Farber Cancer Institute Address Dana Farber Cancer Institute 450 Brookline Avenue Boston MA 02215
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Overview
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. 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, ß-catenin, NF-kappaB 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 GSK3ß 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 block MUC1-C subunit function with soluble receptors and 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 entered Phase I evaluation in patients with refractory solid tumors.
Research
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U01CA233084
(KUFE, DONALD W. ;WONG, KWOK KIN)
Sep 20, 2018 - Aug 31, 2023
MUC1-C is a Target for Reversing Immune Evasion and Resistance to Immunotherapies
Role: Principal Investigator
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R21CA229716
(KUFE, DONALD W.)
Jul 1, 2018 - Jun 30, 2020
Targeting the MUC1-C Oncoprotein in Colitis-Associated Colorectal Cancer
Role: Principal Investigator
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R21CA216553
(KUFE, DONALD W.)
Mar 16, 2017 - Feb 28, 2019
Immunotherapeutic Approaches Targeting the MUC1-C Oncoprotein in Triple-Negative Breast Cancer
Role: Principal Investigator
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UM1CA186709
(SHAPIRO, GEOFFREY I)
Mar 13, 2014 - Feb 28, 2023
Dana?Farber/Harvard Cancer Center Experimental Therapeutics Clinical Trials Network Site (DF/HCC ETCTN Site)
Role: Co-Principal Investigator
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R01CA166480
(KUFE, DONALD W.)
Apr 1, 2012 - Mar 31, 2022
MUC1-C Oncoprotein Evades Immune Destruction in Non-small Cell Lung Cancer
Role: Principal Investigator
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P50CA105009
(CRAMER, DANIEL WILLIAM)
Aug 1, 2004 - Jul 31, 2012
Dana-Farber/Harvard Cancer Center Ovarian Cancer SPORE
Role: Co-Principal Investigator
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P50CA101942
(KAELIN, WILLIAM G.;MCDERMOTT, DAVID)
Sep 18, 2003 - Aug 31, 2025
DF/HCC Kidney Cancer SPORE
Role: Co-Principal Investigator
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P50CA100707
(ANDERSON, KENNETH C. ;MUNSHI, NIKHIL C.)
Sep 1, 2003 - May 31, 2024
SPORE in Multiple Myeloma
Role: Co-Principal Investigator
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R01CA098628
(KUFE, DONALD W.)
Feb 28, 2003 - Jan 31, 2008
Regulation of Oxidative Stress Response by c-Abl and Arg
Role: Principal Investigator
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R01CA097098
(KUFE, DONALD W.)
Jul 1, 2002 - May 31, 2024
Targeting the MUC1-C Oncoprotein in Triple-Negative Breast Cancer
Role: Principal Investigator
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R21CA087421
(KUFE, DONALD W.)
Jul 4, 2000 - Jun 30, 2002
ONCOGENIC SIGNALING BY THE MUC1 BREAST CARCINOMA ANTIGEN
Role: Principal Investigator
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P01CA078378
(ANDERSON, KENNETH C.)
Aug 1, 1998 - Mar 31, 2016
Host-tumor cell interaction in myeloma: therapeutic applications
Role: Co-Principal Investigator
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U01CA062490
(KUFE, DONALD W.)
Mar 2, 1994 - Feb 28, 2014
Early Clinical Trials of New Anti-Cancer Agents with Phase I Emphasis
Role: Principal Investigator
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P20CA058203
(KUFE, DONALD W.)
Sep 30, 1992 - Sep 29, 1995
SPECIALIZED PROGRAM OF RESEARCH EXCELLENCE/BREAST CANCER
Role: Principal Investigator
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R01CA055241
(KUFE, DONALD W.)
Apr 1, 1992 - May 31, 2003
MOLECULAR REGULATION OF SIGNALING BY IONIZING RADIATION
Role: Principal Investigator
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R03CA053414
(KUFE, DONALD W.)
Aug 1, 1991 - Jul 31, 1993
CLONALITY IN ACUTE MYELOID LEUKEMIA AND MYELODYSPLASIA
Role: Principal Investigator
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R01CA042802
(KUFE, DONALD W.)
Aug 1, 1986 - May 31, 2015
Differentiating Agents in Hematologic Malignancies
Role: Principal Investigator
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P01CA038493
(IBRAHIM, JOSEPH)
Jul 1, 1985 - Nov 30, 1999
CORE--BIOSTATISTICS AND DATA MANAGEMENT FACILITY
Role: Co-Principal Investigator
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R01CA038879
(KUFE, DONALD W.)
Jul 1, 1985 - Jun 30, 1991
IMMUNODIAGNOSTIC APPROACHES TO HUMAN BREAST CANCER
Role: Principal Investigator
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R01CA029431
(KUFE, DONALD W.)
Jan 1, 1981 - Aug 31, 2008
Molecular Mechanisms of Ara-C Therapy in Man
Role: Principal Investigator
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R01CA028488
(KUFE, DONALD W.)
Aug 1, 1980 - Jun 30, 1987
MOLECULAR MECHANISMS OF 5-FLUOROURACIL CHEMOTHERAPY
Role: Principal Investigator
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P41RR000862
(CHAIT, BRIAN T)
Dec 1, 1976 - Mar 31, 2012
Natl Resource for Mass Spectrom of Biolog Macromolecules
Role: Co-Principal Investigator
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P30CA006516
(GLIMCHER, LAURIE HOLLIS)
Nov 30, 2026
Dana-Farber/Harvard Cancer Center
Role: Co-Principal Investigator
Bibliographic
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