DF/HCC Program Affiliation

Leader, Translational Pharmacology and Early Therapeutic Trials Program
Member, Prostate Cancer Program
Member, Cancer Immunology Program
Member, Gastrointestinal Malignancies Program
Member, Kidney Cancer Program

DF/HCC Associations

Member, Center Scientific Council

Research Abstract

Basic research in our laboratory focuses on the MUC1 oncoprotein, while translational research has led to the development of four potential therapies that are presently under clinical evaluation. In the early 1980s, our laboratory identified the human DF3/MUC1 carcinoma-associated protein. DF3/MUC1 is aberrantly overexpressed by about 800,000 of the 1.3 million tumors diagnosed in the US each year. Our research demonstrated that MUC1 functions as an oncogene by interacting with growth factor receptor signaling pathways and by stabilizing beta-catenin. MUC1 also functions in the regulation of gene transcription and as an anti-apoptotic factor. We are working to further elucidate the mechanisms responsible for MUC1-mediated transformation and developing strategies to interfere with MUC1 function. Preclinical research in our laboratory has resulted in the development of a recombinant vaccinia virus expressing the MUC1 protein. This vaccine completed phase I trials and is entering phase II studies for the treatment of MUC1-positive tumors. Another vaccine, first developed by our laboratory, involves the fusion of MUC1-positive carcinoma cells with dendritic cells. Phase I and II trials of this vaccine have shown immunologic and clinical activity in the treatment of breast cancer. The vaccine also induces immunologic and clinical responses in MUC1-negative tumors, specifically melanoma and brain tumors. Our translational research has also resulted in the development of an approach for improving treatment of tumors with radiation therapy. This strategy, designated genetic radiotherapy, is a gene therapy using an adenoviral vector that contains a radio-inducible promoter upstream to sequences encoding the tumor necrosis factor (TNF) protein. A phase I trial of this vector and radiation has demonstrated safety and substantial improvement in the treatment of radiation-resistant tumors. Phase II trials are underway for the treatment of pancreatic cancer, melanoma, sarcomas, rectal cancer, and head and neck cancer. As a result of preclinical research in our laboratory, a novel, orally bioavailable small molecule, designated NM-3, has been developed that downregulates VEGF expression and inhibits angiogenesis. NM-3 has been shown to have direct anti-tumor effects. We recently completed a phase I trial of NM-3 without evidence of toxicity, and phase II trials are being planned for the treatment of multiple myeloma and brain tumors.

Publications

• Leng Y, Cao C, Ren J, Huang L, Chen D, Kufe D. Nuclear import of the MUC1-C oncoprotein is mediated by nucleoporin Nup62. J Biol Chem 2007 May 11;
  PMID: 17500061
• Wei X, Xu H, Kufe D. Human mucin 1 oncoprotein represses transcription of the p53 tumor suppressor gene. Cancer Res 2007 Feb 15; 67(4):1853-8
  PMID: 17308127
• Lerma EI, Nguyen VA, Wang T, Tipping A, Melo JV, Kufe D, Austin DJ, Deisseroth A. Novel compounds with antiproliferative activity against imatinib-resistant cell lines. Mol Cancer Ther 2007 Feb; 6(2):655-66
  PMID: 17267662
• Yin L, Kharbanda S, Kufe D. Mucin 1 oncoprotein blocks hypoxia-inducible factor 1alpha activation in a survival response to hypoxia. J Biol Chem 2007 Jan 5; 282(1):257-66
  PMID: 17102128
• Huang L, Chen D, Liu D, Yin L, Kharbanda S, Kufe D. MUC1 oncoprotein blocks GSK3beta-mediated phosphorylation and degradation of beta-catenin Cancer Res 2005; 65:10413-10422
  PMID: 0
• Yoshida K, Yamaguchi T, Natsume T, Kufe JD, Miki Y. JNK phosphorylation of 14-3-3 proteins regulates nuclear targeting of c-Abl in the apoptotic response to DNA damage Eval & Prog Plan 2005 Mar 25; 7:278-285
  PMID: 0
• Wei X, Xu H, Kufe D. Human MUC1 oncoprotein regulates p53-responsive gene transcription in the genotoxic stress response. Eval & Prog Plan 2005 Feb 15; 7(2):167-178
  PMID: 0
• Wei X, Xu H, Kufe D. Human MUC1 oncoprotein regulates p53-responsive gene transcription in the genotoxic stress response. Eval & Prog Plan 2005 Feb 15; 7(2):167-178
  PMID: 0
• Vasir B, Avigan D, Wu Z, Crawford K, Turnquist S, Ren J, Kufe D. Dendritic cells induce MUC1 expression and polarization on human T cells by an IL-7-dependent mechanism. J Immunol 2005 Feb 15; 174(4):2376-86
  PMID: 15699174
• Yin L, Huang L, Kufe D.. MUC1 oncoprotein activates the FOXO3a transcription factor in a survival response to oxidative stress. Eval & Prog Plan 2004 Oct 29; 279(44):45721-45727
  PMID: 0
• Avigan D, Vasir B, Gong J, Borges V, Wu Z, Uhl L, Atkins M, Mier J, McDermott D, Smith T, Giallambardo N, Stone C, Schadt K, Dolgoff J, Tetreault J-C, Villarroel M, Kufe D.. Fusion cell vaccination of patients with metastatic breast and renal cancer induces immunologic and clinical responses. Harrison's Principles of Internal Medicine. 2004 Jul 15; 10(14):4699-4708
  PMID: 0
• Avigan D, Vasir B, Gong J, Borges V, Wu Z, Uhl L, Atkins M, Mier J, McDermott D, Smith T, Giallambardo N, Stone C, Schadt K, Dolgoff J, Tetreault J-C, Villarroel M, Kufe D.. Fusion cell vaccination of patients with metastatic breast and renal cancer induces immunologic and clinical responses. J Am Diet Assoc 2004 Jul 15; 10(14):4699-4708
  PMID: 0
• Raina D, Kharbanda S, Kufe D.. The DF3/MUC1 oncoprotein activates the anti-apoptotic P13K/Akt and Bcl-xL pathways in rat 3Y1 fibroblasts. Eval & Prog Plan 2004 May 14; 279(20):20607-20612
  PMID: 0
• Yin L, Kufe D. Human MUC1 carcinoma antigen regulates intracellular oxidant levels and the apoptotic response to oxidative stress J Biol Chem 2003; 278:35458-64
  PMID: 0
• Yin L, Kufe D. Human MUC1 carcinoma antigen regulates intracellular oxidant levels and the apoptotic response to oxidative stress J Biol Chem 2003; 278:35458-64
  PMID: 0
• Li Y, Liu D, Chen D, Kharbanda S, Kufe D. Human DF3/MUC1 carcinoma-associated protein functions as an oncogene. Oncogene 2003; 22:6107-10
  PMID: 0
• Li Y, Liu D, Chen D, Kharbanda S, Kufe D. Human DF3/MUC1 carcinoma-associated protein functions as an oncogene. Oncogene 2003; 22:6107-10
  PMID: 0
• Li Y, Liu D, Chen D, Kharbanda S, Kufe D. Human DF3/MUC1 carcinoma-associated protein functions as an oncogene. Oncogene 2003; 22:6107-10
  PMID: 0
• Li Y, Liu D, Chen D, Kharbanda S, Kufe D. Human DF3/MUC1 carcinoma-associated protein functions as an oncogene. Oncogene 2003; 22:6107-10
  PMID: 0