Cancer Institute

  • Lucio Miele

    Ergon Professor, Departments of Pharmacology, Biochemistry and Radiation Oncology
    Molecular Cancer Therapeutics Program
    MD, 1982, University of Naples "Federico II," Italy
    PhD, 1987, University of Naples "Federico II," Italy and
    Max-Planck Institute for Molecular Genetics, Berlin, Germany
    Postdoc, 1986-90, National Institutes of Health, Bethesda, MD

    Contact information
    2500 N State St, Suite G751-5
    Jackson, MS 39216
    Phone: (601) 815-6802/3
    E-mail: lmiele@umc.edu

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    Research interests

    The Miele laboratory has been focusing on cancer experimental therapeutics for 17 years. We study the Notch signaling pathway, which mediates communication between contiguous cells and regulates cell fate during embryonic development and postnatal life.

    The 4 mammalian Notch genes encode membrane receptors that are activated by cell surface ligands of the Delta and Jagged families. Upon activation, Notch receptors are cleaved by ϒ-secretase, generating an intracellular domain (NICD) that migrates to the nucleus and controls the expression of numerous genes in a context-dependent fashion.

    In cancer, Notch signals are exchanged between cancer cells, between cancer cells and stroma and between cancer cells and endothelial cells. Drugs that inhibit ϒ-secretase (GSIs) are currently in clinical development, in part as a result of our studies: we and the Osborne lab in Massachusetts simultaneously discovered that Notch1transmits a survival signal to leukemia cells and T-cells respectively.

    We determined that Notch inhibition synergizes with chemotherapy drugs in several models. Subsequently, we showed that Notch1 activation is required for neoplastic transformation induced by H-Ras, and that Notch1 is expressed in breast cancer.

    We discovered that endocrine therapy with SERMS or estrogen deprivation causes re-activation of Notch in ER-positive breast cancer cells and that combinations of endocrine therapy and a GSI are synergistic in vitro and in vivo.

    In collaboration with the Albain group in Chicago, we have recently concluded a first-in-human clinical trial of this combination. We determined that Notch1 activates ERα in the absence of estrogen via IKKα, a potential mechanism of endocrine resistance. Similarly, in Her2/Neu-positive breast cancer cells trastuzumab (Herceptin) re-activates Notch and renders cells sensitive to GSIs. We are pursuing this line of research in collaboration with the Osipo lab.

    We are currently exploring the role of Notch signaling in endocrine-resistant breast cancers, in triple-negative breast cancers (TNBC) and in breast cancer tumor-initiating cells.

    Recent accomplishments and honors

    • 2011 - Co-Organizer, First International Conference on targeting Notch signaling in cancer, Mykonos, Greece
    • 2011 - Invited Speaker, Fifth International Notch conference, Athens, Greece
    • 2011 - Invited Speaker, International Conference on Stem Cells and Cancer, Mumbai, India
    • 2009-present - Co-Chair, task force on cancer stem cells therapeutics, CTEP (Cancer Therapeutics Evaluation Program), National Cancer Institute

    Selected publications

    • Gu JW et al. Postmenopausal obesity promotes tumor angiogenesis and breast cancer progression in mice. Cancer Biol Ther. 11, 910-7, 2011.
    • Hao, L, et al. Notch-1 activates estrogen receptor-alpha-dependent transcription via IKKalpha in breast cancer cells. Oncogene 29, 201-13, 2010
    • Rizzo P et al. Cross-talk between notch and the estrogen receptor in breast cancer suggests new therapeutic approaches. Cancer Res 68, 5226-35, 2008.
    • Osipo C et al. ErbB-2 inhibition activates Notch-1 and sensitizes breast cancer cells to a ϒ-secretase inhibitor: a novel therapeutic opportunity. Oncogene 27, 5019-5032, 2008.
    • Weijzen S. et al. Activation of Notch-1 signaling maintains the neoplastic phenotype in Ras-transformed human cells. Nature Medicine 8, 979-986, 2002.