Ergon Professor, Departments of Pharmacology, Biochemistry and Radiation OncologyMolecular Cancer Therapeutics ProgramMD, 1982, University of Naples "Federico II," ItalyPhD, 1987, University of Naples "Federico II," Italy andMax-Planck Institute for Molecular Genetics, Berlin, GermanyPostdoc, 1986-90, National Institutes of Health, Bethesda, MD
Contact information2500 N State St, Suite G751-5Jackson, MS 39216Phone: (601) 815-6802/3E-mail: firstname.lastname@example.org
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.
2500 North State Street
Jackson, MS 39216
General Information: 601-984-1000
Patient Appointments: 888-815-2005