Associate Professor, Department of BiochemistryTumor Cell Biology ProgramPhD, Molecular Genetics, 1988, University of Naples, ItalyPostdoc, 1989-90, University of North Carolina at Chapel Hill, NC 1990-1992 Emory University, Atlanta GA
Contact information2500 N State St., Room G752Jackson, MS 39216Phone: (601) 815-3512E-mail: email@example.com
"Triple negative" breast cancers (ER-, PR- and Her2 non-overexpressor, henceforth, TNBC) represent 15% of total US cases. This is a biologically heterogeneous group of tumors that are clinically aggressive and are more common in African-Americans. No effective targeted agents have been developed for TNBC, and to date chemotherapy and radiation remain the standard of care. There is strong evidence that active Notch signaling is common in TNBC and is correlated with poor prognosis. In particular, expression of Notch ligand Jagged-1 and Notch receptors Notch-1 and Notch-3 is strongly correlated with poor progression-free survival in Her2-negative breast cancers. Published evidence suggests that a Jagged-1/Notch axis controls expression of genes such as survivin and cyclin D1 in TNBC cell lines. Numerous pharmaceutical and biotechnology companies are developing Notch inhibitors for breast cancer. These include GSIs (Gamma Secretase Inhibitors) that block ligand-induced cleavage of Notch receptors required to produces the "active" Notch Intracellular domain (NIC). However, not even these novel agents are likely to be "magic bullets" that can be used alone. The successful development of therapeutic regimens targeting Notch in TNBC will critically depend upon understanding how Notch interacts with other pathways that are biologically and therapeutically relevant. The Miele lab has recently elucidated a bidirectional cross-talk between Notch and the estrogen receptor α (ERα) in ERα-positive breast cancer that has led to two ongoing clinical trials of antiestrogen-GSI combinations (in early stage and metastatic disease respectively). We have now turned our attention to TNBC. Our preliminary data indicate that a Jagged-1/Notch/AKT/IKKα/NF-κB axis controls survival through the expression of multiple anti-apoptotic genes in TNBC.
Considering that multiple inhibitors of the PI3K-AKT pathway are in clinical development, elucidation of the molecular mechanisms underlying the cross-talk between Notch and PI3K/AKT pathways will provide a basis for developing combination therapies in TNC to be tested in clinical trials.
2500 North State Street
Jackson, MS 39216