Notch genes encode transmembrane receptors that control cell differentiation in numerous cell types during development. Humans and mice have 4 homologous notch genes. Mutations causing constitutive activation of notch-1,-2 and 4 are oncogenic in vivo and in vitro. Clinically, constitutive activation of notch-1 is associated with T-cell acute lymphoblastic leukemia (T-ALL), and strikingly increased expression with altered intracellular distribution of notch-1 have been demonstrated in various human malignancies and pre-neoplastic lesions (uterine cervix, colon and lung). We and others have recently discovered that notch-1 has anti-apoptotic activity in vitro in transformed cells in various experimental models. Additionally, we found that downregulating the expression of notch-1 in murine erythroleukemia (MEL) cells in the presence of differentiation- inducing hybrid polar drugs leads to massive apoptosis. Whether notch-1 affects apoptosis in non-transformed cells which do not overexress it remains unknown. Our hypothesis is that notch-1 plays an important role in regulating apoptosis susceptibility in notch-1 expressing tumor cells. This implies that interfering with notch-1 expression or signaling may be used to enhance the efficacy of chemotherapy or radiotherapy in human malignancies expressing notch-1. Our long term objective is the development of therapeutic regimens targeting notch-1 using gene therapy, recombinant notch-1 antagonists or notch-1 monoclonal antibodies for clinical testing in human malignancies expressing notch-1. We have generated experimental agents in each of these catagories.
Our Aims our as follows: 1. To determine if notch-1 participates in apoptosis regulation in normal cells, by studying its role in thymocyte apoptosis using notch-1 antagonists and novel transgenic mice we have developed. 2. To elucidate the mechanism(s) through which notch-1 protects MEL cells from apoptosis, by investigating signaling pathways known to be linked to notch-1 which participate in regulating apoptosis. 3. To conduct pre-clinical studies of notch-1 inducible antisense retrovirus vectors, a recombinant notch-1 antagonists and a notch-1 blocking monoclonal antibody in mouse tumor models. The experimental agents will be studied alone and in combination with antineoplastic drugs. Studies will be conducted in both immunodeficient animals with human cervical cancer cells and immunocompetent animals with syngeneic murine tumor cells transformed by human papillomavirus 16 (HPV16). These experiments will elucidate the possible uses of notch-1 as a target for cancer treatment and the mechanisms of notch-1 targeting agents. Additionally, they will provide information on the safety profile of these agents and initial proof of concept for clinical trials of notch-1 targeting agents in notch-1 expressing malignancies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA084065-02
Application #
6342201
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Spalholz, Barbara A
Project Start
2000-01-13
Project End
2001-08-31
Budget Start
2001-02-06
Budget End
2001-08-31
Support Year
2
Fiscal Year
2001
Total Cost
$222,920
Indirect Cost
Name
Loyola University Chicago
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
791277940
City
Maywood
State
IL
Country
United States
Zip Code
60153
Rizzo, Paola; Miao, Haixi; D'Souza, Gwendolyn et al. (2008) Cross-talk between notch and the estrogen receptor in breast cancer suggests novel therapeutic approaches. Cancer Res 68:5226-35
Song, L L; Peng, Y; Yun, J et al. (2008) Notch-1 associates with IKKalpha and regulates IKK activity in cervical cancer cells. Oncogene 27:5833-44
Vilimas, Tomas; Mascarenhas, Joaquina; Palomero, Teresa et al. (2007) Targeting the NF-kappaB signaling pathway in Notch1-induced T-cell leukemia. Nat Med 13:70-7
Miele, Lucio (2006) Notch signaling. Clin Cancer Res 12:1074-9
Miele, Lucio; Golde, Todd; Osborne, Barbara (2006) Notch signaling in cancer. Curr Mol Med 6:905-18
Nickoloff, Brian J; Hendrix, Mary J C; Pollock, Pamela M et al. (2005) Notch and NOXA-related pathways in melanoma cells. J Investig Dermatol Symp Proc 10:95-104
Qin, Jian-Zhong; Ziffra, Jeffrey; Stennett, Lawrence et al. (2005) Proteasome inhibitors trigger NOXA-mediated apoptosis in melanoma and myeloma cells. Cancer Res 65:6282-93
Baldi, Alfonso; De Falco, Maria; De Luca, Luca et al. (2004) Characterization of tissue specific expression of Notch-1 in human tissues. Biol Cell 96:303-11
Jang, Mei-Shiang; Miao, Haixi; Carlesso, Nadia et al. (2004) Notch-1 regulates cell death independently of differentiation in murine erythroleukemia cells through multiple apoptosis and cell cycle pathways. J Cell Physiol 199:418-33
Bocchetta, Maurizio; Miele, Lucio; Pass, Harvey I et al. (2003) Notch-1 induction, a novel activity of SV40 required for growth of SV40-transformed human mesothelial cells. Oncogene 22:81-9

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