|
2630
Treating Nasopharyngeal Carcinoma with EGFR
Antagonists. Anne E. Hagey, Jianyu Rao, Genhong Cheng, UCLA
Medical Ctr, Los Angeles, CA.
Our research seeks to define the role the Epstein-Barr virus
(EBV) plays in the development of carcinomas it is consistently
associated with, specifically nasopharyngeal carcinoma (NPC). We
propose that the latent membrane protein 1 (LMP-1) of EBV is
upregulated in NPC. It is thought that LMP-1 uses signal
transduction pathways similar to tumor necrosis factor (TNF) family
members, especially CD40, which is involved in B-cell dependent
T-cell activation. Like CD40, LMP-1 uses TRAF family proteins as its
immediate early mediators and promotes cell survival and
proliferation. Unlike CD40, which requires CD40L for activation,
LMP-1 is constitutively active, providing great potential for cell
transformation. We believe that LMP-1 upregulates epidermal growth
factor receptor (EGFR) and Bcl-X via an NF-kB mediated pathway. We
aim to further characterize the molecular role that EGFR and Bcl-X
play in LMP-1-mediated cellular transformation. Moreover, we plan to
exploit LMP-1-induced EGFR upregulation as a potential diagnostic
marker and therapeutic target for EBV-associated NPC. Antibodies
against EGFR may be used as adjunctive, specific therapy for NPC,
similar to the use of Herceptin in treatment of Her2/neu positive
breast carcinomas. Initially, our methods included transformation of
293t cells with LMP-1 via calcium-phosphate mediated infection and
transfection. Western blot analysis confirmed the presence of LMP-1.
Subsequent gel shift assay revealed upregulation of NF-kB. Tumor
samples were stained immunohistochemically for LMP-1, EGFR, and
Bcl-X. Our results thus far indicate that EGFR is definitely
upregulated versus normal controls in NPC tumor samples.
Preliminarily, it appears as if Bcl-X is also upregulated in NPC
tumor samples. Further studies must be undertaken to correlate the
degree of EGFR upregulation in metastatic versus in situ NPC. Mouse
studies will be done using implanted LMP-1-transformed HaCaT cells
(a human epithelial cell line) and then blocking EGFR using the
small inhibitory molecule PD153035, an EGFR tyrosine kinase
inhibitor. We will assess the mice for tumor involution, thereby
enabling us to draw some conclusions about the therapeutic portion
of our project.
|
