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Poster Papers
varying concentrations of MK-2206. Cell counts were performed using
flow cytometry, and gel electrophoresis on cell lystaes were run to
probe markers of Akt activity by Western Blot. Nude mice with human
SCC1-flank tumor xenografts were treated with oral dosing of 120 mg/
kg of MK-2206 thrice weekly. Tumor size was assessed after each
treatment using digital calipers. Results: Treatment with MK-2206
was sufficient to kill over 50% of all 3 cells lines at 1.5 uM and over
95% of cells at 2.5 uM in 48 hours. Western blots of cell lysates at 48
hours showed decreased phosphorylization of Akt at the T308 residue
as well as lowered expression of the downstream markers GSKb and
pRAS40. MK-2206 treatment of nude mice bearing xenografted SCC1
flank tumor were significantly smaller compared to untreated controls
(p=0.05). Conclusions: This data supports the further exploration of the
AKT pathway inhibitor, MK-2206, as a novel inhibitor in head and neck
cancer.
P013 (COSM Poster #35)
MOLECULAR MARKERS OF MRN IN CISPLATIN-BASED
CHEMORESISTANCE WITH HUMAN HEAD AND NECK CANCER.
Taku Yamashita, MD PhD, Shunsuke Miyamoto, MD, Wei-Ting Hwang,
PhD, Bert W OαMalley, MD PhD, Daqing Li, MD PhD; University of
Pennsylvania School of Medicine, Philadelphia, PA.
Background: Chemoresistance to cisplatin significantly contributes
to treatment failure in clinical practice for head and neck cancer. The
MRE11/RAD50/NBS1 (MRN) complex is well known a major DNA
repair system. Our previous in vitro study shows that enhanced DNA
repairing by MRN is a critical molecular mechanism for cisplatinbased
chemoresistance. The present study further investigates if the
finding of enhanced DNA repairing is responsible for cisplatin-based
chemoresistance with human head and neck squamous cell carcinoma
(HNSCC) in an animal model and if this finding correlates to the clinical
study with patients who suffer from HNSCC. Methods: An animal model
with human HNSCC was used for this study. Tumor volume changes
were measured in two dimensions and the net intensities of fluorescence
from the tumor with tdTomato were also measured before and after
cisplatin treatment. Immunohistochemistry studies were carried out
for detecting the MRN expression and apoptosis. The chemoresistant
profile of the tumor model was established depending on these studies.
The patients with HNSCC who initially received cisplatin monotherapy
were investigated. Immunohistochemistry studies were conducted
for detecting the MRN expression and apoptosis. These results were
analyzed by using a linear regression model with random effects to
compare with established animal tumor model and in vitro findings.
Results: Our animal model demonstrated that chemoresistance
to cisplatin is associated with increased expression levels of MRN
after cisplatin treatment (p