359pancreatic cancer, sensitive and specifi c biomarkers are also required. Extensive
genomics/transcriptomics and proteomics studies are being carried out to fi nd can-
didate biomarkers and contribute to high-throughput systems for large cohort
screening. Among numerous biomarkers histone modifi cations are promising indi-
cators of prognosis and response to therapy.
Histone Modifi cations Predict Treatment Response in Pancreatic Cancer
Measuring levels of specifi c histone modifi cations within cells has previously shown
that low cellular levels of particular histones could determine which prostate cancer
patients were more likely to suffer a recurrence and which patients with lung and
kidney cancers would experience poorer survival rates. An assay to detect histone
modifi cations can now be used to predict prognosis and response to treatment in
subsets of patients with pancreatic cancer (Manuyakorn et al. 2010 ). The scientists
used tissues from a cohort of patients enrolled in the radiation therapy oncology
group (RTOG) 9704 trial, a multicenter, phase III study of pancreatic cancer com-
paring adjuvant gemcitabine with 5-FU, and a separate cohort of patients with stage
1 or 2 pancreatic cancer. Immunohistochemistry was performed for histone H3
lysine 4 dimethylation (H3K4me2), histone H3 lysine 9 dimethylation (H3K9me2),
and histone H3 lysine 18 acetylation (H3K18ac). Positive tumor cell staining for
each histone modifi cation was used to classify patients into low- and high-staining
groups, which were related to clinicopathological parameters and clinical outcome
measures. Low cellular levels of H3K4me2, H3K9me2, or H3K18ac were each sig-
nifi cant and independent predictors of poor survival. Combined low levels of
H3K4me2 and/or H3K18ac were the most signifi cant predictor of overall survival.
In subgroup analyses, histone levels were predictive of survival specifi cally for those
patients with node-negative cancer or for those patients receiving adjuvant 5-FU but
not gemcitabine in RTOG 9704. The investigators concluded that cellular levels of
histone modifi cations defi ne previously unrecognized subsets of patients with pan-
creatic adenocarcinoma with distinct epigenetic phenotypes and clinical outcomes
and represent prognostic and predictive biomarkers that could form basis of clinical
decisions, including the use of 5-FU chemotherapy. Further research in cell lines and
animal models will determine what, if any, role the histone modifi cations have in
causing the development of aggressive forms of pancreatic cancer. Uncovering the
mechanism of how the histone modifi cations are associated with cancer develop-
ment and/or progression may facilitate design of strategies to interfere with that
process and form the basis for a targeted therapy or chemoprevention.
Transport Properties of Pancreatic Cancer and Gemcitabine Delivery
The therapeutic resistance of pancreatic ductal adenocarcinoma (PDAC) is partly
ascribed to ineffective delivery of chemotherapy to cancer cells. To study this prob-
lem, a method has been developed to measure mass transport properties during
Personalized Management of Cancers of Various Organs