287Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) tumor
suppressor is frequently phosphorylated at a conserved tyrosine residue, Y240, in
GBM clinical samples (Fenton et al. 2012 ). Phosphorylation of Y240 is associated
with shortened overall survival and resistance to EGFR inhibitor therapy in GBM
patients and plays an active role in mediating resistance to EGFR inhibition in vitro.
Y240 phosphorylation can be mediated by both FGF receptors and SRC family
kinases but does not affect the ability of PTEN to antagonize PI3K signaling. These
fi ndings show that, in addition to genetic loss and mutation of PTEN, its modulation
by tyrosine phosphorylation has important implications for the development and
treatment of GBM.
Simulating Chemotherapeutic Schemes for Individualization A novel patient
individualized, spatiotemporal Monte Carlo simulation model of tumor response to
chemotherapeutic schemes in vivo has been described (Stamatakos et al. 2006 ).
Treatment of GBM by temozolomide is considered as a paradigm. The model is
based on the patient’s imaging, histopathologic and genetic data. A mesh is super-
imposed upon the anatomical region of interest and within each geometrical cell of
the mesh the most prominent biological “laws” (cell cycling, apoptosis, etc.) in
conjunction with pharmacokinetics and pharmacodynamics information are applied.
A good qualitative agreement of the model’s predictions with clinical experience
supports the applicability of the approach to chemotherapy optimization.
Personalized Therapy of GBM Based on Cancer Stem Cells (CSCs) CSCs play
an important role in determining GBM response to therapy. Hypoxia and stem cell
maintenance pathways may provide therapeutic targets to sensitize CSCs to cyto-
toxic therapies to improve treatment of GBM patients. Although chemotherapy with
temozolomide may contain tumor growth for some months, invariable GBM recur-
rence suggests that CSC maintaining these tumors persist. According to a study of
the effect of temozolomide on CSC lines, although differentiated tumor cells consti-
tuting the bulk of all tumor cells were resistant to the cytotoxic effects of the sub-
stance, temozolomide induced a dose- and time-dependent decline of the stem cell
subpopulation (Beier et al. 2008 ). Temozolomide concentrations that are reached in
patients are only suffi cient to completely eliminate CSC in vitro from MGMT-
negative but not from MGMT-positive tumors. These data strongly suggest that
optimized temozolomide chemotherapeutic protocols based on MGMT status of
CSCs might substantially improve the elimination of GBM stem cells and conse-
quently prolong the survival of patients.
Supratentorial Hemispheric Diffuse Low-Grade Gliomas
Supratentorial hemispheric diffuse low-grade gliomas (LGG), i.e. World Health
Organization (WHO) grade II gliomas, are a heterogeneous group of tumors. During
their natural course, LGG tend to progress to a higher grade of malignancy, leading
to neurological disability and ultimately to death. During their low-grade period,
these tumors exhibit systematically a spontaneous and continuous radiological
Personalized Management of Cancers of Various Organs