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Pharmacogenomic-Based Chemotherapy
Whole Genome Technology to Predict Drug Resistance
Millennium Pharmaceuticals Inc uses whole genome technologies, including gene
and protein expression data, to predict the potential sensitivity or resistance of an
individual patient’s tumor to a single or group of drugs. The multi-center phase II
trial of the proteasome inhibitor, Velcade™ (bortezomib™; PS-341) in relapsed and
refractory myeloma patients has revealed signifi cant activity in a heavily pre-treated
patient population and represents the fi rst anti-cancer agent to include pharmacoge-
nomic (PGx) assessments during its clinical development. PGx analysis of bone
marrow samples using bioinformatic algorithms indicate there are signifi cant differ-
ences in gene expression profi les, which may predict patients likely to respond to
Velcade and those likely to be refractory to treatment. These PGx analyses also
show promise in their ability to detect the relevant biological pathways associated
with disease progression and the mechanism(s) associated with drug resistance.
The mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R)
encodes for a multifunctional receptor involved in lysosomal enzyme traffi cking,
fetal organogenesis, cytotoxic T cell-induced apoptosis and tumor suppression.
M6P/IGF2R loss of heterozygosity predicts poor therapeutic outcome in patients
treated with radiotherapy alone. It also indicates that head and neck cancer
patients with M6P/IGF2R allelic loss benefi t most from chemotherapy added to
radiotherapy.
Anticancer Drug Selection Based on Molecular
Characteristics of Tumor
Cancer cells have defects within their systems related to the control of the cell cycle.
These modifi cations may, however, confer selective sensitivity to appropriately
designed drug therapy. Thus, molecular defects could potentially be linked to spe-
cifi c drug sensitivities. Such correlations might guide the selection of drugs for
therapy based on the molecular characteristics of individual tumors. An example is
the treatment of breast cancer with trastuzumab (Herceptin; Genentech, USA), a
humanized monoclonal antibody against the HER2 receptor. Overexpression of
HER2 may occur as a somatic genetic change in breast cancer and other tumors.
This correlates with poor clinical prognosis and serves as a marker for effective
therapy with trastuzumab, either alone or in combination with chemotherapy.
Results from randomized controlled studies show that adding trastuzumab to fi rst-
line chemotherapy seems to be benefi cial in women with metastatic breast cancer
that overexpresses HER2.
The molecular characterization of childhood leukemias directly affects treatment
strategies. Acute lymphoblastic leukemia patients whose leukemic lymphoblasts
10 Personalized Therapy of Cancer