277pockets of residual disease quickly (Predina et al. 2013 ). These authors found that
recurrent tumors and draining lymph nodes are infi ltrated with M2 macrophages
and CD4+ Foxp3+ regulatory T cells. This complex network of immunosuppression
in the tumor microenvironment explains the resistance of tumor recurrences to con-
ventional cancer vaccines despite small tumor size, an intact antitumor immune
response, and unaltered cancer cells. Therapeutic strategies coupling anticancer
agents with inhibition of immunosuppressive cells potentially could impact the out-
comes in these patients.
Systems Biology Approach to Drug-Resistant Cancer
Resistance to targeted cancer therapies such as trastuzumab may occur not only
because of insuffi cient expression of HER2 receptor but also because of the overrid-
ing activation states of cell signaling pathways. Systems biology approaches lend
themselves to rapid in silico testing of factors, which may confer resistance to tar-
geted therapies. A new kinetic model could be interrogated to predict resistance to
receptor tyrosine kinase (RTK) inhibitor therapies and directly test predictions
in vitro and in clinical samples (Faratian et al. 2009 ). The mathematical model
includes RTK inhibitor antibody binding, HER2/HER3 dimerization and inhibition,
AKT/mitogen-activated protein kinase cross-talk, and the regulatory properties of
PTEN. The model includes parameters based on quantitative phosphoprotein
expression data from cancer cell lines using reverse-phase protein microarrays.
Quantitative PTEN protein expression was found to be the key determinant of resis-
tance to anti-HER2 therapy in silico, which was predictive of virtual experiments
in vitro using the PTEN inhibitor bp(V). When measured in cancer cell lines, PTEN
expression predicts sensitivity to anti-HER2 therapy; furthermore, this quantitative
measurement is more predictive of response than other pathway components taken
in isolation and when tested by multivariate analysis in a cohort of 122 breast can-
cers treated with trastuzumab. Thus a systems biology approach has been success-
fully used to stratify patients for personalized therapy in cancer and is further
compelling evidence that PTEN, appropriately measured in the clinical setting,
refi nes clinical decision making in patients treated with anti-HER2 therapies.
Personalized Therapy of Cancer Metastases
Metastasis is the major cause of mortality in cancer. Primary tumors tend to metas-
tasize to defi ned subsets of secondary organs, but the underlying mechanisms are
not well understood. A microfl uidic 3D in vitro model was developed to analyze
organ-specifi c human breast cancer cell extravasation into bone- and muscle-
mimicking microenvironments through a microvascular network (Jeon et al. 2015 ).
Extravasation rates and microvasculature permeabilities in the bone-mimicking
Personalized Therapy of Cancer Metastases