Biomedical Engineering Reference
In-Depth Information
et al.
2005, Buettner
et al.
2008, Chang
et al.
2008, Eustace
et al.
2008). Similarly,
loss of paxillin pY
118
(Serrels
et al.
2006) and p130Cas pY
249
(Johnson
et al.
2005)
and pY
410
(Buettner
et al.
2008, Chang
et al.
2008) is observed following Src
inhibition.
Adhesion Protein Phosphorylation in Response to Anti-
integrin Therapies
In recent times, there has been a major ef ort to develop anti-integrin therapies
to block angiogenesis that is required for tumour survival. Since integrins
regulate FAK, Src, paxillin and p130Cas phosphorylation, it is likely that the
phosphorylation of these proteins may also rel ect the ei cacy of the anti-integrin
treatments. One such promising anti-integrin therapy is the agent cilengitide
that targets αVβ3 integrin receptors. Cilengitide caused FAK dephosphorylation
and apoptosis in both endothelial cells (required for the formation of new blood
vessels) and glioblastoma cell lines that express elevated levels of αVβ3 (Oliveira-
Ferrer
et al.
2008). Although a recent pharmacodynamics investigation of
cilengitide administered to patients with a range of solid tumours failed to identify
statistically signii cant dif erences in soluble angiogenic molecule expression and
tumour microvessel density (Hariharan
et al.
2007), the authors concluded that
the phosphorylation of FAK and paxillin may serve as superior biomarkers for
cilengitide action in future studies.
Adhesion Phospho-proteins as Biomarkers for Drug Activity
Mounting data suggest that the phospho-adhesion proteins may be excellent
candidates as biomarkers for drug activity. Some interesting recent studies suggest
that it is feasible to assess adhesion protein phosphorylation in tissue samples that
can be easily obtained from patients undergoing therapy. Following dasatinib
treatment of mice with experimentally stimulated cancer, both Src pY
418
and
paxillin pY
118
(Serrels
et al.
2006, Luo
et al.
2008) were reduced in peripheral
blood mononuclear cells (PBMCs) isolated from the treated mice. h ese data
suggest that PBMCs may provide a useful surrogate tissue for biomarker analysis
of anti-Src therapeutics.
Circulating micro-metastatic populations of cancer cells can also be detected
at low frequency in preparations of PBMCs by staining cell preparations for the
epithelial cell marker cytokeratin, to distinguish the circulating metastatic tumour
cells. Kallergi and colleagues used this approach to investigate PBMC preparations
from breast cancer patients and examined the levels of FAK pY
397
in the circulating
metastatic tumour cells by confocal microscopy (Kallergi
et al.
2007). In future
studies, if elevated FAK pY
397
can be demonstrated to predict response to anti-FAK
targeted therapies, the examination of FAK pY
397
in circulating micrometastases
may provide a method to select patients for treatment with anti-FAK therapies.
