Difference in tumor pO2 in sunitinib treated group to the control. The significant synergy with mTOR inhibitors including rapamycin and radiation reported by Shinohara et al may point out the Oligomycin A 579-13-5 characteristic influences of the microenvironment of each tumor type as pointed out in other studies where the synergy was attributed only to rapamycin targeting the enhanced activity of signaling pathways controlled by mTOR in the host endothelial cells. Recent studies with a dual inhibitor of the PI3K and mTOR pathway found that the period of vascular remodeling is relatively more sustained than that observed with anti-angiogenic drugs resulting in substantial therapeutic gain. These studies point to the importance of longitudinally monitoring such changes to realize maximal efficacy in combined chemo-radiation treatments. Imaging studies of the tumor microenvironment can establish a strategy in preclinical models to identify an optimal treatment schedule to realize enhanced response to combination treatments. In summary, results from the current study show that molecular imaging techniques provide an opportunity to serially monitor changes in tumor physiology non-invasively and quantitatively and identify subtle physiological changes in response to rapamycin treatment. Therefore these techniques have the ability to provide valuable non-invasive biomarkers which predict treatment outcome and also identify temporal windows where radiation therapy can be advantageously combined to elicit improved response. Tyrosine phosphorylation is a critical mechanism by which cells exert control over signaling processes. Protein tyrosine kinases and phosphatases work in concert to control these signaling cascades, and alterations in the expression or activity of these enzymes hallmark many human diseases. While PTKs have long been the focus of extensive research and drug development efforts, the role of PTPs as critical mediators of signal transduction was initially underappreciated. Consequently, the molecular characterization of these phosphatases has trailed that of PTKs, and only recently has the PTP field reached the forefront of disease based-research. As validation for phosphastases in human disease, half of PTP genes are now implicated in at least one human disease. The critical role of PTPs in cell 
function and their role in disease etiology highlight the importance of developing phosphatase agonists and inhibitors. Unfortunately, phosphatases have historically been perceived as “undruggable” for several important reasons. First, phosphatases often control multiple signaling pathways and thus, inhibition of a single enzyme may not yield a specific cellular effect. Second, signaling cascades are generally controlled by multiple phosphatases and accordingly, blocking the activity of one may not sufficiently induce the desired modulation to a signaling pathway. Finally, and most importantly, phosphatase active sites display high conservation which hinders the ability to develop catalysis-directed inhibitors with any degree of selectivity. Despite these pitfalls, the emerging role of PTPs in human disease etiology has Screening Libraries necessitated a solution. Largely through use of structure-based drug design, several PTPs now represent promising targets for disease treatment. Most notably, bidentate inhibitors of PTP1B, implicated in type II diabetes and obesity, have been developed which span both the catalytic pocket and a second substrate binding pocket discovered.