Signal Pathway Profiling of Human Cancer Using RPMA

Recent case studies demonstrate the utility of RPMA for the analysis of surgically obtained tissues and thereby demonstrate the potential of this format for aiding in therapeutic decision-making by providing information about the activity of signalling proteins. The first published demonstration of RPMA analyzed human prostate surgical specimens, and revealed that members of the PI3 kinase/pro-survival protein pathways are activated at the invasion front during prostate cancer progression (Paweletz, et al. 2001). In another study, the investigators examined the differences in pro-survival signalling between Bcl-2+/- lymphomas (Zha, et al. 2004). Comparison of various pro-survival proteins in Bcl-2+ and Bcl-2- follicular lymphoma subtypes by reverse phase protein microarrays suggested that there are pro-survival signals independent of Bcl-2. RPMA analysis has also been applied to evaluation of cellular signalling within the stromal and epithelial compartments from patient-matched prostate cancer study sets (Grubb, et al. 2003). Ovarian and breast cancers have also been analyzed for cell signalling activation fingerprints using this approach (Wulfkuhle, et al. 2003; Petricoin, et al. 2005). These studies reveal the patient-specific nature of signalling at a molecular level: each cancer presents a unique constellation of cellular signalling. However, that being said, signalling class-specific groupings (i.e, mTOR pathway activation) are also observed (Petricoin, et al. 2005) and indicate that a new type of molecular classification of human cancer built on functional signalling activity may be possible.

Reverse phase protein microarrays have also been used to compare cell-signalling portraits in patient-matched primary and metastatic cancer lesions (Petricoin, et al. 2005; Sheeehan, et al. 2005). Because the tissue micro-ecology of the metastatic lesion is inherently different from the environment within the primary tumor, cell signalling events may be significantly altered depending on the site of metastasis.

Since the signalling changes in the metastasis would be the most appropriate for the selection of targeted therapy due to the fact that metastasis most often determines mortality, it might be critical to develop a profile of metastatic cells themselves. This appears to be so, as these initial studies indicate a significant difference between the patient-matched primary and metastatic lesion. In the future, a patient that presents with multiple metastatic sites could be treated with a selected combination of different targeted therapies, tailored to the different signalling changes.

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