Other Surrogate Tissue Profiling Studies In Oncology

Pharmacogenomic studies conducted on PBMCs of patients with melanoma receiving interleukin-2 (IL-2) therapy37 demonstrated that treatment with this cytokine results in large gene expression changes in circulating PBMCs. By carefully comparing expression patterns in the circulating mononuclear cells with expression changes identified in the tumor microenvironment, the authors did not find substantial

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Figure 4.3 (Color figure follows p. 138.) Unsupervised hierarchical clustering of RCC patient PBMC profiles and correlation with overall survival. (a) The dendrogram of sample relatedness using all 5424 genes' expression values is shown. Four distinct nodes were identified (nodes A, B, C, and D). Of the 12 patients with PBMC profiles in cluster A, 9 exhibited survival of less than 1 year (red outline), while 10 of the 12 patients with PBMC profiles in cluster C exhibited survival greater than 1 year (blue outline). The associated Motzer risk classifications (green = favorable, black = intermediate, red = poor, yellow = unassigned) are presented underneath the dendrogram. Year-long survival (blue squares indicate > 1 year survival) is also presented. (b) Kaplan-Meier survival curves for patients in the unsupervised analysis. Patients in cluster A possessed significantly shorter survival (median survival = 281 days) relative to patients in clusters B (median survival = 566 days), C (median survival = 573), and D (median survival = 502 days). (With permission from Burczynski et al., Clin. Cancer Res., 11, 1181-1189, 2005.)

overlap, but rather evidence for an IL-2-based activation of antigen-presenting monocytes, release of chemoattractants, and the activation of lytic systems in monocytes and natural killer (NK) cells. On the basis of the results the authors postulated that the main effect of IL-2 administered in vivo may be the facilitation of T-cell effector function rather than sustaining their proliferation and noted that if this hypothesis proves true then adoptive transfer of effector T cells should follow, rather than precede, administration of IL-2.

In addition to the above analysis of a cytokine, pharmacogenomic analyses of small molecule inhibitors have also been conducted in PBMCs. DePrimo et al.38 evaluated the effects of the kinase inhibitor SU5416 in PBMCs of patients with colorectal cancer and identified four transcripts that could accurately reflect control and treatment arms. Since SU5416 is an antagonist of the vascular endothelial growth factor (VEGF) receptor, the authors reasoned that PBMC profiling may reflect SU5416 exposure through direct effects of VEGF receptor antagonism on VEGF receptor-expressing monocytes, or through indirect effects of therapy-induced perturbations in circulating cells. Although transcripts that appeared specific to SU5416 were identified, no transcripts appeared to correlate with responses measured in the study.

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